ISTANBUL FACULTY OF MEDICINE

ENGLISH CLASS 3RD GRADE

BLOOD AND IMMUNE SYSTEM-II
SUMMARY NOTES

(Part 2)
 İçindekiler

Son Kalan Dersler

Osteosynthesis & Implants 3
Acute Leukemia 18
Non-Neoplastic Diseases of Lymph Nodes 27
Genetic Analysis in Hematological Malignancies 38
Abdominal Mass in Children 47
APPROACH TO PLATELET DISORDERS 53
AŞI ENTEGRE OTURUMU I 60
ENTERGRE OTURUM 2. kısım 67
IMMUNOPHARMACOLOGY AND GROWTH FACTOR 74
Hematopoietic System Drugs 88
PROTEİN SYNTHESİS İNHİBİTOR ANTİBİOTİCS-1 91
OTHER CELL WALL & MEMBRANE-ACTIVE ANTIBIOTICS 94
FEVER OF UNKNOWN ORIGIN 101
TRANSFUSION PRİNCİPLES 110
ANEMIA AND CONTROL PROGRAMS AS A PUBLIC HEALTH PROBLEM 117
 Osteosynthesis & Implants

Interaction Principles of Orthopedic Implants with Human Body:

1) Biocompatibility It is the ‘sine qua non’ feature of every medical device used in
orthopedic practice.
*** It must have no harmful effects on local or systemic structures (bone, soft tissues, ionic
composition of plasma, intracellular and extracellular fluids)
2) Appropriate Design of Implants and Production Quality Principles
All orthopedic implants must be manufactured in accordance with the quality standards
specified in the relevant laws and regulations.
• CE Marking is the symbol of conformity with the EU New Approach Directives,
which shows that the product on which it has been affixed is healthy and safe for the
purposes of people, domestic animals and environment.
3) Mechanical and Biological Stability
• Biomechanical stability; if the implant is used for osteosynthesis, its integrity and
stability remains almost unchanged until bone union is complete,
• Biological stability refers to not participating in or leading to a reaction other than the
desired biological interaction (eg osteoinduction in the graft material) during the time
or intended time of stay inside the body.
4) Basic properties of biomaterials
A. Stiffness, hardness
B. Ductility
C. Strength
D. Resistance to Abrasion (Corrosion and Erosion)
E. Surface structure
F. MR compatibility

A) Stiffness (=hardness)
• It is the capacity of a material to resist deformation and is measured by the relationship
between the applied load and the elastic deformation that occurs.

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 B) Ductility (= Softness)
How much plastic deformation a biomaterial can undergo before it breaks.
* The softness of a plate determines how much it can be shaped.

C) Strength
• Capacity of the material to withstand the applied loads without undergoing permanent
deformation (plastic deformation)
• The capacity to withstand cyclic (repetitive) loads is very important for internal
fixation materials.
• * Steel is more durable in a single high load, while titanium is more durable in
repetitive loads.
D) Resistance to Abrasion (Corrosion and Erosion):
• Corrosion is an electrochemical event that leads to the destruction of metal by
releasing metal ions into the medium
• On the surface of surgical steel and titanium, a protective surface layer called
passivation oxidation occurs quickly and protects the material against electrochemical
corrosion. This protective surface forms much better in titanium, so titanium hardly
interferes with any biological interaction and can almost be called as biologically inert.
• Erosion, on the other hand, is a form of physical wear in which metal particles are
poured into the environment.
• In orthopedics, most abrasion is in the form of (fretting erosion) (= friction erosion)
🡪 e.g. micro-movement of the screw in the plate results in the submicroscopic
particles pouring into the tissue.
E) Surface structure
• Protein adsorption and cell adhesion onto the implant occurs within minutes of
implantation. Without these two, a fibrous capsule is formed in the presence of micro-
motion
• If the surface of the implant is micro-roughened, the surrounding tissue (bone or soft
tissue) adheres to the implant instead of the formation of a fibrosis capsule.
This is undesirable in areas with tendons that need to move, such as hands and feet.
Therefore, it is preferred to use titanium material with polished (smoothened) surface in these
regions

E) MR compatibility:

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• AO-approved implants [cpTi or titanium alloys (TAN and Ti-15Mo)] are completely
non-magnetic and MRI compatible.
• They lead to much less artifact than stainless steel materials, including those with low
nickel content.
• 316 L stainless steel (surgical steel according to AO standards) is called
‘paramagnetic’ or ‘non-ferromagnetic’ material and the patient can enter MRI device
with implants made from this material.

Bone (Fracture) Healing:

Primary Healing
• Requires direct reduction and absolute stability
• Requires increased bone stability and low fracture circumference tension (≤ 2%)
• It heals by enchondral / intra-membranous ossification.
• Haversian remodelation
• No callus formation
• Interfragmentary Lag screws, Compression plates are used.
Secondary Healing:
• It requires indirect reduction and relative stability.
• Requires high tension around the fracture (≥ 2%).
• Callus / cartilage is mineralized and replaced by bone.
• Plaster, Bridge plating, External fixator, Intramedullary nails, Functional brace
(Sarmiento)
SELECTION OF FIXATION MATERIAL (IMPLANT):
• Anatomical location,
• Shape/configuration
• Bone quality
• Condition of soft tissue cover
• Simple fractures and joint injuries are treated with direct reduction and absolute
stability
• Complex and partial fractures are treated with indirect reduction and relative
stability.

History:

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A) Wires
--Kirchner wires
--Cerclage wires
B) Screws
--Cortical screws
--Spongious (cancellous) screws
--Cannulated – uncannulated Screws
--Locking screws
C) Plates (Plate-screw systems)
D) External Fixators
--Mono-lateral External Fixators
--AO Type Multi-joint & Multi-planar External Fixators
--Circular External Fixators
E) Intramedullary Nails

• A papyrus (1553-1550 BC) in ancient Egypt mentions methods of fixation for

fractures. Wrapped Birch woods in bandages are reported.
• The first publication was Rodgers' treatment of humerus pseudoarthrosis with silver
cerclage wires (1827). Lapujude used them first.
• The screw fixation method was first reported by the French surgeon Rigaud (1850).
But Sherman set the standarts.
• The use of plate for fracture fixation was first reported by the German surgeon
Hansmann (1886).
• W. Steinbach reported his treatment with silver plate in 1900 and presented x-rays of
the cases.
• Lambotte, who introduced the term osteosynthesis and considered the father of
internal fixation, designed many instruments and implants used in fracture treatment.
• In 1951, Müller published the first in a large case series of internal fixation with open
reduction and plate & screw systems.He stressed the importance of stable fixation and
early mobilization in a series of 75 cases

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 • In 1958, AO (Arbeitsgemeinschaft für Osteosynthesefragen) was founded, which could be
considered the beginning of a new era.

• * Atraumatic surgical technique

• * Anatomical reduction

• * Stable internal fixation

• * Early mobilization

• Gerhard Küntscher is considered as the father of the standard IM nails used today.
• In 1938, Hoffmann developed a technique based on percutaneous pin insertion after
closed reduction. This can be shown as the first example of minimally invasive orthopedic
surgery

• Gavriil Abramovich Ilizarov in the 1950s. (Circular fixator)

• Elastic nails are used in pediatric surgeries.At least two nails must be used.

The genera Leishmania, Trypanosoma, and

Toxoplasma:
Leishmania:
➢ Leishmaniasis is principally a zoonosis, and the organisms are obligate intracellular
parasites transmitted to humans by bites of infected female phlebotomine sand flies
(kum sineği, tatarcık, yakarca, üvez) which feed on blood to produce eggs.

Morphology:
➢ The parasite has two distinct phases in its life cycle, amastigote (Leishmania) and
promastigote (Leptomonas). The amastigote stage (Leishman-Donovan body) is
found in reticuloendothelial cells of the host.
➢ The amastigote form is small, round or oval, measures 3 to 5 μm. Upon ingestion
during a blood meal by the insect vector (sand fly), the amastigote transforms into the
flagellated promastigote stage in the gut of the insect and multply, then, transform to
metacyclic promastigotes (infectious form), and migrate to the hyposome (ağız
boşluğu, farinks) of the sand fly, where they are released when the next bloodmeal is
taken. Cycle is 4 -18 once in the bite site promastigote -→ Amastigote
Life Cycle:

➢ 1. The sand flies inject the infective stage [i.e., promastigotes-(leptomonas)] from their
proboscis during blood meals.

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 ➢ 2. Promastigotes are phagocytized by macrophages and other phagocytic cells.
➢ 3. Promastigotes transform in these cells into the tissue stage of the parasite [i.e.,
amastigotes-(leishmania)],
➢ 4. which multiply by simple division and proceed to infect other mononuclear
phagocytic cells.
➢ 5-6. Sand flies become infected by ingesting macrophages infected with amastigotes
during blood meals.
➢ 7-8. In sand flies, amastigotes transform into promastigotes, develop in the gut and
migrate to the proboscis.
➢ The disease is considered primarily a zoonosis with natural reservoirs, including rodents,
dogs, anteaters (feeding by ants), sloths (slow mammals). Or some times human to human in
prevalent areas.

➢ Greater than 90% of cutaneous leishmaniasis cases occur in Afghanistan, Algeria,

Brazil, Iran, Iraq, Peru, Saudi Arabia, and Syria.

Visceral leishmaniasis (kala-azar):

➢ Visceral leishmaniasis affects reticuloendothelial system organs (spleen, liver, and
bone marrow) and can be life threatening. Caused by L. Dovani or L.Infantum
mostly.
➢ Symptoms: fever, weight loss, enlargement (swelling) of the spleen and liver, and
low blood counts; anemia, leukopenia, and thrombocytopenia. Symptoms can
develop in months to years. HIV Infacted individuals also develop different systemic
symptoms.

Cutaneous leishmaniasis:
➢ It is the most common form of leishmaniasis and causes skin lesions, mainly ulsers,
on exposed parts of the body, leaving life-long scars and serious disability or
stigma.Caused by L. Tropica or L. Major. Painless macules develop to nodes and
bumps then to ulcers and can be painful.

Mucosal (mucocutaneous) leishmaniasis:

➢ Metastatic spread to the nasal or oral mucosa may occur in the presence of the active
primary lesion or many years later after the primary lesion has healed. Untreated
primary lesions may develop into the mucocutaneous form in up to 80% of cases.
Leads to destruction of mucocutenous membranes.
➢ Leishmania braziliensis causes it with Over 90% of mucocutaneous leishmaniasis
cases occur in Bolivia, Brazil, Ethiopia and Peru.

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Post-kala-azar dermal leishmaniasis (PKDL):
➢ Post-kala-azar dermal leishmaniasis (PKDL) is usually a sequel of visceral
leishmaniasis that appears as hypopigmented macular, papular or nodular rash usually
on face, upper arms, trunks and other parts of the body. 5-10% of cases develop it
within 6-12 months after infection.

Diagnosis:
➢ Leishmaniasis is diagnosed by detecting Leishmania parasites (or DNA) in tissue
specimens—such as from skin lesions, for cutaneous leishmaniasis; or from bone
marrow, for visceral leishmaniasis—via light-microscopic examination of stained
slides, molecular methods, and specialized culture techniques.
➢ Definitive diagnosis depends on detecting either the amastigotes in clinical specimen
or the promastigotes in culture.

Direct examination:
➢ Amastigote stages are found within macrophages (monocytes, leukocytes with
polymorphic nucleus) or close to distrupted cells. The cytoplasm will stain light blue,
and the nucleus and kinetoplast will stain red or purple with Giemsa stain.
➢ Novy, MacNeal, and Nicolle’s medium (NNN) and Schneider’s Drosophila medium
suppemented with bovine serum inoculated for 4 weeks 25 degrees. Promastigote
stages can be detected microscopically in wet-mount and then stained with Giemsa
stain to observe their morphology.

Indirect diagnostic tests:

In kala-azar, there is a large increase in both immunoglobulin G (IgG) and IgM. This is the
basis for the formol-gel test, which has been used as screening test in areas of endemicity.
In visceral leishmaniasis, diagnosis is made by combining clinical signs with parasitological,
or serological tests.

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A number of serologies, including indirect fluorescent-antibody assay (IFA), enzyme-linked
immunoassay (ELISA), and immunoblot tests have been developed for diagnostic purposes;
however, they are not widely available exept in areas of endemicity.
Montenegro skin test: intradermal application of a solution containing antigenic
preparation of promastigote forms of Leishmania. The result should be evaluated within
48 hours with a ballpoint pen, being positive if the papule formed is equal or greater than
5mm.
PCR and Animal inoculation methods can also be used. HIV patients may not Show
antibodies against Leishmania so some test are not useful.

Treatment:
Pentavalent antimonial (SbV) compounds,liposomal amphotericin B (lipid formulation of
amphotericin B),‘’azoles” (ketoconazole, itraconazole, and fluconazole).

Prevention & Control:

No vaccine, it’s best to protect yourself from sandflies when going to endemic areas. Low
socioeconomic regions with poverty contribute to major risks.

Trypanosoma:
➢ Trypanosoma spp. are hemoflagellate protozoa(kamçılı kan prozotozoonları) that live
in the blood and tissues of the human host. A central nucleus and a posterior
kinetoplast are usually easily seen.
➢ They can be detected in thick or thin blood smears. In addition to taking thin and thick
blood films, determining the buffy coat concentration is recommended to detect the
parasites.
➢ (the buffy coat is the fraction of an anticoagulated blood sample that contains most of the
white blood cells following centrifugation)

➢ Trypanosomes are parasites of humans, and wild and domestic mammals, in which
they cause several important diseases, including
➢ Sleeping sickness in Africa caused by Trypanosoma brucei subsp. gambiense and T.
brucei subsp. rhodesience species;
➢ American trypanosomiasis (Chagas disease) in the Americas is a zoonosis caused
by Trypanosoma cruzi.

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 Life Cycle:
➢ 1- During a blood meal on the mammalian host, an infected tsetse fly (genus Glossina)
injects metacyclic trypomastigotes into skin tissue. The parasites enter the lymphatic
system and pass into the bloodstream.
➢ 2- Inside the host, they transform into bloodstream trypomastigotes.
➢ 3- They are carried to other sites throughout the body, reach other body fluids (e.g.,
lymph, spinal fluid), and continue the replication by binary fission.
➢ 4,5- The entire life cycle of African trypanosomes is represented by extracellular
stages. The tsetse fly becomes infected with bloodstream trypomastigotes when taking
a blood meal on an infected mammalian host.
➢ 6- In the fly’s midgut, the parasites transform into procyclic trypomastigotes, multiply
by binary fission, 7- leave the midgut, and transform into epimastigotes.
➢ 8- The epimastigotes reach the fly’s salivary glands and continue multiplication by
binary fission.
➢ Cycle takes 3 weeks. Humans are infected when metacyclic forms from the salivary
glands are introduced into the bite site as the blood meal is taken by the tsetse fly. T.
brucei gambiense may be acquired congenitally if the mother is infected during
pregnancy.

African trypanosomiasis (sleeping sickness):

➢ African trypanosomiasis (African sleeping sickness) is caused by Trypanosoma brucei
subsp. gambiense and T. brucei subsp. rhodesience.
➢ Tsetse flies (Glossina cinsi çeçe sineği) (both femele and male) transmit T. brucei to
humans.

Clinic:
The West African (Gambian) form of sleeping sickness is responsible for 99% of the
sleeping sickness cases, which is caused by T. brucei gambiense. It is more chronic. Its
infections can last for months to years with slow CNS involvement, characterized by
neurologic deterioration.
The East African (Rhodesian) form of sleeping sickness causes acute morbidity and
mortality within months of infection, which is caused by T. brucei rhodesiense. It tends to be
more rapid onset with a greater tendency to become rapidly progressive, even leading to death
(rapidly).

Epidemiology and transmission:

➢ Fewer than 10% of tsetse flies become infective after obtaining blood from infected
patients. Although there is no evidence of animal-to-human transmission of T. brucei
gambience, trypanosomal strains isolated from kob (bir cins antilop), chickens, dogs, cows,
and domestic pigs in West Africa are identical to those isolated from humans in the same

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 area. The tsetse fly vectors of Rhodesian trypanosomiasis may transmit the disease from
human to human or from animal to human.

➢ Infections can also occur through placental transfer from mother to fetus and by needle
sticks.

Chagas disease AKA American trypanosomiasis:

➢ It is caused by Trypanosoma cruzi, which is transmitted to humans by triatomine bugs
(reduviid bugs-kan emen böcekler) living in close associated with reservoirs (dogs,
cats, armadillos (köstebek), opossums (bir çeşit sıçan) raccoons (rakun), and rodent
(kemiriciler).

Life Cycle:
➢ Trypomastigotes are ingested by the triatomine bugs (triatomids, kissing bugs) (or
reduviid bug) as it obtain a blood meal from infected animal or person.
➢ The trypomastigotes transform into epimastigotes that multiply in the midgut.
➢ After 8-10 days, metacyclic trypomastigotes develop from the epimastigotes.
➢ These metacyclic trypomastigotes passed in the feces of the triatomine bugs are the
infectious stage for humans.
➢ Infected bugs then deposit the parasites with their faeces on the skin of another person
during or shortly afted feeding.
➢ Scratching or rubbing helps the parasites to enter the body through the bite wound or
broken skin carried by the finger. They can also penetrate through the mucosae of the
eyes, nose or mouth, eventually reaching the bloodstream.
➢ The parasites invade and slowly affect most organs in the body, and this eventually
results in chronic symptoms, suc as irreversible damage to the heart,and almost all
organs.

Diagnosis:
➢ Definitive diagnosis depends upon demonstration of trypomastigotes in blood, lymph
node aspirate, sternum bone marrow, chancre fluid and CSF(cerebrospinal fluid).
➢ In addition to taking thin and thick blood films, determining the buffy coat
concentration is recommended to detect the parasites.
➢ In suspected and confirmed cases. Lumbar Puncture is a must considering diseases
involvement in CSF.
➢ Molecular methods, ELISA or IFA can also be used.

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 Treatment and control:
No vaccine available, Treatment in done with specific drugs according to sub-species.
Best way is eliminate revuiid bug or stay away from it.

Toxoplasma:
➢ Toxoplasma gondii is a protozoan parasite that infects most species of warm-blooded
animals, humans and causes the disease toxoplasmosis.
➢ One of the most common parastatic infection in humans. And mostly asymptomatic.
However sometimes it can have grave consequences.

Life Cycle:
➢ Members of the cat family Felidae (kedigiller) are the only known definitive
hosts for T. gondii.
The three stages of this obligate intracellular parasite are
(i) tachyzoites (trophozoites), which rapidly proliferate and destroy infected cells during
acute infection;
(ii) bradyzoites, which slowly multiply in tissue cysts; and
(iii) sporozoites in oocysts
➢ The sexual stage occurs in the intestine of cats, where infective oocysts, replicate
within the intestinal epithelial cells and are excreted in the feces.
➢ The asexual stage commonly occurs in a variety of herbivorous (ot ile beslenen) and
carnivorous (et ile beslenen) animals that ingest the infective oocysts.
Humans may also become infected by ingesting food or water contaminated with oocysts.
Cockroaches (hamam böceği), earthworms(solucan), snails (salyangos) and slugs (sümüklü
böcek) may also serve as transport hosts for oocysts

Humans are infected by ingesting Oocyts or Tissue Cyst The

unsporulated (i.e., noninfective) oocyst takes 1 to 5 days after
excretion to become sporulated (infective).
Also congenital infections are possible.
➢ After infecting cells as Oocyst The host cell dies and releases tachyzoites, which
invade adjacent cells and continue the process. The tachyzoites are pressured by the
host’s immune response to transform into bradyzoites and form tissue cysts, most
commonly in skeletal muscle, myocardium, and brain; these cysts may remain
throughout the life of the host.
Most people have no symptoms when infected some may experience Flu like symptoms for a
short duration, however parasite enters inactive stage and remains that way unless someone is
immunosuppressed and can be reactivated then.

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Mother-to-child (congenital transmission):
Generally, if a woman has been infected before becoming pregnant, the unborn child will be
protected because the mother has developed immunity. If a woman becomes newly infected
with Toxoplasma during or just before pregnancy, she can pass the infection to her unborn
baby.
➢ Potenatial results can be
A miscarriage,
A stillborn child,
A child born with signs of congenital toxoplasmosis
(i.e., abnormal enlargement –(hydrocephalus or smallness (microcephaly) of the head)
➢ Also can have eye infections in birth. Eye lesion from congenital infection are often not
identified at birth but occur in 20-80% of congenitally-infected persons by adulthood.

Laboratory diagnosis:
Microscopy: Only very rarely can the diagnosis of toxoplasmosis be documented by the
direct observation of parasites in patient specimens. Tachyzoites may be observed as free
organisms or within host cells, such as leukocytes on the slide stained with Giemsa stain.
Well-preserved tachyzoites are crescent (hilal) shaped and stain well, but degenerating
organisms may be oval and stain poorly.
Serologic tests: Serologic testing for T. gondii-specific antibodies is the most commonly
used method for diagnosis of toxoplasmosis. IgG may stay high for years and a good indicator
of recent infection. IgM can be used to screen for neonate infection.

Prevention:
Cook the meat properly, Wash your vegtables and fruits. Wear gloves when soing gardening
stuff cat feces might contaminated the soil. Pregnant woman should stay away from cat litter
and possibly form cats too.

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 Organ-Specific Autoimmune Diseases

Celiac Disease (Gluten Enteropathy):

Celiac disease is largely a disease of the small intestine, although other organs may be
affected. Mostly patients in age group of 30-40 and children are affected but can start in any
age. It results from a reaction to proteins, commonly called GLUTEN, found mainly in
wheat, barley, rye, and some other grains.
The disease has several genetic predispositions and environmental influences. When exposure
to gluten, humoral immune system produces various autoantibodies and an inflammatory
response.
The inflammatory response in the small intestine leads to a reduction in the depth of the
microvilli of the mucosa (villous atrophy), which hinders malabsorption and can lead to
weight loss, anemia, and osteoporosis. These cases may have increased risk of lymphoma.
Celiac disease can commonly be misdiagnosed with Inflammatory bowel syndrome.
Diagnosis of celiac disease is accomplished from serological tests for the presence of
primarily IgA antibodies to components of gluten (gliadin), tissue transglutinaminase
enzyme, and autoantibodies to endomysium, a connective tissue surrounding muscle fibers.
Endoscopy screenings showed that %1 of population has these antibodies but may not show
symptoms of the disease this can be useful for early diagnosis.
Celiac disease is treated with complete removal of gluten-containing foods from the diet,
which results in improved symptoms and reduced risk of complications.
Anti-gliadin IgA , Anti-gliadin IgG, Anti-endomysium IgA (EMA), Anti-tissue
transglutaminase (IgA) are detected in patients with Celiac Disease, EMA and Anti-tissue
transglutaminase having highest sensitivity and specificity.

Autoimmune Thyroid Disorders:

Graves disease is the most common cause of hyperthyroidism. Symptoms of Graves disease
result from the production of TSHreceptor antibody (TRAB), previously called
thyroidstimulating immunoglobulin (TSI). TRAB targets and binds to the receptor for
TSH, produced by the anterior region of the pituitary gland.
TRAB may cause conflicting symptoms because it may stimulate the thyroid to make thyroid
hormone or block thyroid hormone production entirely, making the diagnosis more difficult.
Symptoms:
Heat intolerance
Tachycardia and palpitation,

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Rapid and irregular heartbeat (atrial fibrillation)
Weight loss (despite increased appetite)
Goiter
Ophthalmopathy (orbitopathy) exophthalmia

The most common cause of hypothyroidism is Hashimoto thyroiditis, also called chronic
lymphocytic thyroiditis. Hashimoto patients can develop variety of diseases. These diseases
are more likely to develop additional autoimmune diseases such as Addison disease, type 1
diabetes mellitus (T1DM), rheumatoid arthritis (RA), and celiac disease.
Hashimoto thyroiditis is a Th1 cell-mediated disease that occurs when the thyroid gland is
attacked by cytotoxic lymphocytes, macrophages, and autoantibodies. Symptoms include:
Goiter

Cold intolerance

Muscle weakness

Painful and stiff joints

Depression

Memory loss

Thyroid Peroxidase (Anti-TPO) and Anti-Thyroglobulin(Anti-Tg) are the

antibodies found in the disease.

Type 1 Diabetes Mellitus:

Also known as Juvenile diabetes, usually diagnosed in children and young adults. It is a T-
cell-dependent autoimmune disease characterized by the selective destruction of the β-cells
of the islets of Langerhans in the pancreas by CD4+ Th1-mediated CD8+ T cells, anti-β-
cell antibodies, and macrophage activity.
In adult T1DM, β-cell destruction may take place over several years (or children it may take
few months), but with symptoms of hyperglycemia, extreme increase in thirst and urination,
weight loss, and extreme fatigue usually it has a sudden onset. Can be only diagnosed once
80% of B-Cells are destroyed.

Islet Cell Cytoplasmic Antibody (ICA) can be checked but also insulin levels give
hint.

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Autoimmune Addison Disease:
Destruction of the adrenal glands (that produce glucocorticoids, mineralocorticoids, and sex
steroids) is the cause of Addison disease, also called primary adrenal insufficiency (PAI).
Today 80% of the Addison cases are associated with autoimmunity. There is evidence that
both humoral and CD4+ Th-1-driven CD8 T-cell–mediated immune mechanisms are
directed at the adrenal cortex in AAD.
In up to 80% of patients with AAD, antibodies are produced to three enzymes involved in
steroid synthesis: 21-hydroxylase (21-OH), 17α-hydroxylase, and cholesterol side-chain–
cleaving enzyme. 90% of the adrenal cortex is destroyed before symptoms become
diagnostic.
Weakness, nausea Decreased appetite, weight loss o Hyperpigmentation o Hyperkalemia,
hyponatremia o Hypoglycemia o Hypotension o Anemia o Lymphocytosis, o Fatigue
Under extreme stress, such as surgery, trauma, or infection, patients may experience an
adrenal crisis

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Acute Leukemia - Assoc. Prof. MD, Gülçin Yeğen - 21.10.2020

KMPN:Chronic myo perforated neoplasm. It occur from myeloid lineage. There is

maturation and differentiation.
MDS: Myelodysplastic syndrome. There is maturation and differentiation but there is
deffective production.
Acute Leukemia’s: (both) there is no maturation and differentiation.

Diagnostic Tools for Acute Leukemia:

1-Clinical and laboratory findings.

2-Cytomorphological evaluation of
Peripheral blood, Bone marrow aspiration, Bone marrow trephine biopsy
3-Histochemical examination.
4-Antigenic examination
5-Cytogenetic and molecular biologic examination.

*In 2017, WHO divides bone precursors neoplasms into 3 section:

1-Acute T/B Lymphoblastic Leukemia/Lymphoma

2-Acute Myeloid Lymphoma
3-Ambiguous Leukemia

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Bone Marrow Aspiration Biopsy:(Hoca bu resimde çok durdu. İyi anlamanızı

öneririm.)

ALL: These cells expresses CD22 and TdT together. CD22 is the B Cell marker. TdT is
Precursor Cell Marker. The Precursor Cells of T/B lymphocytes expresses TdT. When
they get mature they lose the TdT expression. If lymphocyte neoplasias show TdT
positivity, then we have to think about something there is lymphoblastic cell. Not a mature
B Cell neoplasia or mature T cell neoplasia. B cell lineaged cells that are TdT positive so
they are blastic cells. There is CD10 positivity. We call the CD10 as “Calla”. Calla
positive B Cell Lymphoblastic Leukemia is seen here.

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AML: CD34 has same role as TdT. It can be positive both myeloid or lymphoid lineage, it
is not be lineage specific. It just show that the cell is precursor. 3.square shows CD34
positivity and CD64 positivity. 4.square shows CD33 positivity and CD15 positivity that
are lineage antigens. The tumor has blastic morphology and blastic marker expression and
myeloid lineage expression so this is Acute Myeloid Leukemia.

Acute Leukemia

-Clonal proliferation of precursor/blastic cells.

-Arrest of the differentiation is the major efect.
-It happens due to acquired mutations in transcription factor coding genes that regulates
differentiation.
-Blastic cell count should be over %20 in peripheral blood and bone marrow.

Clinical Features:

1)Blastic cells that proliferating in bone marrow supresses normal hemapoietic cells
-Anemia->Fatigue
-Neutropenia->Fever, susceptible for infections
-Trombocytopenia->Petechia, purpura, hemorrhagia
2)Acute and severe onset
3)Bone pain and tenderness (frequent in ALL, mostly B Cell-ALL(BLL):hoca ders
arasında bunu sordu). (Mediastenal lesions frequently T(thymus) Cell-ALL:hoca bunu da
sordu)
4)Leukemic spread (generalised LAP, hepatomegalia, splenomegalia,paralysis, frequent in
ALL)
5)Meningeal involvement (headache, vomiting, strike, paralysis, frequent in ALL)
6)Testicular involvement(Frequent in ALL)

-Pre-B Cell>Pre-T Cell

-Pre-B Cell lineage, pediatric, involvement of bone marrow and peripheral blood more
common
-Pre-T Cell lineage, adolescent/young adult, involvement of thymus-mediastenum more
common

<< 20 >>
If CD34 and TdT are positive->B-ALL exist
CD10 positive->Calla positive->B-ALL exist
CD19 positive from precursor time to mature time
CD20 is usually negative in B-ALL, but small portion is positive.
CD38 is plasma cell marker. It can be use for precursor B-cell marker. If CD38 is positive,
it might be blastic cell. If we see plasmacytoid cell with eccentric nuclei, it is a plasma cell,

than CD38 positivity means this is a plasma cell.

CD34, TdT, CD10 are positive.
CD7, CD2, CD5, CD3 are shows that this cell is T cell.
CD4 and CD8 are in the beginning double negative and then double negative and then
either one them is positive in mature cells. Double negative if ALL is there, Double
positive if ALL is there. We usually see CD4 and CD8 double negative or positive.

<< 21 >>
Acute Myeloid Leukemia

-Adulthood, more frequent between 15-40 years.

-Can be seen in childhood and elderly.
-%20 of pediatric acute leukemias.
-Blast count >%20

Immunophenotype:

Myeloblast->CD34, HLA-DR, CD33, MPO

Monoblast->CD34, HLA-DR, CD4
Eytrhoblast->Glikoforin A
Megakaryoblast->CD41, CD61, CD33

Genotypic Features:

1-Cytogenetic analysis: Structural ad numeric abnormalities.

2-Moleculer analysis:
-Various fusion genes has a diagnostic and prognostic role,
-Chromosomal abnormalities.
-Gene expression profiling, molecular classification.

AML and Related Neoplasms

a)AML with recurrent genetic abnormalities (like BLL) –>Can give about information to
diagnosis
-AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1->good diagnosis
-AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11->better prognosis
b)AML with myelodysplasia-related changes->worst prognosis
c)Therapy related AML->worst prognosis

<< 22 >>
d)AML-NOS

AML M0:
-Immunophenotype:
Primitive Cell: CD34, CD38, HLA-DR (+)
Maturation antigens: -
-Cytogenetic:
Complex caryotype
Tri 13, Tri 8, Tri 4, Mono 7
Prognosis:

AML M1:

AML M2:

<< 23 >>
AML M4:

Myeloid Sarkoma AML M4

We can see AML in the bone marrow. We have lisozim expression. CD68, CD34, CD15
positivity.

AML M5:

AML M7: There is so fibrosis. Ususally dont see fibrosis in other leukemia’s

<< 24 >>
 Acute Panmyelosis=Acute Myelofibrosis

Acute Promyolocytic Leukemia AML M3

Auer Rode

<< 25 >>
Çıkmışlar:

1)A 4 year-old boy appeared listless during the past week. In the past *****chymoses have
appeared on the Right thigh and left shoulder. CBC shows Hb: 9.3 g / dL, PLT count 45,000
/****count :13,990/mm3 Examination of the peripheral blood smear shows blasts that lack
peroxidase ****and stain positively ***TdT. . Flow cytometry shows the phenotype of blasts to
be CD19 +, CD3-, and sig****following is the most likely diagnosis?

-Acute Lymphoblastic Leukemia

2) A 33-year-old man has experienced nosebleeds, along with bleeding gums for the past week.
Laboratory studies show anemia, thrombocytopenia and leukocytosis. Examination of his bone
marrow aspiration smear shows blasts that have delicate nuclear chromatin along with fine
cytoplasmic azurophilic granules. These blasts are CD33 +, Which of the following morphologic
findings is most likely to be present on his bone marrow aspiration smear?

-Auer Rods

Selçuk Maraşlı

<< 26 >>
Non-Neoplastic Diseases of Lymph Nodes/Doç. Dr. Şule
Sarı/ Pathology
Department/27.10.2020/14.00-14.50/Kuzey YILDIZAK
Hoca dersi Türkçe anlattı. O yüzden ben de Türkçe yazacağım fakat terimleri İngilizce olarak
koruyacağım.

Lenf Nodlarının üç önemli görevi vardır:

1-Lymphopesis (Lenf nodlarında lenf hücresi bölünmesini ve çoğalması anlamına gelir)

2-Mechanic filtraion of lymph (lenfi süzme)

3-Recognition of antigens and immune reaction (antijenleri tanıma ve cevap)

Lenf Nodunun Genel özellikleri: Böbrek biçimli, NON-PALPABLE, yerine göre değişik
büyüklüklerde ve şekillerde olabilir ve sağlıklı insanlarda 0,5-1 cm olması normaldir.

Lenf Nodu İnceleme yöntemleri: Fine Needle Aspiration, tru-cut, incisional, excisional

İnguinal ve superficial nod biyopsileri kaçınımlaıdır

Büyümüş değil de daha ziyade büyümekte olan lenf nodları tercih edilmelidir, aktif olanı
incelemek için.

Viral Lenfadenit

Infectious Mononucleosis Lymphadenitis

Cytomegalovirus LAP

Herpes Simplex LAP

Varicella-Herpes Zoster LAP

Measles (kızamık)

Viral aşı

HIV LAP

Iatrogenic LAP: İlaç bağımlı, methotrexate

Foreign Body: JOINT PROSTHESIS RELATED METAL DEBRIS

<< 27 >>
(Bunlar önemli olanlar)

INFECTIOUS MONONUCLEOSIS LAP

EBV ( HERPES TYPE)

Çocuklar ve gençler özellikle etkilenir

Öpüşme ve salya ile geçer

Virüs nasopharynx'e ve oropharynx'e yerleşir.

30-40 GÜNLÜK KULUÇKA SÜRESİ,

Ateş, soreness (halsizlik), cervical LAP

Splenohepatomegaly ile karakterizedir.

Periferik yaymada böyle tuhaf şekilli lenfositler görülür. Bunlara Downey Cells adı verilir.

Reed-Sternberg hücreleri görüldüğü için bazı hastalara yanlışlıkla Hodgkin Lenfoma tanısı
konulablir. Dikkatlı olmak gerek.

Tanı için çekirdekleri mor ile boyayan EBV için spesifik olan EBER-in-situ testi kullanılır.

CYTOMEGALOVIRUS LYMPHADENITIS

Lenf nodları büyümüş, gergin ve ağrılıdır.

<< 28 >>
Şekilde görüldüğü gibi çekirdekte intranuclear inclusion of viral particles HALO FORMATION
(hale görünümü)

CMV antibody'leri serolojik olarak bulunabilir.

Halo Formation hücreleri REED-STERNBERG hücrelerine benzerdir fakat HODKIN LAP değildir.

MEASLES LYMPHADENITIS

Kızamık aşısından sonra prodromal dönemde bile görülebilir ve hastalık sırasında devam
edebilir.

Genel viral LAP bulguları vardır

WARTING FINKELDEY GIANT CELLS görülür.

Böyle resimdeki gibi bir araya gelmiş

hücrelerdir. Kızamık için klinik ile birlikte tanı koydurucudur.

HIV LAP

<< 29 >>
Diğer LAP nedenlerinin dışlanması gerekir ve birden fazla nodda LAP olması gereklidir. O zaman
HIV LAP düşünülebilir.

CD4/CD8 oranı 1 den büyül olması gerekirken tam tersi 1'den küçüktür.

Üç faza ayrılır:

A (Acute): Normal herhangi bir virüs enfeksiyonu lenf nodudur. Follicle hyperpleasia, reactive
germinal centers, apoptosis, folliculolisis, tingible-body macrophages, Monocytoid B cell
hyperplasia. Wartin-Finkeldey gaint-cells

B (Chronic): Follikül sayısı azalmıştır, germinal merkez atrofisi, dentritic hücre yapısı bozulması,
lympocyte delpetion (lenfosit tükenmesi azalmış yani), vascular hyperplasia in paracortical
space. Kısaca lenf nodu regrese olur ve damarlar yapıların yerini alırlari, plazma hücreleri aksine
artmıştır

C (Burn-out): Atrofik ya da tamamen yok olmuş foliküller, hyalinize germinal merkez, LOLLIPOP
LIKE FOLLICLES, lenfosit tükenmesi, vascular hyperplasia, plazma hücreleri artmıştır aksine.

Bakın burada lolipopa benzetilmeye çalışılmış.

ACUTE BACTERIAL LYMPHADENITIS

<< 30 >>
SUPPURATIVE (SÜPÜRATİFTİR YANİ İÇİ BÖYLE SARI CERAHAT DOLUDUR)

Staphylacoccus aureus, streptococcus genel nedenlerdir (Tooth abcess, skin-soft tissue of

extremities) Bu gibi durumlarda CHRONIC GRANULOMATOUS DISEASE gibi immune sistemi
defektleri akılda tutulmalıdır.

Lenf Nodu büyümüştür yumuşaktır ve hassastır. Kırmızı renkte, ödemli ve üstündeki deri
sıcaktır.

Nötrofiller ön plandanır.

CAT SCRATCH DISEASE LYMPHADENITIS

NECROTISING GRANULOMAS (BU ÇOK ÖNEMLİDİR VE)

Mikroapseler görülür.

Bartonella henselae neden olur.

Palisading zone of epitheloid histiocytes ( Yani palisade ing. çit demek. Histiyositler ise bağ
dokusu makrofajı demektir. Burada olan şey ise histiyositler nekroze abseyi çevreleyerek daha
fazla yayılmasını önlüyorlar suç yerinin çevrelenmesi gibi. Bu hücreler epitel özelliği gösterirler
makrofaj olmalarına rağmen çünkü nekroz çevresinde sıkı sıkı bağlanarak sınırlandırma yapmak
istedikleri için özelliklerini değiştirirler o yüzden epitheloid histiocyte denirler.)

Bakın aynen böyle. Daire kenarında

epitel hücresi gibi görününler aslında histiyosit yani makrofaj ama epitel hücresi gibi.

Nekrotizan Granülom=Tüberküloz olarak aklımıza gelmesi gerekiyor ilk olarak ama sonradan
Cat-Scratch disease gibi hastalıkları da klinik bulgulara göre düşünmeliyiz. Farkı ise tüberkülozda
apse olmaz. Cat-scratch disease'de ise var.

<< 31 >>
LYMPHOGRANULOMA VENEREUM LYMPHADENITIS (NICHOLAS-FAVRE DISEASE)

Chlamydia Trachomatis neden olur.

Sexually-transmitted

Sadece genital değil servikal LAP de yapabilir.

Cat-stcratch disease gibi abseli NECROTIZAN GRANULOMA görülür.

Fakat FARKLI OLARAK STELLATE LIKE ABCESS RICH IN NEUTROPHILS (YILDIZSI NÖTROFİLLİ
ABSELER GÖRÜLÜR

SYPHILITIC LYMPHADENITIS
Treponema pallidum nedendir.

Reactive follicular hyperplasia gibi klasik LAP bulgular eşlik eder.

ARTERITIS AND PHELBITIS (FRENGİ YANİ SİFİLİZ GENEL OLARAK DAMAR TUTULUMU YAPAR O
YÜZDEN LENF NODUNUN DAMARLARINDA ARTERİT VE FLEBİT GÖRÜLÜR BURASI ÖNEMLİ)

Kapsülde fibroz görülür.

WHIPPLE DISEASE LYMPHADENITIS

Nadir bir tablo vardır. Tropherima whipplei etkendir.

Semptomlar: Diarrhea, malabsorbtion, local lenf donu LAP

MYCOBACTERIUM TUBERCULOSIS LYMPHADENITIS (EN ÖNEMLİLERİNDEN BİRİ TÜBERKÜLOZ)

Ağrısız LAP, caseification necrosis

<< 32 >>
 Şekildeki gibi langerhans dev
hücreli histiyositleri tüberkülozda görülür.

BACILLE-CALMETTE-GUERIN LAP (YANİ KISACA BCG aşısı ile ilişkili)

BCG aşısından sonra gelişen yeni doğan LAP

Mesane kanserli hastalarda BCG aşısı uygulandığı zaman inguinal lenf nodları şişebilir..

Kendiliğinden iyileşir eğer hasta immunsüpresif değil ise.

MYCOBACTERIUM AVIUM-INTRACELLULARE LAP

HIV +, immunsüpresif hastalarda ve IL-12 (bu önemli)

Sadece köpüksü histiyositler var (FOAMY HISTIOSCYTES)

Hücre için mikobacteriler tüberküloza kıyasla çok daha fazla görülür.

LEPRA MYCOBATERIUM da LAP yapabilir ama hoca direkt geçti.

TULAREMIA (Bu önemli)

Francisella Tularensis etkendir.

Kemirkenlerden (rodents) bulaşır

Çok çeşitli yollardan bulaşabilir:

-Arthropod bite (tick-kene ısırması yoluyla)

- Infected animal tissues, blood and secretion (Avcılar)

<< 33 >>
-Oral intake of contaminated water and food (BU ÖNEMLİ ÖZELLİKLE ÜLKEMİZDE)

-Inhalation of infective aerosols (BİYOLOJİK SİLAH)

Boyunda şişkin LAP özellikle oropharynx'e yerleşmesi bakımından önemlidir.

PNEUMOCYSTIS LYMPHADENITIS (BENCE ÖNEMLİ DEĞİL)

Pneumocystis jiroveci etkendir

İmmunsupresif hastalarda görülür. Mediastinum tutulumu yapar.

Protozoa LAPs

Ayrıca toxoplasma da LAP yapar. Makrofajların içerisinde trofozoidler görülebilir.

Leismania LAP: Leishmania Donavani etkendir. Phlebotomus fly (Tatarcık ), Donovan bodies
görülür. ORIENT BOIL (YANİ ŞARK ÇIBANI GÖRÜLÜR)

Cala-Azar denen viceral türü splenomegali yapar.

REACTIVE LYMPHOID HYPERPLASIA (BENCE ÖNEMLİ DEĞİL)

Genel bir terimdir. Lenfoid parenkima değişik antijenik stimuluslara bağlı olarak büyümüştür.
Sadece nodlarda değil bütün sekonder lenf organlarında büyüme söz konusudur. Genellikle
non-neoplastic nedenlere bağlıdır. Neoplastisite yaş ile artar.

Symptoms

-Folicular pattern

-Diffuse paracortical hyperplasia

-Mixed pattern

-Atypical lymphoid hyperplasia

ROSAI-DORFMAN DISEASE (SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY)

Bu hastalıkta çok önemli bir özellik vardır ve bilinmesi gerektir çok ilginç ve çok değişik:

EMPERIPOLESIS (LYMPHOCYTE ENGULFMENT)

Bu ne demek? Yani bizim histiyositlerimiz (Bağ-dokusu makrofajları) lenfositleri FAGOSİTE
ETMİŞTİR:

<< 34 >>
 Bakın
burada histiyositlerin içerisinde lenfositler vardır. CD 68 + boyaması ile histiyositler gösterilir.

Kicuchi Fujimoto LAP

Bu hastalığın nekrotizan granuloma yaptığını bilmek yeterlidir.

LUPUS LAP

Lupus her şeye neden olabildiği gibi LAP de yapabilir. Neutrophil ve eosinophil azlığı vardır.
Nuclear debris (apoptotic materyal) ve hematoxilen parçacıkları görülebilir. Özellikle damar
duvarlarında apoptotik hücreler.

SARCOIDOSIS LAP

Nedeni bilinmeyen granulomatik bir hastalıktır ve LAP sık görülür genellikle pulmonary
hillum'da görülür.

ÖNEMLİ NOKTALAR

GRANULOMLAR NEKROZSUZDUR VE KALSİFİKASTON YOKTUR

GRANULOMLAR AYRIDIR BİRLEŞMEZ : SEPERATE GRANULOMA

ASTEROID AND SCHUMANN BODIES

<< 35 >>
 Yıldızsı yani asteroid body.

Burada da bir schaumann corpuscule görülüyor

siyah renkte.

Romatoid artrit ve Dermatopathic Lymphadenopathy de LAP yapanbilen hastalıklar arasındadır.

Aklımızda bunun kalması gerekir.

ÇIKMIŞLAR:

<< 36 >>
S-1)Aşağıdakilerden hangisi yanlıştır?
A-) Lenf nodülleri ovoid yuvarlak veya fasülyeye benzeyen sağlıklı bir insanda palpe edilemeyen
nodüllerdir
B-) Lenf nodülü biyopsisi yapılırken aktif bir lenf ganglionu eksizyonal(kapsülüyle birlikte) olarak
çıkarılmalı ve uygun fiksatife konulup ayrıntılı bilgiler verilerek laboratuara gönderilmelidir
C-)Lenf nodülleri yaşa ve bulunduğu yere göre bazı değişiklikler göstermezler.
D-)Lenf nodülleri lenfopoezi sağlar
E-) Lenf nodüllerinin kesit yüzeyi gri- pembe, yumuşak ve homojen görünümlüdür.

S-2)İnfeksiyoz Mononükleoz Lenfadeniti hakkında aşağıdakilerden hangisi yanlıştır.

A-)Öpüşme ve tükrük yoluyla bulaşır bu yüzden öpücük hastalığıda denmektedir.
B-). HODGKİN lenfoması ile sıkça karıştırılır.
C-) Splenomegali , hepatomegali izlenebilir.
D-)İnkübasyon süresi 1-2 haftadır
E-) Sinüslarda ve pulpada atipik mononükleer hücreler vardır

S-3)Akut bakterial lenfadenitler için hangisi doğrudur?

A-) Bakteri infeksiyonlarının oluşturduğu akut bazen süpüratif lenfadenittir.
B-) Etkeni bartonella henselae gram negatif basilidir.
C-) Kemirgenler başta olmak üzere hayvanlarda görülen, insanlarda sporadik zaman zaman da endemik
olarak rastlanabilen bir infeksiyon hastalığıdır.
D-) Ortası erimeler gösteren, nötrofi PNL lerden oluşan yıldızvari şekilli abseleşme alanı ve bunun
çevresinde epiteloid histiositlerden oluşan granulomatöz reaksiyon zonu vardır
E-) HIV(+), immunyetmezlikli kişiler, IL-12 yetersizliği sonucu görülür

S-4) Kene-böcek ısırması, av hayvanlarından ve kontamine sulardan bulaşabilen, biyolojik silah olarak
kullanılan dünyada ve ülkemizde endemiler yapabilen mikroskobik nekrozlu granülomatöz iltihap ile
karakterize, tanısı serolojik olarak konulabilen lenfadenit etkeni hastalık aşağıdakilerden hangisidir?
TULAREMİ

S-5) Lenf gangliyonunun yapısı ile ilgili aşağıdakilerden hangisi yanlıştır?

Lenf nodunun büyümesine lenfadenit denir.

S-6) Aşağıdakilerden hangisi dermatopatik lenfadenopati tanımlamasına uygun değildir?

Parakortekste CD68(+) lenfofagositoz gösteren histiosit proliferasyonu vardır.

(Dermatopatik lenfadenopati:Genellikle bir deri hastalığı bulunur. Lenfatik drenajın olduğu lenf nodülü
tutulur.(En sık aksilla ve inguinal). Kaşıntı ve eosinofili eşlik edebilir.Bu lenf ganglionlarının bazılarında
minimal veya belirgin derecede neoplastik T lenfositleri bulunur. )

CD68+ için özette bkz: ROSAI-DORFMAN DISEASE resimin altında.

<< 37 >>
Genetic Analysis in Hematological Malignancies – Medical Genetics
Dr. Aynur Dağlar Aday– M. Mahmut Lahmuni
27 Ekim 2020 (15:00 – 15:50)

● Cancer: The description of all malignant tumors that devemllop as a result of uncontrolled
cell proliferation
● Factors that have a role in carcinogenesis:
→ Genetic factors (Tumor suppressor genes, oncogenes)
→ Environmental factors (Radiation, carcinogens)
● There are three main types on cancer:
- Sarcoma
- Carcinoma
- Hematopoietic and lymphoid malignancies (leukemia-lymphoma) -BUGÜNKÜ KONUMUZ-
● Diagnostic methods in leukemia:
→ Quantification of blood cells (erythrocytes, leukocytes and platelets)
→ Morphological and cytochemical evaluation
→ Genetic analysis -ŞUANKİ KONUMUZ-

● Genetic Approach in Leukemia

→ Conventional cytogenetics
→ Fluorescent In Situ hybridization (FISH)
→ Molecular evaluation
- Southern blotting
- Northern blotting
- Western blotting
- Conventional PCR
- RT-CR
- Microarray
- Sanger Sequencing
- NGS (şuan çok pupüler olan)

● Leukemias (FAB Classification):

→ Acute:
- Myeloblastic ◦ M1 ◦ M2 ◦ M3 ◦ M3 variant
◦ M4 ◦ M4 EO ◦ M5a ◦ M5b
◦ M6 ◦ M7 ◦ M0

- Lymphoblastic ◦ L1 ◦ L2 ◦ L3
→ Chronic
- CML
- CLL

<< 38 >>
● The Importance of Cytogenetic Evaluation in Leukemias
→ Diagnosis
→ Classification and determining the origin of the malignancy
→ Prognosis
→ Direction of the treatment
→ Detection of relapses and remissions
→ Evaluation the success of bone marrow transplantation
● Development of Malignancies based on Chromosomal Anomalies
Changes in the chromosomal breakage regions:

Mutated region Protein Disease

Oncogenic activation t(5;12) TEL-PDGF MDS, AML
Tumor suppressor gene loss or inactivation del(17p) p53 AML, MDS
Chimeric (fusion gene) formation t(9;22) bcr-abl fusion CML

● Cytogenetics in Leukemia:
→ Different chromosomes and different regions can be affected
→ Certain leukemia types have specific anomalies:
- CML t(9;22)
- Burkitt’s Lymphoma t(8;14)
→ The frequencies and occurrences of these anomalies vary
● Material Selection for Cytogenetic Study in Leukemias
- Bone marrow material (The most ideal choice)
- Peripheral blood (in cases with high number of blast)
- Lymph node biopsy or aspiration

● Methods of obtaining chromosomes from peripheral blood and bone marrow (short term
culture):
→ To obtain chromosomes from peripheral blood:
- 72 hours T or B lymphocyte cell culture
- Harvest method
→ To obtain chromosomes from bone marrow:
- Preferably HRB method or direct acquisition method with 24 to 48 hours cell
culture
- Harvest method

<< 39 >>
 ● FISH (Fluoreasan In Situ Hybridisation)
→ Basis of the method: Molecular cytogenetic method that provides insight about a target
region using the fluorescent labeled complementary probes specific to target DNA
→ Purpose: To detect changes between 20-200 kb (microdeletion, translocation, etc.) or to
verify cytogenetic findings
→ Types of probes:
- Centromeric
- Whole chromosome
- Locus specific
- Telomeric

● KML hastası:

22nd chromosome

9th chromosome

Fusion gene

●The Most Common Anomalies in AML

→ t(8;21) AML-ETO fusion
→ t(15;17) PML-RAR∝ fusion (AML-M3)
→ inv (16) CBF β-MYH11 rearrangement
→ 11q23 MLL rearrangement
→ Complex karyotype

● Cytogenetic Findings in MDS is similar to AML (50% of cases are transformed into AML)
◦ 5q- or –5 ◦ 7q- or –7 ◦11q-
◦ +8 ◦ del 13q ◦ Complex Karyotype
● The Most Common Anomalies in CLL
→ % 95 of the cases are B-cell originated
→ B lymphocyte cell culture is performed for the detection of cytogenetic anomaly
◦ +12
◦ +8
◦ +15
◦ 13q-
◦ 6q and 12p rearrangements

<< 40 >>
● The Most Common Anomalies in CML
→ t(9;22)
→ t(9;22)+der22q
→ Variant translocations

→ The ABL gene encodes a tyrosine kinase

→ The Ph chromosome can be detected in myeloid, monocytic, erythroid and megakaryocytic cells,
B cells and occasionally in T-cells

● The biological results of this increased activity:

→ Triggering transformation and proliferation in immature hematopoietic cells,
→ The emergence of an antiapoptotic effect
→ Impaired interaction of leukemic progenitor cells with bone marrow stroma and
decreased adhesion ability

● The Targets of CML Treatment:

→ Hematological response
→ Cytogenetic response (Complete cytogenetic response)
→ Molecular response (Disappear of Bcr-abl)

● Cytogenetic Response (CR) (with Chromosome Band Analysis):

CR (-) Ph+ metaphase ratio > % 95

Minimal (minCR) Ph+ metaphase ratio % 66-95

Minor (mCR) Ph+ metaphase ratio % 36-65

Partial (PCR) Ph+ metaphase ratio % 1-35

Complete (CCR) Ph+ metaphase (-)

<< 41 >>
● BCR-ABL transcript levels reflect
the number of residual leukemic cells:

● The history of CML:

● Complete hematological response (CHR):

→ Leukocyte <10 x 109 / L
→ Absence of myelocytes, promyelocytes and myeloblasts in peripheral smear
→ Basophil <5%
→ Platelet <450 x 109 / L
→ Splenomegaly (-)

● Cytogenetic follow-up
→ 3rd month
→ 6th month
→ Once every 6 months until the confirmation of CCR
→ Once every 12 months (FISH can be used in case of CCR)
→ In case of warning it can be done once a month with other molecular tests
→ In the event of failure or progression to accelerations and blastic phase, mutation
analysis should also be included.

<< 42 >>
● Roadmap for Optimal Response
→ 3rd month: Bcr-abl ≤ %10 and/or Ph+ < %35
→ 6th month: Bcr-abl < %1 and/or Ph+ 0
→ 12nd month: Bcr-abl ≤ % 0.1
→ Then and always Bcr-abl ≤ % 0.1

● Cytogenetic Analysis in Fanconi Aplastic Anemia

→ It is an inherited bone marrow deficiency
→ Two parallel cultures are made
→ Clastogenic (chromosomal breaker) alkylating agent (mitomycin C or DEB) is added to one of the
cultures. (Chromosome Clastogenicity Test)

● Sister Chromatid Exchange (SCE)

→ SCE: method of showing changes between two sister chromatids.
→ The basis of the method: the different staining of each chromatid during the replication
of the mitotic chromosomes.
→ The purpose of the method:
◦ Demonstrate changes in diseases with increased chromosome instability such as
Bloom syndrome
◦ To determine the biological effects of these agents causing DNA damage in
individuals exposed to mutagen and carcinogens

● The importance of molecular assessment in leukemias:

→ Diagnosis
→ Classification and determination of the origin of malignancy
→ Prognosis determination
→ Guiding treatment
→ Detecting relapses
→ Evaluation of bone marrow transplantation success
→ Molecular monitorization

<< 43 >>
● DNA, RNA Extraction
→ Material: Blood, bone marrow
→ Most commonly used isolation methods:
- Salting out
- Organic extraction
- Binding of DNA and RNA to solid surfaces

● Then the concentration and purity of DNA/RNA is measured by spectrophotometry

● Peripheral blood or bone marrow must be taken to a sterile tube containing EDTA
(Samples with heparin are not preferred because heparin blocks the PCR)
● for RNA based tests, 10ml of blood is enough
for DNA based tests, 2ml of blood is enough
for both DNA and RNA based tests, 1-2ml of bone marrow is enough
● cDNA synthesis:
→ Single stranded RNA molecule is the sample
→ Double-stranded cDNA is synthesized in the reaction
→ Unlike PCR, Reverse Transcriptase is used instead of Taq Polymerase
● Chronic Myeloid Leukemia:
→ ~95% of CML patients and ~35% of ALL patients harbor Ph ((t,22)(q34;q11))
→ BCR-ABL variant transcripts according to broken points:
◦ Major-BCR (p210) -SIKLIKLA KULLANDIĞIMIZ-
◦ Minor-BCR (p190)
◦ Micro-BCR (p230)

● QRT-PCR:

<< 44 >>
● CML and TKI Therapy:
→ Imatinib (Glivec), the first tyrosine kinase inhibitor (TKI) developed in 2001, is the first
line-treatment for CML
→ Response to TKI treatment is at hematological, cytogenetic and molecular levels, and
these responses are expected to be obtained in certain periods
→ If there is a cytogenic response, the patient should be followed up molecularly every 3
months with QRT-PCR method
→ Investigation of mutations associated with imatinib resistance by sequence analysis

● Molecular follow-up in a case with CML

Mavi (altta): optimal bölge
BCR-ABL graphic: Sarı (ortada): uyarı bölgesi
Kırmızı (yukarıda): başarısızlık

3 aylık dönem

● Myeloproliferative Neoplasm: A clonal stem cell disorder characterized by excessive cell

production in the bone marrow.
→ Blood cells accumulate in the bloodstream
→ Philadelphia-negative (Ph-) MPNs;
◦ Polycythemia vera (PV)
◦ Essential thrombocytopenia (ET)
◦ Primary myelofibrosis (PMF)
● Genetic alteration in MPNs
→ MPNs are thought to be formed as a result of acquired genetic alterations in
hematopoietic stem cells
→ JAK-2 V617F is present in approximately:
90% of patients with PV
50-60% of ET and PMF patients
→ JAK-2 exon 12 mutations are seen in 5% of PVs
→ If no JAK-2 mutation: MPL and CALR mutations should be investigated in ET and PMF
cases mutation
●

Mutations in JAK2, CALR and MPL

cause myeloproliferation by activating
the JAK/STAT pathway

<< 45 >>
● Acute Lymphoblastic Leukemia (ALL)
→ Most common type of leukemia in children
→ constitutes 80% of childhood leukemias and 20% of adult leukemias
→ Occurs as a result of abnormal controlled and excessive proliferation of lymphoblasts
→ Markers investigated in ALL differ according to their B and T cell nature

● Acute Myeloid Leukemia:

→ Most common type of leukemia in adults
→ Genotypically heterogenous complex disease
→ Most of the chromosomal abnormalities observed in AML are new centrifugations or
large chromosomal deletions
→ Most common anomalies:
t(8;21)(AML1-ETO) - M2
t(15;17)(PML-RARA) - M3
inv(16)(CBFB-MYH11) - M4
→ The expression levels of these fusions genes are molecularly determined by QRT-PCR and
MRD follow-up is performed

ÇIKMIŞ SORULAR
1. Which of the following sentences about the assessment of hematological malignancies is
incorrect?
c) T (8; 14) is the typical cytogenetic abnormality in AML-M3

2. Which of the following information about Philadelphia chromosome is incorrect?

c) The fusion protein that origins from Philadelphia chromosome has low tyrosine kinase activity

<< 46 >>
 Abdominal Mass in Children- Deniz Tuğcu- 30.10.2020
Mustafa Çalkap

Altough abdominal mass is a very important finding in children not all of the masses are malign.
Mass lesion can be painless. Rupture and hemorrhage(internal, free) can accompany painfull mass
lesion.
Mass can disrupt normal organ functions: acute urinary obstruction, bowel obstruction.
Neurologic findings, pain, fatigue/pallor, bad appearance are the manifastations of a metastatic
disease.
Age:
It is important to differentiate embryonal and non-embryonal tumors. First 4-5 years we see
embryogenic tumors at children. These are: Hepatoblastoma, retinoblastoma, wilms tumor,
neuroblastoma. Mass in the liver indicates a hepatoblastoma not a hepatocellular carcinoma.
Neonate(<1 year):
Most of the time a congenital malformation(GU, GI). Rarely a malignancy.

Causes:
Urinary( about 50%):
-hydronephrosis: Posterior urethral valves, uretero-vesicaljunction/uretero-pelcic junction
obstruction.
-Multicystic dysplastic kidney
-Polycystic kidney
-Ectopic/horseshoe kidney
-Urachal cyst
-Kidney tumor: Wilms tumor, mesoblastic nephroma, nephroblastomatosis.
Adrenal:
-Adrenal hemorrhage

-Neuroblastoma
Liver/spleen:
-Congestive heart failure
-Congenital infections
-Metabolic disorders

-Backwith-Wiedemann

<< 47 >>
 -Choledochal cyst
-Hepatic cyst

-Hepatic tumor: Hemangioma, hemangioendothelioma, mesenchymal hamartoma,

hepatoblastoma, metastatic tumor(wilms, neuroblastoma)

Genital tract:
-Ovarian cyst: Follicular, dermoid/teratoma
-Hydro(metro)colpos: imperforate hymen, vaginal atresia/stenosis, cloacal anomalies.
-Sacrococcygeal teratoma.
Gastrointestinal:

-Feces
-Enteric duplication
-Mesenteric cyst(lymphangioma)
-Intussusception
-Intestinal stenosis/atresia

-Malrotation/volvulus
-Meconium plug
Child(1-10 years):
Incidence of malignancy peaks between 1-5 years. Most important tumor is neuroblastoma.
Second important tumor is wilms tumor.
Causes:

Malignancies:
-Teratoma
-Lymphoma(after 4 years)
-Rhabdomyosarcoma
GI:

-Feces
-Duplication
-Mesenteric cyst(lymphangioma)
-Intussusception
-Malrotation/valvulus

<< 48 >>
 Adolescent(>10 years):
Non-hodgkin lymphoma and burkitt lymphoma. Esspeacially for non-hodgkin lymphoma: rapidly
enlarging mass producing pain, obstruction(GU, GI) and metabolic derangements of tumor lysis.
Intussusception: Part of the intestine folds into section immediately ahead of it.

Inflammatory bowel disease.

Causes:
Malignancies:
-Lymphoma
-Rhabdomyosarcoma

-Soft tissue sarcoma

-Ewing sarcoma/PNET
-Desmoplastic small round cell tumor
-Adrenocortical carcinoma
-Pheochromocytoma

-Colorectal sarcoma
GI:
-Feces
-Inflammatory: Appendicitis, Inflammatory bowel disease
Other considerations:

For females always look for pregnancy and ovarian tumors.

Ask for prematurity because it may have a relation with hepatoblastoma and some other tumors.
Ask for family history. Familial Adenomatous polyposis may present in children as early as teenage
years.
Location of the mass must be checked. Aniridia and Hemihypertrophy may accompany wilms
tumor. They are very important.
Check all of the skin for subcutaneous nodules(related with neuroblastoma).
Periorbital ecchymosis(finding of distant metastasis of neuroblastoma).

Opsoclonus-Myoclonus syndrome(related with neuroblastoma). Rapid, multi-directional eye

movements(opsoclonus) and quick, involuntary muscle jerks(myoclonus). Not directly related to
the tumor itself but to the onchogenic and neurogenic mechanisms.

Precocious puberty may be related to ovarian tumor.

<< 49 >>
Evaluation:
-History

-Physical examination
-Laboratory
-CBC, Lactate dehydrogenase(LDH), uric acid, calcium
-Tumor markers: AFP(germ cell tumors, hepatoblastoma, hepatocellular carcinoma), bHCG(germ
cell tumors and also pregnancy), urinary cathecolamines(neuroblastoma)
-Imaging
-Ultrasound

-CT abdomen/pelvis
Hoca slaytta ilk dört sene içinde neuroblastoma ve wilms tumor’e dikkat çekti diğerlerini sadece
okudu.
Adrenal tumors of childhood:
Neuroblastoma(>90%):
The most common solid abdominal tumor.

Sympathetic chain originated and also 50% are adrenal in origin.

8% of all childhood cancers.
Yine neuroblastoma üzerinde durup diğerlerini sadece söyleyip geçti.
Neuroblastoma developing points.
Patients with neuroblastoma:

Horner-Wright rosettes in bone marrow is an important finding of neuroblastoma. When

accompanied with adrenal mass, elevated urinary vanillylmandelic acid and elevated neuron
specific enolase diagnosis is neuroblastoma.
Therapy:

<< 50 >>
Therapy is about progression of tumor. For low risk groups and early stage cancers overall survival
rate is >90% whereas for high risk groups and late stage cancers it decreases about 30-40%.
Low risk:
-Surgery

-Observation
-Chemotherapy(similar to intermediate risk) for symptoms. Symptoms are spinal cord
compromise, respiratory compromise, obstruction
Intermediate risk:
-Surgery
-Chemotherapy

High risk:
-Surgery
-Intensive chemotherapy
-Radiation therapy(higher dose to gross residual disease)
-Stem cell transplantation(Tandem transplant)

-Retinoic acid
-Immunotherapy
Renal tumors of childhood:
Wilms tumor(most seen renal tumor and 2nd most common abdominal tumor)
Clear cell carcoma of kidney, malignant rhabdoid tumor of kidney, renal cell carcinoma,
mesoblastic nephroma.
Bilateral wilms tumor. When bilateral wilms
tumor’s stage is 5.

Hepatoblastoma:
Most important liver tumor for children that whose age is about 1 or 2 years.

<< 51 >>
Sacrococcygeal teratoma:
Very important tumor in neonate. Surgery required.

1 day old neonate with sacrococcygeal teratoma.

ÇIKMIŞLAR

1-) Which of the following is the most important cause of abdominal masses in the
newborn?
Congenital genitourinary anomalies
2-) Çocukluk çağının en sık görülen ekstrakranyel solid tümörü aşağıdakilerden
hangisidir?
C) Nöroblastom
3-) Aşağıdakilerden hangisi yenidoğan döneminde batın kitlelerinin en önemli
nedenidir?
C) Konjenital genitoüriner anomaliler

<< 52 >>
APPROACH TO PLATELET DISORDERS-İPEK HİNDİLERDEN-02.11.2020-ARDA ÇAPAR

Hoca full slayt okudu.

Thrombocyte disorders

1.Quantitative defects

Decreased – Thrombocytopenia

Increased – Thrombocytosis

2.Qualitative Defects (Functional disorders)

Platelet adhesion defects

Defects of platelet granule secretion

Defects of platelet aggregation

Thrombocytes: Formed in bone marrow,their progenitor is megakaryocytes.

Disc shaped,don’t have nucleus,have blue grey cytoplasm with red lysosomal granules.

Normal count in blood is → 150.000-400.000 mm3

1/3 in spleen,2/3 in circulation.Life span is 9-10 days.

Megakaryocytes= Giant cells with multilobed nuclei,Produce platelets by budding.

Thrombopoiesis

Thrombopoetin(TPO) is the main regulator.Secreted from the liver.

Thrombocytes bind the circulating TPO.

In thrombocytopenia – unbound TPO binds megakaryocytes → Production is stimulated.

In thrombocytosis – TPO is bound by thrombocytes.There is no TPO left to bind for megakaryocytes.

→ Production is inhibited.

Thrombocytopenia

Less than 150.000 mm3.

Severe= 20.000 mm3

Moderate= 20.000-70.000 mm3

Mild = >70.000 mm3

Thrombocytopenia = Primary hemostasis

• Petechia
• Cutaneous purpura,ecchymosis
• Gingival bleeding
• Menorrhagia

<< 53 >>
 • Epistaxis (Nosebleeding)
• GIS Bleeding and hematuria
• Intracranial hemorrhage → Most serious but uncommon.

Causes

1. Decreased production

Megakaryocytes may be absent or decreased.

Maturation defects.Normal megakaryocytes

In both,life span is normal.

a.Bone marrow hypoplasia,causes

• Aplastic anemia
• Cytotoxic drugs,chemical agents,radiation,infection
• Which drugs? → Estrogen,Thiazides,Interferon,Chlorpropamide

b.Infiltrating bone marrow,causes

• Leukemia,lymphoma,miyelofibrosis,multiple myeloma,cancer metastasis

c.Infective thrombopoiesis,causes

• Vit B12,folic acid def.,PNH(paroxysmal nocturnal hem),MDS(myelodysplastic)

Causes of congenital thrombocytopenia

• Congenital aplastic anemia/Fanconi’s

• Congenital amegakaryocytic tpenia.
• Absent Radius syndrome

o
• Wiskott-Aldrich syn.(Microthrombocytes)(In Bernard-Soulier,it is macro.)
• May-hegglin anomaly and related disorders (May be congenital or acquired
due to Myelodysplastic syndrome)
o Leukocyte inclusions
o Giant platelets
o MYH-9 mutation
• Gray thrombocyte syn.
2. Increased destruction

Life span is shortened.Megakaryocytes are normal

a.Immune mediated destruction

Mediated by autoimmune antibodies: Idiopathic thrombocytopenic

purpura,SLE,Lymphoproliferative dis.,hyperthyroidism

<< 54 >>
 Mediated by alloimmune antibodies: Neonatal purpura,posttransfusion purpura

Mediated by immune complexes:

• Drug mediated: Acetaminophen,aspirin,quinine,gold,heparin

• Infection: Streptococci,EBV,HCV,Measles

b.Non-immunological

• Disseminated intravascular coag.

• Thrombotic thrombocytopenic purpura,hemolytic uremic syn.
• Prostethic heart valves,infections(gram neg. Septicemia)

Pregnancy and thrombocytopenia

Gestational(Physiological) Thrombocytopenia: At 2nd trimester,count may be decreased to

70.000/mm3.

It’s frequency is %5.At any time period during pregnancy,requires investigation.

3. Increased sequestration of platelets in spleen

a.Caused by pooling in spleen

Normally,1/3 is in spleen.In presence of splenomegaly %90 gets in spleen.

During hypothermic anesthesia,pools in spleen and liver.Transient tpenia.

b.Hemangioma (Kasabach-Merrit syn)

4.Loss of thrombocytes

• Massive bleeding
• Open heart surgery
• Massive transfusion and fluid resuscitation may cause dilutional tpenia.

Idiopathic Thrombocytopenic Purpura(Immune)

Isolated thrombocytopenia

Most of them is primary.Secondary develops in SLE,APS,HIV,CVID,CLL…..

Pathogenesis: Platelet reactive autoantibodies is present.Antibody coated platelets are

cleared by macrophages.Life span is shortened.

• Prevalence is: 1-10/10.000

• More common in males during childhood.
• More common in women childbearing.
• After postmenopausal,prevalence is lower in females.

Symptoms: Purpura,mucosal gingival GIS bleedings,epistaxis,hematuria,rarely cerebral

bleeding.

Diagnostic approach: It is diagnosis of exclusion.

• Rule out pseudothrombocytopenia and TTP.

• Ask for drugs.

<< 55 >>
 • Rule out underlying systemic disease.(Liver,thyroid,infection,pregnancy)
• Rule out hematological or rheumatological disease.(SLE,CLL,lymphoma)

Physical exam and lab tests: SMG and LAP are NOT expected findings.

• CBC is normal except for thrombocytopenia.

• B12/Folate normal.
• Coag. Tests normal
• HIV,hepatitis serology,TSH
• Bone marrow examination in over 60.

Treatment: May Show spontaneous remission with recovery of thrombocytes counts.

Over 30.000/mm3 or no bleeding patients dont need treatment.

1st line treatment: Prednisolone 1-2 mg/kg/day

If life threatening bleeding,IVIG 1gr/kg/day may be added.

Follow up: After 3 weeks of prednisolone,it is slowly tapered.

1/3 of patients remission with steroids,2/3 relapse or do not respond

Splenectomy,Anti CD20 (rituximab),TPO mimetics

Heparin induced thrombocytopenia

• Should be considered in heparin using patient.

• Heparin binds PF4 on thrombocyte surface.
• When there are autoantibodies against PF4-heparin complex on thrombocytes.
• There are both thrombosis and thrombocytopenia.
• Develops 5-15 days after exposure.
• Less than 100.000mm3.Rarely less than 20.000/mm3
• Typical finding-Decreases to 1/3 to ½ of the inital count.
• X30-50 increased risk of thrombosis.
• HIT antibodies demonstrated by functional and immunological assays.

Treatment is stop heparin,start anticoag. Which dont bind

PF4(Lepirudin,argatroban,fondaparinux)

Thrombotic thrombocytopenic purpura

• Rare,clotting in small blood vessels.

• Defined by a pentad →microangiopathic hemolytic anemia,tpenic
purpura,neurological problems,fever and renal disease.

Pathogenesis: ADAMTS13 is inhibited.vWF are not cleared in circulation.

• Thrombosis and thrombocytopenia develops.

• Thrombosis causes microvascular stenosis and damage.
• High shear stress → Microangiopathic hem. anemia,a hallmark of TTP.In
presence of m.a.pathic hem. anemia,TTP should be ruled out.

<< 56 >>
 Microangiopathic hemolytic anemia is defined as D.Coombs negative hemolytic anemia
and presence of schistiocytes in peripheral blood.

Qualitative defects of thrombocyte function(functional disorders)

1.Congenital

a.Abnormalities of the platelet receptors for adhesive proteins

Bernard Soulier: Thrombocytopenia + Giant thrombocytes

o GpIb def.
o Autosomal recessive.Carriers asymptomatic.

Diagnosis:

o Thrombocyte aggregation test-Defective aggregation with

ristocetin.
o Flow cytometry-No expression of CD42

Glanzmann thrombastenia:

• GpIIb/IIIa def.

Diagnosis:

• Peripheral smear-No thrombocyte aggregates

• Bleeding time prolonged
• Thrombocyte aggregation test-Defective agg. With other
agonists except ristocetin.
• Flow cytometry-No expression of CD41 and CD61.

b.Abnormal platelet secretion (Common,inherited)

Primary secretion defect

c.Acquired defects

1.Systemic diseases: Uremia,MPS,plasma cell dyscrasia(MM,Waldenström

macroglobulinemia),liver disease,Vit C deficiency.

2.Drug mediated: Aspirin,antiinflammatory

drugs,dipiridamol,penicillins,antihistaminics,anesthetics,tricyclic antidepressants

Therapy of platelet function disorders

• PLT Transfusion
• Antifibrinolytic agents(e.g tranexamic acid)

<< 57 >>
 • Recombinant factor VIIa
• Desmopressin(stimulates vWF secretion from endothelium)

Risk of hemorrhage

>100.000 → No risk.

50.000-100.000 → No risk.May have bleeding with major trauma or surgery.

20.000-50.000 → May have minor spontaneous bleeding,major bleeding is uncommon.

10.000-20.000 → Minor bleeding likely,some risk of major.

Less than 5.000-10.000 → Significant risk of severe bleeding.

Recommendation of safe platelet counts in adults

If there is thrombocytopenia,pseudothrombocytopenia must be ruled out.

Clumping.

Satellitism.Platelets adhering to neutrophil.

<< 58 >>
Thrombocytosis: >450.000/mm3

1.Clonal

Myeloproliferative diseases(ET,PV,CML,PMF)

2.Familial

3.Reactive: Surgery,trauma,systemic inf disease,Hodgkin,iron def anemia,some

drugs(vincristin,epinephrine,ATRA,GFs)

<< 59 >>
 AŞI ENTEGRE OTURUMU I/ 02.11.2020 09.00 Dersi

Özet:Gizem Bayram

KORUYUCU TIP MODÜLÜ

Ders gonca hocanın anlatımıyla başladı

Modülün sonunda akılda neler kalmalı?

- Kızamığın ağır bir enfeksiyon hastalığı olduğu ve sspe ‘nin ağır bir komplikasyon olduğu
- Kızamık aşısının kızamık için koruyucu olduğu
- Sağlık uygulamalarında olasılıklar üzerinden hareket edilir.
- Veri toplamak ve bunların kaydı önemlidir.

KIZAMIK
Birçok hayat kaybına yol açan viral enfeksiyon.
Kızamık virüsü solunum yoluyla bulaşır , ateş-döküntü ile seyreder.
Beraberinde öksürük , burun akıntısı , halsizlik görülebilir
Kuluçka dönemi 7-18 gündür
Hastalık döküntülerin çıkmasından 14 gün sonra sona erer.
KIZAMIK EPİDEMİYOLOJİSİ
-TEK KONAK İNSAN
-kolay bulaş, döküntü öncesi ve sonrası 4er gün bulaşıcı
-endemik bulaşın önlenmesi için toplumun yüzde 95inin bağışık olması gerekir

KIZAMIK İÇİN KLİNİK TANIMLAMA:

- 38den yüksek ateş
- Makülopapüler döküntü
- Öksürük veya burun akıntısı veya konjuktivit
KIZAMIK TANISI İÇİN GEREKLİ LAB TANISI:
-kızamığa özgü ıgM
-kızamık virüs izolasyonu
-kızamık viral rna saptanması
-kızamığa özgü ıgG titresinde artış

<< 60 >>
Koplik lekesi(patognomik)

KIZAMIK ENFEKSİYONU

✓ İmmun sistemi hem baskılar hem aktive eder

✓ Hastalıktan sonra oluşan bağışıklık ömür boyudur
✓ Genelde kendiliğinden düzelir
✓ Komplikasyonlar küçük yaşta ve malnutrisyon olanlarda daha fazla

KIZAMIK ENFEKSİYONUNDA KOMPLİKASYONLAR

Orta kulak iltihabı(%7-9) ) *** EN SIK
viral pnömoni(%1-6)
ishal(%8)
ölüm
postenfeksiyöz ensefalit
SSPE
diğer (trombositopeni, glomerulonefrit, perikardit, miyokardit, Stevens Johnson, özellikle A
vitamini eksikliğinin olduğu ülkelerde)

KIZAMIK
Spesifik bir tedavi yok. TEK KORUNMA YOLU İSE AŞI.
Aşılama sonrası gelişen bağışıklık genel olarak yaşam boyu devam eder.

Primer aşı başarısızlığı: Aşılananların %5-10’unda hiç aşı yanıtı gelişmez

Sekonder aşı başarısızlığı: Aşılananların %5’inde bağışıklık 10-15 yıl sonra kaybolabilir.

KIZAMIK AŞISI:
✓ Canlı zayıflatılmış aşı (civciv embriyo fibroblastlarından üretim)
✓ aşıdan 6-10 gün sonra ateş ve döküntüler görülebilir
✓ Bağışıklığı baskılanmış kişilere yapılmaz
✓ Toz halde (liyofilize), sulandırıldıktan sonra hemen uygulanmalı
✓ Işığa,ısıya duyarlı
✓ iyi saklanmalı
✓ Subkutan enjeksiyon ile uygulanır
✓ Aşı sonrası oluşan bağışıklık, doğal enfeksiyondakine benzer .
✓ Aşılı kişiler doğal enfeksiyon ile karşılaşmadıklarında aşıya bağlı immunite azalır.
✓ En iyi immünolojik yanıt maternal antikorlardır. kaybolduktan sonra gelişir.

<< 61 >>
 ✓ En önemli komplikasyon nadiren gelişen anafilaksidir. Aşıya bağlı SSPE
gelişmez.**Ama aşı başarısız olursa kızamık gelişebilir bunun ardından SSPE
komplikasyonu görülebilir.
✓ 2 doz aşılama önerilir. Ülkemizde ilki 12.ayda(anneden geçen antikorlar en aza
indiği zaman), ikincisi 4-6 yaşları arasında yapılır. İkinci dozun uygulanmasındaki
amaç, hem hiç aşılanmayanları hem de primer aşı yanıtsızlığı olanları bağışık hale
getirmektir.

Salgın zamanında ilk aşılama tarihi geri çekilir(6-12. ay).

✓ Toplumda hassas kişiler aşılanır
✓ Aşılanamayacaklar döküntüden 2 hafta sonrasına kadar toplu yerlere girişi önler.

Kızamığa Karşı Mücadele Stratejileri

Global Stratejik Plan 2012-2020
1. Yüksek oranda 2 doz aşılama ile toplumsal bağışıklığın artırılması ve sürekliliğin
sağlanması
2. Etkin sürveyans sistemi ile hastalığın izlenmesi ve bu konuda çabaların değerlendirilmesi
3. Salgınlara karşı hazırlıklı olmak, salgın anlarında hızlı yanıt ve vakalara doğru
yaklaşımda bulunmak
4. Aşılama konusunda toplum ile iletişimde olmak ve güven sağlamak
5. Aşılamayı ve tanı yöntemlerini geliştirmek için araştırmaları ve etkin yöntemleri
Desteklemek

SUBAKUT SKLEROZAN PANENSEFALİT- PINAR TOPALOĞLU

✓ Kızamık virüs enfeksiyonuna sekonder oluşur.

✓ 9 aydan daha kısa sürer--subakut
Patolojik lezyon--sklerozan
Tüm beyni etkiler—panensefalit
✓ Santral sinir sistem demiyelinizasyonu
✓ Kızamığın Çeşitli Nörolojik Komplikasyonları
Post-measles ensefaliti: Enfeksiyondan hemen sonra oluşan bir hastalıktır.
Measles inklüzyon cisimciği ensefaliti

SSPE***

Postenfeksiyöz akut immün reaksiyonlar

Transvers Miyelit→sadece myelin cord etkilenir.

PATOLOJİ:

✓ Hastalık seyrine göre değişken

✓ Akut dönemde oligodentrosit ve nöronda nukleokapsitler ve astrositte granülomatöz
inklüzyonlu nükleer cisim**
✓ Dna ve ribonükleik asit oksidatif hasarı
✓ İnflamatuar değişiklik beynin arka tarafında sık
✓ Serebellum korunmuş
✓ Medial talamusta belirgin

<< 62 >>
 ✓ Sıgnaling lymphocytic activation molecule (SLAM)→nöronda yok
✓ İntraserebral yayılım;

Olfaktör bulbus

Viral partiküllerin

beyin parankimine geçişi

KBByi geçerler

✓ CD4-CD8 hücreleri
Genetik yatkınlık
Her hasta SSPE olmaz. Bu iki faktör önemli*

SSPE VE KIZAMIK VİRÜS FARKI

✓ Parankim girişi sonrası mutasyon
✓ %2 nükleotid mutasyonu
✓ %35 aa değişikliği
✓ M prot değişikliği
✓ Nötralizan antikor oluşumu engellenir

SSPE Klinik Bulguları

✓ Başlangıç yaşı genellikle 8-11 yaş ( sinsi )

✓ Kızamık geçirdikten yaklaşık 6 yıl sonra ortaya çıkar.
✓ Okul başarısında düşme
✓ Progresif entelektüel kötüleşme
✓ Kişilik ve davranış değişiklikleri (ilk klinik belirti**)
✓ Takiben kalıcı motor kötüleşme; miyokloni (ani sıçramalar ya da boşluğa düşer tarzda olabilir),
fokal paralizi, nöbet
✓ Sonunda motor kötüleşme ciddi ilerleyerek akinetik mutizm görülür. Hasta bakıma muhtaçtır.

SSPE Klinik Evreleri

1.Evre 1: Kişilik değişikliği, okul başarısında düşme, garip davranışlar

2.Evre 2: Miyoklonik ataklar (Bu ataklar yoğun olabilir; fark edilmesi güç, silik miyokloniler de
görülebilir), nöbet, demans

3. Evre 3: Hareket bozuklukları, rijidite, ekstrapiramidal semptomlar, parkinson tipi bulgular,

ilerleyici cevapsızlık

4.Evre 4: Koma, vejetatif durum, otonomik bozukluk ve akinetik mutizm

- atipik prezentasyon hastaların %10’unda

<< 63 >>
-Bazılarında önce motor komplikasyon

-evre 1 ve 2 ayırt edilemez

SSPE’DE OFTALMOLOJİK BULGULAR

✓ Koroid ve retina
✓ Optik sinir
✓ Korteks

TANI KRİTERLERİ

Major Kriterler

1. BOS’da artmış kızamık antikor titresi

2. Klinik öykü

Minör Kriterler

1. EEG bulguları

2. Artmış BOS IgG****

3. Beyin biyopsi bulguları

4. Özel testler

Tanı koymak için 2 major+1 minör kriter yeterlidir.

DYKEN KRİTERLERİ (3/5)

✓ Klinik olarak; progresif, miyokloni gibi tipik bulguların olduğu subakut mental bir kötüleşme
✓ EEG’de; periyodik, stereotipik, yüksek voltajlı deşarjlar
✓ BOSda artmış gamaglobülin ya da oligoklonal bant
✓ Serumda artmış kızamık antikor titresi
✓ Beyin biyopsisinde panensefalit bulguları

EEG –periodk kompleks

İleri dönemde kaybolabilr (yani olmaması tanı olmadığı anlamına gelmiyor)**

Uykuda veya erken dönemde

Tetiklenebilir

Nedeni nöronal deşarjlar

<< 64 >>
MRI:

Tanıda daha az yardımcı

Progresyon takibi için

Klinik evreyle uyumsuz

Değişiklik hastalık süresine bağlı

Orta evre→periventriküler ak maddede

İleri evre→daha derin yapılar

Ayırıcı Tanı:

Hızlı seyirli demans

Miyokloni

Nöbetler.

Tedavi

İzoprinozin, interferon alfa ve beta, intravenöz immunoglobin gibi birçok şey denenmiş.

şu ana kadar bulunmuş kesin bir tedavisi yok.

İzoprinozin hala kullanılıyor. Ama sadece prognozu

Yavaşlatır.

Ifnler çok az kullanılır.

Prognoz:%95 fatal

ÖNLEMEK İÇİN Tek yol aşı***

SSPE EPİDEMİYOLOJİSİ- EMEL ÖNAL

✓ Kızamık aşısı rutin aşı programında var

✓ 12. Ayda ve 1. Sınıfta yapılır
✓ Hedef grubun %95i aşılanmalı
✓ Eliminasyon=hastalığı ortadan kaldırmak
Eradikasyon=virüsü ortada kaldırmak
✓ ---Ülkemizde 2002 yılında Kızamık Eliminasyonu Programı başlatıldı. Bu programdaki
hedefler; 2015 yılı sonuna kadar Türkiye’de yerli virüs girişini durdurmak, 2015 yılından
sonra Türkiye dışından gelecek yeni kızamık virüslerinin Türkiye’de yerleşmesini ve ölümleri
engellemek.
İmporte vaka=dışarıdan gelen
✓ 2009da vaka sayısı 4→3 importe
✓ Sıcak vaka***
Kesin vaka ile temas öyküsü olanlar

<< 65 >>
 Döküntünün başlamasından önceki 3 hafta içerisinde seyahat öyküsü olanlar
Aşısızlar
Yaşına göre eksik aşılı olanlar
Kümelenme gösteren olası kızamık/kızamıkçık vaka tanımına uyanlar
Vaka, Sıcak vaka ise serum, idrar ve boğaz sürüntüsü alınmalı ve numune nakli
24 saat içerisinde gerçekleştirilmeli.****
***Şüpheli ya da Olası Vaka ile Karşılaşıldığında;
Vakanın sıcak vaka olup olmadığını değerlendirdikten sonra TSM’yi bilgilendirmeliyiz. Vaka
Bildirim ve Laboratuar Formlarını eksiksiz doldurmalı-kan, boğaz sürüntüsü ve idrar
örneklerini alıp 24 saat içinde TSM’ye göndermeliyiz.
✓ SSpe de kriter: EEG bulguları ve bosta yüksek ıgG
✓ Kızamık aşısı koruyucudur Ve SSpe en çok kızamık geçirme ile alakalıdır
✓ SSPE kızamıktan yaklaşık 7 yıl sonra; ort 9 yaşında ;erkekte daha sık

1. Kızamık aşı uygulaması sonucu aşağıdakilerden hangisi hedeflenir?

I)Aşılanan kişiyi komplikasyonlardan korumak
II)kızamık enfeksiyonuna karşı toplumsal bağışıklığı arttırmak
III)kızamığa bağlı ölümleri engellemek
IV)aşı uygulanması mümkün olmayan ****korunmasını sağlamak
Hepsi

2.SSPE için hangisi doğrudur?

1)sspe kızamık sonrası gelişen akut hastalık
2)sspe de baskılanmış mmün yanıt nedeniyleortadan kaldırılamama
3)bos da anti kızamık antikor pozitifliği sspe nin tanı kriterleri arasındadır
4)sspe aşı ile önlenebilir.
2,3,4

3.aşağıakilerden hangisi kızamık epidemiyolojisi için doğrudur?

I)tek konak insandır
II)infeksiyon sırasında immun sistem baskılanabilir.
III)infeksiyon sırasından immun sistem uyarılabilir
IV)epidemiler toplumdaki duyarlı kişi sayısına bağlıdır

I.II.III.IV

İYİ ÇALIŞMALAR.

<< 66 >>
ENTERGRE OTURUM 2.kısım ( arkadaşlar word de olan sıkıntılardan dolayı yazım kurallarını otomatik
denetleyen sistem devre dışı kaldı daha sonra düzeltilmiş halini atacağım )

2.11.2020

Kızamık aşısı olanlarda sspe saptanmadı. Kızamık aşısı SSPE ye karşı korur

Yüzde 87 aşılanma oranı buda Istanbul oranı TC ortalaması altında. 2012 de ortalama yüzde 97 ye çıkmış .
Yüzde 95 korunduğu zaman kalan yüzde 5 de korunur.

Sonuçlar

Karadenizde epilepsi hik SSPE fazla görülmesi (genle ilgili)

Akraba evliliği ile beraber görülmesi az sayıda var

Doğumsal anormali

En önemli sonuç kızamık ile ilişkili

Yurtdışında aşı yapılınca azalma örnekleri var ABD de örneği var

Türkideyeden başka bir çalışmada yaş ortalaması oldukça erkendi latent kısaydı

2005 yılından itibaren SSPE Sağlık bakanlığına bildirilmesi zounlu bir hastalık haline geldi( C grubu bildirimi
zorunlu hastalaık)

Bildirim formu var ( gösterdi )

Dünyadaki örneklere bakarsak örnek Papau Yeni Ginede aşı yok sspe fazla

2012 de peak var ( Kızamık ve SSPE paralel peak yapmış )

Japanyoda bir çalışmaya bakalım

Yine erkeklerde fazla. ( 16 ya 6)

2 YAŞTAN önce geçirilen kızamık risk faktörüdür

Hindistanda

Erkeklerin 4 kat fazla hasta olduğu

Ortalama yaz 13.3 biraz yüksek

Latent periyot uzun 7.8 yıl

72 vakadan 8 i aşı olmuş

Başka bir çalışmada ( bunu slayttan bak )

Perinatal dönemde geçirilen kızamık hastalığı sspe yapar

Anneden SSPE OLARAK doğan çocuk saptanmamış ama normalde geçer

Aşı sspe yapmaz

İngilterede bir çalışmada aşı insidansı artınca SSPE nin azaldığı görülmüş ( Amerika İrlanda israil ….de de
benzer çalışmalar yapılmış )

<< 67 >>
Türkiyede kapsayıcılıkta düşüş inişler var

Benzer grafik japonyada da var

Prognoz

SSPE nin sadece yüzde 5 I spontan iyileşme gösterir

Yüzde 95 I de tanıdan snra 5 yıl sonra

Kızamık immunoglöbünü ( aşısı ) yoksa kızamık virüsü ile temastan hemen sonra yapılmalı

YENİ HOCA

SUBAKUT SKLEROZAN PANENSEFALİT HASTALIRNDA İMMÜN YANIT

Hoca bantlar gösterdi ( IGG antikor varlığına bakıyormuşuz )

Hastalık mekanizması açıklanamamıştır!

• KV, T ve B hücreleri gibi immün sistemin efektör hücrelerini mi etkiler?

• Monosit, makrofaj, DH gibi hücrelerin fonksiyonlarını mı değiştirir?

• Antijen sunumu

• İL-12 salgısı

Yukarıdakiler bilinmeyen konular

SSPE

Nadir görülen, persistan bir yavaş virüs infeksiyonu

Etkeni kızamık virüsüdür (KV)

Aktivasyon tetikleyicisi ve persistan mekanizması bilinmiyor.

OKB pozitifliği vardır.

Mekanizma açıklanamamıştır.

SSPE Gelişiminde Olası Mekanizmalar

* Virüsle ilgili faktörler::

Mutant suş ( M geni-matriks geni) : Virüs tomurcuklanmasında görevli

Mutant Protein ( M proteiniF: Füzyon H proteini): Virüsün hücreye yapışıp hücreye girmesini sağlar.

* Konakla ilgili faktörler:

Çalışmalar bu yönde

Kızamık geçirme yaşı (2 yaşında küçük etkili)

Tam gelişmemiş immün sistem (yeterli düzeyde antikor yanıtı ve hücresel immün yanıt oluşturmamıştır.

<< 68 >>
 Genetik yatkınlık

Kızamıkta İnmünosupresyon

Lenfositlerde PPD ve mitojenlere in vitro proliferatif yanıt baskılanır.

• Erken aşama Th1 yanıtı

• Geç aşama Th2 yanıtı

• İn vivo gecikmiş tip aşırı duyarlılık deri testlerine (DTH) yanıt azalmıştır.

• Hücresel immünitenin hümoral immüniteye göre daha önemli olduğu

düşünülmüştür çünkü Konjenital agamaglobulinemik çocuklar kızamık sonrası iyileşirken, hücresel immün
sisteminde bozukluk olan çocuklarda iyileşme gözlenmez. İmmün sistemin baskılandığı gösterilen ilk
hastalıktır.

SSPE’de Hücresel İmmün Yanıt

Kızamıktaki baskılanmış immün yanıt SSPE’de de görülüyor mu? Evet

• MSS harabiyetine yol açan mekanizmalarda immün yanıtının rolü?

• Yandaş bir T hücre yanıtı ve sitokinler MSS’deki hasarda etkili mi?

Genetik Yatkınlık İşaretleri

IL-2

IL-12

MxA

TLRA-2 poliformizmi

GRANZİM B :monositi apoptoza getirir bu vücudun kendini korumaya almasıdır. Granzim A da da hastalıga
yatkınlık var.

SSPE’de Sitokin ve KemokinYanıtı

IL-12 p-40 salgısı BOS ve serumda artar

IL-10 Bosta artar

CXCL 10 T hücre çağırıcısıdır. .BOS ta artar.

CXCL8 nötrofil çağırıcısıdır.BOS ta azalır.

SSPE’de Spontan İmmün Yanıt

Periferik ve sitokin yanıtlarnna baktık: Sponton proliferatif yanıt baskılanmış IL-10 salgısı yüksek, yani
düzenleyici sitokin yüksek bulunmuş.

SSPE’de Antijene Özgül Yanıt

<< 69 >>
• KV aşısı (antijene özgül yanıt)

• SSPE hastalarında İL-12 salgısı ↓

SSPE’de MSS Antijenlerine Yanıt

SSPE hastalarında İL-12 salgısı MBPY yanıtı düşük bulunmasına rağmen bu fark anlamlılığa ulaşmadı MSS nin
SSPE de otoimmün bir yanıtın bir hedefi olmadığına işaret etmektedir.

SSPE’de Yandaş T Hücre Yanıtı

Bellek antijeni (PPD)

• Proliferatif yanıt SSPE’de ↓ PPD karşı karşı proliferatif yanıt SSPE tekliflerinde daha düşük

• İL-12, İL-10 ve İFN-g salgısı ↓ PPD uyarısıyla İL-12, İL-10 ve İFN-g salgisında SSPE de azalma

SSPE Hastalarında Hücre Fenotipleri

CD3+ de azalma var

, CD4+ CD8+ belirgin fark yok

NK hücre hafif artar

IL 10 salgısını yüksek bulmuştuk , bunun alt hücrelerini inceledik

Düzenleyici t hücrelerinin yetersizliğini gördük

Treg hücreleri azalır

CD8+ T Hücrelerinde NKG2A ve NKG2C Ekspresyonu

başka neler olabilir diye aktivatör etkili moleküllere baktik.

Antiviral immün yanıtta CD8T ve NK hücrelerinde NKG2A ve NKGZC ekspresyonu önemli NKG2A:
İnhibitör etki NKG2C: aktifleyici etki SSPE de CD8 + NKG2A azalmış, CD8 + NKG2C fark yok

T Hücre Yorgunluğu (CD8+PD1+

Immune yanıtta baskılanma görülüyor

SSPE’de Th1/Th2 Yönlenmesi

• Kızamıkta

− Baskılanmış Th1 yanıtı

− Th2 yönünde yanıt

Sspe de

Th1 yine baskılanıyır

CCR4 TH2 markeri immatür tipteki hafıza hücrelerini gösterir ve hafifçe yükselir

KV RESEPTÖRLERİ

• SLAM (CD150): Yabanıl KV suşlarının öncelikli reseptörüdür.

<< 70 >>
• CD46 (MCP): CD46’yı hücreye giriş için kullanan KV suşları sınırlıdır.

• Daha çok aşı suşları

• İn vitro koşullar

• Nektin-4: Hücre-hücre yapışmasında görevli bir adezyon molekülü.

• Solunum yolu mukozasında epitel hücrelerinde bulunur.

• Ayrıca:

• DC-SIGN (CD209)

• Langerin

• TLR-2

• FcgRII (CD32)

Değerlendirme
• SSPE’de bozulmuş immün yanıt.
• Th1 yanıtında baskılanma.
• Myelin antijenlerine karşı immün yanıt gelişmiyor.
• MSS otoimmün bir yanıtın hedefi değil.
• Sitokin ve GrB polimorfizmlerinin etkisi.
• İL-10 salgısında artış.
• Düzenleyici T hücrelerinde azalma.
• NK hücrelerinde aktivasyon molekülü artmış.
• CD8+ T hücrelerde inhibitör sinyalin azalması. Anerji?
• Antijen spesifik yanıt var.
• Yetersiz immün yanıt, virüs yok edilemiyor.

Yeni Bulgular (Kasım 2019)

• Aşılanmamış çocuklar kızamık infeksiyonu öncesi ve sonrası incelenmiş.

• KV ve diğer patojenlere karşı gelişen antikor yanıtı baskılanmış.

• Hafıza B hücre popülasyonu azalmış.

• Kızamık infeksiyonundan sonra tüm aşılar tekrarlanmalıdır!!!

− Petrova VN et al, Sci Immunol. 2019 Nov 1;4(41).

− Mina MJ et. al. , Science. 2019 Nov 1;366(6465):599-606.

Yeni hoca

Aşı Uygulamalarının Amacı:

Kişiyi ciddi yan etkileri ve ölüm riskli olan hastalıklardan korumak

Genel aşılanma oranlarını yükselterek toplumda bulaşıcı hastalık salgınlarını toplumsal uygulama (sürü
bağışıklığı) kişilere aşılanmaları olanaksız kişileri korumak

<< 71 >>
Ölümcül hastalıkların kökünü kazımak

Aşı ile Yaratılan Bağlanan:

1. Bireysel Bağ
Bazı aşılar renfeksiyon gelişimini önleyebilir. > kızamık aşısı
Bazı aşılar hastalığın gelişimini önleyebilir ama enfeksiyon gelişimini önleyemez. rota aşısı

Aşıların koruyuculuğu hiçbir zaman %100 olamaz. Aşılanan kişi bazı koşullarda kızamık geçirebilir.
(immünolojik özelliğini yitimiş aşılar, uygun yapılmamış aşılar, aşi uygulamasI sırasında maternal antikorların
kanda bulunması, bir yaşından sonra tek doz aşı uygulanması, toplumsal bağışıklığın düşük olması gibi
durumlar

2. Toplumsal Bağışıklık
Aşı yolu ile toplumda o hastalığa karşı bağışık kişilerin artması sonucu hastalığın sıklığının azalması ve
böylece aşılanamayan hassas kişilerin korunmasidır
. Toplumsal bağışıklık= Koruyuculuk(seropozitivite) oranı x Toplumun aşılanma oranı
Toplumsal bağışıklık eşik değeri: Salgin gelişmemesi için gereken aşılanma oranıdır. Kızamık
bulaşıcılığı yüksek olduğundan toplumsal eşik değeri de yüksektir.
Bir aşı enfeksiyonu önleyemiyorsa toplumsal bağışıklık yaratamaz. kızamik aşıs toplumsal bağışıklık
yaratabilir, rota aşısı yaratamaz

Kızamığa Karşı Mücadele Stratejileri Global Stratejik Plan 2012-2020

1. Yüksek oranda 2 doz aşılama ile toplumsal bağışıklığın artırılması ve sürekliliğin sağlanması 2. Etkin
sürveyans sistemi ile hastalığın izlenmesi ve bu konuda çabaların değerlendirilmesi 3. Salgınlara karşı hazırlıklı
olmak, salgın anlarında hızlı yanıt ve vakalara doğru yaklaşımda bulunmak 4. Aşılama konusunda toplum ile
iletişimde olmak ve güven sağlamak 5. Aşılamayı ve tanı yöntemlerini geliştirmek için araştırmaları ve etkin
yöntemleri desteklemek

ÜLKEMİZDE KIZAMIK SALGINI 2011

Ülkemizde yıllarca yakalama (aşılama) programları uygulanmış, 1970-1998 arası tek doz, 1998 den sonra 2
doz kızamık aşisı ulusal takviminde yer almış. Türkiye bu uğraşlar sonucunda kızamık eliminasyonu aşamasına
gelmişti. Bildirilen olgularda kızamık uzun süre saptanmamıştı. 12.01.2011 tarihinde ilk kızamik bildirimi oldu.
Hasta Avrupa dan gelen bir turistle karşılaşmış olan bir genç yetişkindi. 14.01.2011 de iki erişkin hastaya ait
kan örneğinde kızamik IgM pozitifliği olduğu bildirildi ve bildirimi yapilan vaka sayıları giderek artti.

İSTANBUL DA VE TÜRKIYE DE KIZAMIK SALGINI 2012

Ardından Türkiye nin çok sayıda ilinden kızamık vakaları bildirilmeye başlandı. Bildirilenler arasında yabancı
uyruklu oran yüksek idi (göçler).

KIZAMIK VAKALARI NEDEN ARTTI?

Avrupa 'da gelişen kızamık salgını sonucu Erişkin yaşta aşılama eksikliği nedeniyte

<< 72 >>
ASI YOLU ILE GELISEN TOPLUMSAL BAĞIŞIKLIK VE KIZAMIK

Bir çok Avrupa ülkesinde ve Latin Amerika ülkesinde aşılanma oranları ile yaratılan toplumsal bağışıklik
salgınları önler nitelikte idi. Ancak 2000 li yıllann başında gelişen aşi karşıtı söylemler sonucunda başta
Ingiltere olmak üzere bazı Avrupa ülkelerinde aşılanma oranları düşmüş ve salgınlar yaşanmaya başlanmıştır.

AVRUPA ÜLKELERINDE KIZAMIK 2012 SALGINI

WHO, başta Avrupa ülkeleri olmak üzere bu konuda öntem almalan için çağrıda bulundu.

ASI ILE ÖNLENEBILIR HASTALIKLARDA YAŞANAN SÜREÇ

1. Aşılama öncesi hastalıklar yaygındır. 2. Artan aşılama yaygınlığı ile hastalık insidansı düşer. 3. Aşıya olan
güven kaybı ile salgınlar olur 4. Güvenin yeniden doğması ile hastalıklar tekrar azalır. 5. Eradikasyon sağlanır
ve aşı uygulaması durur.

Hoca bu konu ile ilgili İngiltere de Wakefield ve arkadasları tarafından 12 çocuk üzerinde yürütülen bir
araştırmanın sonuçlarına göre KKK aşı uygulaması ile otizm gelişmesi arasında bir ilişki olabileceği öne
sürülmüş. Bununla ilgili (gerçekligi olmayan) bir çalışma yapıp Lancet' de yayınlamıştır. Araştırma
yayınlandıktan sonra gerçekleri yansıtmadığı için 2010 yılında yayından kaldırılmıştır. v

KKK ile otizm arasında ilişki olmadığını belirleyen ölçütler

Birliktelik nedenselliği göstermez.

Doz arttıkça yan etki gelişme riski artmalı Doku kültürleri ve hayvan modellerinde aşı yan etkisi-etken
ilişkisi gösterilmeli

Toplumda görülme sıklığından daha fazla oranda aşıdan sonra görülmeli

Bir çok farklı çalışmada aynı sonuçlar bulunmalı Kızamık aşılamasının otizmle ilişkili olmadığı sonucuna
vanlmıştır.

<< 73 >>
IMMUNOPHARMACOLOGY AND GROWTH FACTOR
PHARMACOLOGY / ALİ OSMAN GÜROL / 03.11.2020 / 13.00
Furkan Ergün
Arkadaşlar öncelikle herkese merhaba. Hocamız slayta koyduğu bazı yerlerden sınavda
sorumlu olmayacağımızı belirtti. Ancak birer hekim olarak belirttiği şeyleri bilmemizin bizlere
faydalı olacağını söyledi. Ben de elimden geldiğince sınavda soru sorulacak yerlerin ön planda
olduğu aynı zamanda hekimlik yaparken işimize yarayacak yerlerin de eksik olmadığı bir özet
hazırlamaya çalıştım. Aynı zamanda daha iyi anlaşılacağına inandığım için Türkçe
açıklamalarda da bulundum. Umarım faydalı olur.

Immunopharmacology: It is a science that has the ability to alter immune response and
studies pharmacological agents.
Immunosuppressive Drugs: Supresses immune respond(adı üstünde)(organ transplants…)
Immunostimulant Drugs: Stimulates immune respond (AIDS)
(Burdan sonra hoca hızlı bir şekilde immün yanıtı özetledi, sınavda soru gelmeyeceğini
düşündüğüm için eklemiyorum.)

A. IMMUNSUPPRESIVE DRUGS
-Inhibits reactions that occur at organ transplantation. Immunsuppressive drugs also inhibits
bone marrow incompatible transplant (GVHD: Graft Versus Host Disease)
-Also acting on autoimmune diseases to preventing formition of autoantibodies.
(Burdan sonra ilaçların hangi gruplarda olduğunu bilmemiz ÇOKOMELLİ)

a-ANTITUMORAL CHEMOTHERAPEUTICS
1-Cyclophosphamide
-We use cyclophosphamides in most tumor treatments.
-Could be used alone or combination with cyclosporine or corticosteroids.
-Antineoplastic belonging to a group of nitrogen mustards containing cyclophophamide
group.
(Aynı zamanda kanser farmasında da görecekmişiz bunu)

<< 74 >>
Mechanism of Action
(Hoca mekanizmayı anlatırken
ara basamakları bilmemize
gerek yok dedi, sadece 1. ve 5.
basamaktan sorumluyuz
sınavda)
Guanine is alkylated in DNA

There is not DNA replication

-Effects stronger on proliferating cells in S phase

-Effective on T and B lymphocytes (Lenfositlerin ölümüne sebep olur)
-It’s very effective in suppressing antibody responds in SLE

Pharmacokinetic Properties

-It is well absorbed orally.

Clinical Use
Klinikteki kullanım için bazı hastalıkları slayta eklemiş hocamız, şu an işimize yaramayacak
fakat ilerde klinikte işimize yarayacakmış. Merak eden varsa slayttan bakabilir.

Adverse Effects
Because of the cell killing effect against all proliferating tissues, we can see;
-marrow suppression with leukopenia and thrombocytopenia
-increased susceptibility to infections,
-alopecia (halk adıyla saçkıran, lokal saç dökülmeleri görülür),
-germinal gonad damage and infertility.

2-Azathioprine
Antiproliferative on lymphocytes.

<< 75 >>
Mechanism of Action
-Suppressive effect on T and B lymphocytes
6-mercaptopurine (thioinosinic acid),
which is formed in the metabolic -Especially effective on S phase cells
transformation of azathioprine,
incorporates into RNA and DNA -It is potent in inhibiting proliferation of cells in the
molecules and inhibits their synthesis. primary response. (Sekonder yanıtta hafıza hücre-

leri üzerinde etkinliği daha azdır.)

Protein synthesis is also inhibited.

Pharmacokinetic Properties
-It is well absorbed in the gastrointestinal tract.
-It is more metabolized to 6-mercaptopurine.
-It is converted by 6-mercaptopurine xanthine-oxidase into 6-thiouric acid, the inactive
metabolite.
Drugs such as allopurinol, which inhibit xanthineoxidase, may also cause an increase in
azathioprine toxicity.

Clinical Use
-Immunosuppressive treatment of transplanted patients.
-Combination of cyclosporine and prednisone in heart transplantation.
-Forms of RA resistant to other drugs.
-Autoimmune hemolytic anemia.
-Ulcerative colitis, Crohn's disease in combination with corticosteroids.

Adverse Effects
-Leukopenia and trobocytopenia.
-Gastrointestinal and hepatic toxicity
-Nausea and vomiting
-Mutagenic and carcinogenic effects with increased secondary neoplasia in long-term
treatments(Kanser için kullanılan ilacın yan etkisi kanser..)

<< 76 >>
3-Methotrexate
Mechanism of Action
-It inhibits the conversion of dihydrofolic acid to tetrahydrofolic acid as a dihydrofolate-
reductase inhibitor.(Tetrahidrofolik asit: M5,N1 metilentetrahidrofolata dönüşerek timidilat,
pürinler, metionin ve glisin sentezi için esansiyel bir kofaktördür.)(Parantez içindeki kısımdan
sorumlu değiliz)

No formation of tetrahydrofolic acid

thymidylate-synthetase inhibition and

deoxyuridylic acid to thymidilic acid
transformation is also inhibited

DNA and RNA synthesis is interrupted.

Immunodepressive Effect: DNA synthesis inhibition leads to T and B lymphocytes inhibition

of proliferation

Pharmacokinetic Properties
-Rapidly absorbed in the gastrointestinal tract.
-It is given intravenously in high doses.

-Its excretion is mostly through the renal route.

Clinical Use
Immunosuppressive combined with cyclosporinA for GVHD prophylaxis in patients with bone
marrow transplantation.

Adverse Effects
The greatest adverse effects after low-dose and longterm immunosuppressive therapy are
different from those seen in antineoplastic therapy:
-Hepatic and pulmonary fibrosis,

-Cirrhosis,

-Chronic aseptic pneumonia

<< 77 >>
b-SPECIFIC IMMUNOSUPPRESSIVE DRUGS
1-Mycophenolate Mofetil (MFM)
-Prototype of mizoribine, merimepodib (VX497).
-They act by inhibiting the enzyme inosine monophosphate dehydrogenase (IMPDH).

Mechanism of Action
(Yanda sadece
en alttaki
basamak
önemli dedi
hoca, okumak
isteyen olursa
diye hepsini
bıraktım)

-With this mechanism MFM inhibits various lymphocyte functions and proliferation, such as
antibody production and leukocyte migration.

Pharmacokinetic Properties
-It is well absorbed orally.
-Rapidly hydrolyses to mycophenolic acid with a plasma half-life of about 16 hours.
-Mycophenolic acid is metabolized in the liver to the pharmacologically inactive glucuronide
derivative.
-The glucoronide-derived metabolite is released into the bile and re-releases high
concentrations of mycophenolic acid under the influence of bacterial glucoronidases in the
intestine and forms an enterohepatic cycle responsible for the intestinal toxicity of the
drug.(Bu kısım biraz daha hekim olarak bilmemiz gereken bir kısım)

Clinical Use
-MFM is used for kidney transplantation with cyclosporine A (CsA) or prednisolone or
both.(tercihe bağlı ister MFM i tek kullanırız, ister başka birkaç ilaçla kombinleyip
kullanırız)(Japonyada sadece MFM kullanılıyomuş; ABD ve Türkiyede ilaçları kombinliyorlar)

<< 78 >>
Adverse Effects
-Due to its highly selective effect on lymphocytes, the adverse effects of MFM, especially on
bone marrow, are milder compared to cyclophosphamide and azathioprine, and treatment is
rarely discontinued.

2-Mizoribine
MFM analoğu bir ilaç.

3-Brequinar
New drug. Used for 10-15 years.
When it was first found, it was used as an antitumoral agent. Actually, involved in organ
transplantations.

4-Deoxyspergualin
New drug. DSG and its analogue LF15-0195: treatment of systemic vasculitis and prevention
of rejection in kidney, pancreas and heart transplants.

5-Thalidomide
Hamile kadınlarda kullanılırsa çocukta phacomelia görülür.(60 larda dünyada bir çok sakat
doğum oldu)
-Thalidomide is an anxiolytic-hypnotic drug that can be given orally, but if it is taken during
pregnancy, it is not available for this purpose due to its teratogenic effects.
-Very important tumor killer and immunomodulant activity
-The mechanism of action is unknown;
-Suppresses TNF-alpha production
-It has antiproliferative, proapoptotic and antiangiogenic effects.
-Leflunomide ve Lenalidomide, Thalidomide analoglarıdır.

c-Calcineurin Inhibitors
1-Calcineurin (Cn) antagonists
Cyclosporine (CsA) and FK-506 (Tacrolimus)→ The most powerful immunosuppressive drugs
in clinical use.
CsA and FK-506: Selective immunosuppressants with Rapamycin: They inhibit activation and
proliferation by blocking signal transduction of T lymphocytes.

They have same mechanism of action but FK-506 is stronger than CsA.(About 10-100 times)

<< 79 >>
Mechanism of Action
-The immunosuppressive effect of CsA and FK506 primarily depends on inhibition of T
lymphocyte proliferation.
-They blocks the pathway in the transcription regulation of the IL-2 gene.
-IL-2 gene is main cytokine to allow the proliferation of T lymphocytes. (IL-2 üzerinden T
lenfositleri bloklaması önemli)
-Block in transition of G0 to G1
-They interact with immunophilins (cytoplasm proteins).
-CsA interacts with cyclophilins.
-Among these, cyclophilin-A (CyPA) is considered to be the most important receptor for CsA.
-Drug-receptor interaction leads to the formation of a macromolecular complex in which 2
CyPA pentamers overlap. (Bu madde kalın yazılmamış slaytta, fakat derste hoca okudu.)
-Macrolide FK-506 binding FK Binding Protein (FKBP 12, 25, 56-59 kDa….) acts similarly to
CsA.
-The CsA-CyPA or FK506-FKBP12 complex interacts with another cytoplasm protein,
serine/threonine phosphatase (Cn:Calcineurin).
-Cn is a calcium-calmodulin-dependent serine / threonine phosphatase essential for
transduction of the TCR signal. (Burada Calcineurin in fosfataz aktivitesini inhibe ediyoruz.)
(Bu yüzden Cn inhibitörleri olarak adlandırıyoruz bunları)
-With this inhibition;
Inhibition of IL-2 and IL-4 genes
Inhibition of transcription of genes such as TNF-alpha, IL-3, IL-5, IL-6, IL-8, IL-9, IL-10, IL-17,
GM-CSF and IFN-gamma. (Sayıları okumadı hoca, hızlıca üstünden geçti.)
-CsA and FK-506 can inhibit T lymphocyte response and T-dependent B lymphocyte
response.

Pharmacokinetic Properties
CsA and FK-506 may be administered intravenously or orally. CsA karaciğerde 18 metabolite
kadar parçalanır. FK-506 ise 9 metabolite parçalanır.

<< 80 >>
Clinical Use
CsA
-In bone marrow, kidney, liver, heart, lungs transplants is often used in combination with
azathioprine, glucocorticoids and, more recently, with MFM or rapamycin...
-It’s also used in acute and chronic GVHD and is advantageous over other
immunosuppressants as it does not inhibit regeneration of the transplanted marrow.(Hoca
bu madde için önemli dedi)
-Severe forms of rheumatoid arthritis that do not respond to methotrexate and psoriasis.
FK-506
-Can be added to CsA in organ transplants
-It is also used in rejection episodes that cannot be controlled by CsA.

Adverse Effects
-CsA and FK-506 have the advantage that they do not cause infections compared to other
immunosuppressives because of their relative selectivity in the mechanisms of action and
not affecting rapidly dividing bone marrow cells. (Bu yüzden transplantasyonlarda çok tercih
edilirler.)
-The most important adverse effect is renal toxicity.

2-Rapamycin(RAPA)
It’s an analog of FK-506.

Mechanism of Action
-Like FK-506, RAPA binds to the same cytoplasm receptor but the target is different.
-Target of the RAPA-FKBP12 complex is a protein with kinase activity(There is phosphatase
activity at FK-506) (TOR, Target of Rapamycin) or FRAP (FKBP and rapamycin target).
-RAPA is particularly effective in inhibiting IL2-induced T cell proliferation.

Pharmacokinetic Properties
It is excreted through bile.

Clinical Use
It is used with Cn inhibitors and steroids to prevent organ rejection, or in combination with
steroids and MFM in patients to eliminate the nephrotoxicity of CsA and FK-506.

<< 81 >>
Adverse Effects
-Hyperlipidemia is the most common adverse effect.
-If we combine with CsA it strengthens the nephrotoxicity.
NOT: Yukarda CsA ve FK-506 nın oluşturduğu nefrotoksisiteyi azaltmak için steroidler ve
MFM ler ile kullanılır dedik. Şimdi de sadece CsA ile kullanırsak CsA nın sebep olduğu
nefrotoksisiteyi güçlendirir diyoruz.

3-Corticosteroids
For many years, glucocorticoid (GC) effective corticosteroids have been used in autoimmune
disorders and immunosuppressive treatment of organ transplant patients.

Mechanism of Action
-The effects of GCs are mediated by regulation of gene expression mediated by intracellular
receptors that exhibit similar activity to transcription factors. (Endokrinden bildiğimiz üzere
kortikosteroid yapılı hormonlar hücre zarından kolaylıkla geçerler, steroid yapıda oldukları
için.)
-There are different receptors for glucocorticoids(GR: Glucocorticoid Receptors)
-Activation of GRs is supported by drug binding, but there are various receptor isotypes, and
there is no data on their binding-dependent regulation to the drug.
-Presence of isoforms, different expression in different organs and individuals→ it creates
problems in personalizing and optimizing the treatment approach. (2 kişi aynı kortikosteroidi
kullanıp birinin yarar gördüğü, diğerinin görmediği bir durumla karşılaşılabilir.)
-Inhibition of the production of chemotactic substances and factors that increase capillary
permeability by the infiltrate cells at the site of inflammation→ inhibition of leukocyte and
monocyte accumulation at areas of inflammation can be seen (antiinflamatuar etki)
-Inhibition of synthesis and / or release of Platelet Activating Factor (PAF), Macrophage
Inhibiting Factor (MIF).
-Lymphocytotoxic effect occurs both in the thymus lymphocyte population and on T
lymphocytes in the periphery →Use as an antitumoral agent in the treatment of leukemia
and lymphomas.

Pharmacokinetic Properties
-Highly lipophilic(Effective absorption orally)

-Prolonged topical administration may result in high systemic absorption of the drug.

<< 82 >>
Clinical Use
Main indications:
-Leukemia,
-Lymphomas
-Autoimmune diseases.
-Organ transplants
-High-dose prednisone is the first-line therapy for dermatomyositis-polymyositis.
-It is used in conjunction with sulfasalazine in ulcerative colitis and Crohn's
disease.(sulfasalazine i tek başına kullanma ya da prednisone(glukokortikoid) ile beraber
kullanma doktorun tercihindedir.)
-Corticosteroids can also be used to prevent allergic reactions.(Penisilin alerjisinde kötü sonuçlarla
karşılaşmamak için kortikosteroid, antihistamin ve adrenalin kullanırız.)

Adverse Effects
-The toxicity of corticosteroids is directly related to the dose used and the duration of
treatment.
-The major adverse effects are increased susceptibility to infections, hyperglycemia,
hypertension, edema, glaucoma, hydroelectrolytic imbalance, osteoporosis, myopathy, body
fat distribution, capillary fragility, ulcers, behavior disorder, irritability, insomnia, psychosis
and hirsutism, acne, impotence, endocrine alterations. (Bu maddeyi hoca: ‘işte bu da bazı
yan etkileri’ deyip geçti.)
-Discontinuation of treatment should be done by spreading the dosage over time and
gradually reducing it. (aksi taktirde acute surrenal insufficiency)

d- SELECTIVE IMMUNOSUPPRESSIVES: ANTIBODIES

Targets of antibodies:
-Cytokines
-Cytokine receptors
-Surface antigens expressed by cells in the immune system
Polyclonal antibodies, hybridomas, chimeric and humanized antibodies, human-anti-human
antibodies are very common use antibodies.
Polyclonal Antibodies: Among polyclonal antibodies we see antilymphocyte (Anti-
Lymphocyte Globulin, ALG) and antithymocyte (Anti-Thymocyte Globulin, ATG).
-Cytotoxic antibodies that bind their molecules leads to inhibition of lymphocyte functions
and depletion of circulating lymphocytes.

<< 83 >>
Monoclonal Antibodies: Monoclonal murine antibody (muromonabCD3; OKT3) is very
effective in renal transplantation(also in common use).
-By binding to the CD3 component of the TCR, it rapidly internalizes in the cell.

Apoptosis induction and

complement activation with cell death
Rapid T lymphocyte depletion in

blood, spleen and lymph nodes.

Distribution of lymphocytes to
non-lymphoid organs such as lungs
-Reduction of the function of the remaining T lymphocytes by inhibition of production of
major cytokines, including IL-2 is seen with use of this antibody.

TNF- Antagonists: TNF--proinflamatuar bir sitokin.

Binds TNF-→ Formation of inflammatory cytokines IL-1 and IL-6 and expression of
adhesion molecules involved in lymphocyte activation are suppressed
Infliximab:
-Crohn's disease
-RA
-Ankylosing spondylitis
-Psoriatic arthritis
Adalimumab: Human origin that has been approved for RA new monoclonal binding human
TNF-’ antibody (the first monoclonal antibody included in the treatment as a fully human
monoclonal antibody; immunogenicity much lower than antibodies)
Etanercept and Certolizumab: Bazı otoimmün hastalıklarda kullanılır, son 10 yıldır da organ
transplantlarında kullanılıyorlar.

TNF- Antagonists, Advers Effects: Fever, dyspnea, severe infections, iatrogen lupus

e- OTHER IMMUNOMODULANT DRUGS

IL-2 receptor (CD25) antibodies: Binds with high affinity to the subunit α of IL-2 receptors on
activated T lymphocytes and blocks all IL-2 mediated effects.
Basiliximab, Rituximab
-CTLA-4Ig fusion proteins: Abatacept, Belatacept, Alefacept, Efalizumab, Tocilizumab, Omalizumab,
Prebiotics / Probiotics(inflamatuar sitokinleri azaltır)

<< 84 >>
Problems Due to Antibody Use
-Rhinitis
-Fever
-Respiratory difficulty
-Tremor
-Lymphomas
Immunogenicity= Neutralizing antibodies produced by the host.
Humanized (hybrid human / animal) or fully human antibody use is usefull for lowering
antigenicity.

B. IMMUNOSTIMULANT DRUGS
They are using at:
-Immunodeficiency diseases
-Viral infections
-Bacterial infections
-Tumor treatment

1-Microorganism Origin Products

-Glycans prepared from fungal extracts
-Bacterial lipopolysaccharides (lipid A)
-BCG and mycobacterial cell wall preparations (muramyl dipeptide, MDP)
-Bacterial derivatives of polymeric structure(NK stimulation)

2-Thymic extracts
-Thymic hormones

3-Immunostimulants with chemical structure

-MDP derivatives
-Lipid A analogues
-Bestatin(very important in clinic to substain the NK and macrophage activation)
Thymomimetic drugs: Levamisole, dithiocarb, inosine and its derivatives are very common used
agents

IFN inductors: Poly A, Poly IC derivatives (increasing NK activity)

<< 85 >>
C. CYTOKINES
1-Interleukin-2 (IL-2)
When the gene of IKL-2 is inhibited, the proliferation of T lymphocyte is stops. If we use IL-2,
it increases the proliferation of T.

2-Interferons
Antiviral
Immunomodulant
Antiproliferative
The most important factors in treatment: antitumoral and antiviral.

Clinical Use
-IFN-→can be useful

-IFN-

-IFN-

Adverse Effects
If with the use of the drugs, you notice influenza type symptomatology you can use the
paracetamol to treat it.

D.HEMATOPOIETIC GROWTH FACTORS (G-CSF, GM-CSF and IL-3)

-Reducing leukopenia caused by chemotherapy
-Acceleration of myeloid regeneration
-Reducing the risk of infection
It’s very commonly using in clinic
In the future we will see that cytocines will be used as immunoadjuvants and
immunostimulation.
Sorular
1-Aşağıdakilerden hangisi bir spesifik immünsüpresif ilaç değildir?
A)MFM B)Talidomit C)Takrolimus D)Azatioprin E)Sirolimus
2-Etkisini dihidrofolat redüktaz enzimini inhibe ederek gösteren ilaç hangisidir?
A)Siklosfamid B)Azatioprin C)Metotreksat D)Mizoribin E)Rapamisin

<< 86 >>
3-Serin/treonin fosfataz ile etkileşime giren ilaç grubu hangisidir?
A)Siklosporin A B)Rapamisin C)Prednizon D)Talidomit E)Levamizol
4-Gebelikte kesinlikle kullanılmaması gereken ilaç hangisidir?
A)MFM B)Siklosfamid C)Siklosporin A D)Prednizon E)Talidomit
5-Romatoid artrit için onay almış olan ve TNF-a yı bağlayan ilaç hangisidir?
A)İnfliximab B)Adalimumab C)Etanercept D)Certolizumab E)Abatacept
6-Nefrotoksisitesinin olmadığı ancak CsA ile kullanıldığında nefrotoksisiteyi artıran ilaç
hangisidir?
A)FK-506 B)Sulfasalazin C)Sirolimus D)Brekuinar E)Dezoksispergualin
7-Tümörlerin immün sistemden kaçış yolları vardır. Tümörlü bir hastaya hangi ilaç
verilebilir?
A)Mizoribin B)Metotreksat C)MFM D)Levamizol E)RAPA
8-Aşağıdakilerden hangisi siklosfamidin bir özelliği değildir?
A)En büyük etkisini S fazındaki hücrelerde gösterir.
B)Oral emilimi fazladır. C)DNA’da timini alkilleyerek etki gösterir.
D)Tek başına kullanılabilir.
E)Siklosporin ile kullanılabilir.
9-Hangisi Talidomit için doğrudur?
A)Gebelerde kullanılması bir sorun yaratmaz.
B)Tromboz riski yoktur.
C)IL-2 üretimini baskılayarak etki gösterir.
D)Multipl Myelomda kullanılması için izin alınmıştır.
E)Anjiyojenik etkisi vardır.

Dipnot: Derste hoca numarasını verdi, istediğimiz zaman ulaşabilelim diye, 0544 794 31 44

“Ne demiş yılmaz babamız? Ben en azından katilimi tanıyorum. Fakat sen bir gün
sevilmediğin bir yürekte kimvurduya gideceksin..”

Cevaplar: 1-D 2-C 3-A 4-E 5-B 6-C 7-D 8-C 9-D

<< 87 >>
Hematopoietic System Drugs
Farmakoloji
Selçuk Şen
03.11.2020 16.00
Sezin Esen

Bu konuyla ilgili birçok ilacı seneye görecekmişiz, hoca bugün temel olarak anemi tedavisinde
kullanılan ilaçları anlattı. İyi çalışmalarJ

Anemia
• There may be a problem with Hb production. Hypochromic microcytic anemia which
occurs due to iron deficiency.
• There may be a problem with DNA synthesis related to Hb production. Factors such as
folic acid and vitamin B12 might be deficient which causes abnormal maturation in
erythrocyte precursors resulting in megaloblastic anemia.
• There may be a problem with the maturation and synthesis of blood cells in bone
marrow (erythropoietin, necessary for erythrocyte differentiation and colony
stimulating factors necessary for maturation of white blood cells)

When we see a decrease in Hb and hematocrit levels, we start to investigate the cause.
There are different parameters and lab tests for this such as iron levels, vitB12 levels, peripheral
smear, bone marrow smear, etc. We try to figure out whether there is some type of deficiency,
bone marrow depression (some diseases, antineoplastic drugs, radiation can cause BM
depression) or an increased destruction (hemoglobinopathies, hemolytic anemia, drugs such as
aspirin in G6PD deficient patients, inappropriate immune response)

Þ Iron
It is absorbed in duodenum, carried bound to transferrin, stored as ferritin. Its deficiency
results in microcytic anemia.
Fast growth during childhood, pregnancy, blood loss, abnormal menstruation flow or period
may increase the need for iron intake.
In this scenario, Hb, iron, ferritin levels decrease and iron binding capacity increases (blood
count).
Primary thing to treat is anemia, not iron deficiency. So acute iron treatment might not
always be necessary.
For oral iron treatment, know the difference between ferrous form (Fe2+) and ferric form
(Fe3+) Ferrous forms are absorbed easier and faster. So, they are more efficient than ferric
forms. When there is a serious iron deficiency, it is better to start the treatment with ferrous
forms. However, the side effects are more prominent in ferrous forms. So, for patients who
cannot tolerate ferrous forms, you can prescribe ferric forms as treatment.
After the treatment, the first changes occur in the number of reticulocytes, they increase in
5-7 days. Hb levels take longer to normalize (1-3 months). Patients should continue the
treatment for at least 3-6 months.

<< 88 >>
 The most common side effects are GIS side effects such as nausea, vomiting, abdominal
cramps. It is suggested to take iron before meals (2 hours before meals or 4 hours after meals)
since food decreases the absorption of iron. However, if the patient cannot tolerate, they can
take iron with their meals, which decreases these side effects.
For parenteral iron treatment, the first preparation that comes to mind is iron dextran (it is
the first one developed but there are a lot of negative experiences with it). Parenteral iron
treatments are usually feared because of the hypersensitivity risk. On the other hand, newly
developed parenteral iron preparations have less risk. If patients cannot tolerate oral
treatment, if they have a deep chronic anemia, or if they had a previous duodenal resection, it
is better to use parenteral iron preparations.
Iron toxicity: Chelator agents used in acute/chronic iron toxicity are deferoxamine or
deferasirox. When you encounter a patient with iron toxicity, you should be careful about
necrotizing gastroenteritis which might even lead to coma. Chronic toxicity may also lead to
hemochromatosis, same chelator agents can be used to treat it.

Þ Folic acid (vitB9)

Folic acid has no toxic effects for the body but deficiency of it during pregnancy may cause
neural tube defects, so you shouldn’t doubt prescribing it. For patients using dihydrofolate
reductase inhibitors such as methotrexate (antineoplastic agent), folic acid is also prescribed.

Þ VitB12
It is a cofactor for many enzymes, derived from animal products. Vegetarian diet, gastric
resection and some drugs may cause vitB12 deficiency.
Most common reason for vitB12 deficiency is pernicious anemia (due to intrinsic factor
deficiency).
Megaloblastic anemia and neurologic symptoms are observed in vitB12 deficiency.
VitB12 and folic acid are usually together in preparations, so you don’t need to differentiate
them while prescribing.
Hydroxocobalamin or cyanocobalamin are used as preparations.
Pernicious anemia requires constant treatment. Otherwise, you should monitor the
treatment period.

Þ Erythropoietin
Recombinant analogs are epoetin alpha and darbepoetin alpha (longer half-life). They are
primarily used in anemia due to chronic kidney disease, however they may have cardiovascular
side effects.
Abuse in sports for enhanced performance.

Þ Colony stimulating factors

GM-CSFs stimulate the growth of leukocyte precursors (sargramostim, molgramostim,
regramostim. They are used for bone marrow transplantation since they have a broad effect (in
all blood cell series).
G-CSFs especially stimulate neutrophils (filgrastim, pegfilgrastim). They are used for
chemotherapy induced neutropenia. Peg forms (pegfilgrastim) are safer and more tolerable.

<< 89 >>
 IL-11 stimulate platelet production and maturation (oprelvekin). It is used if in
thrombocytopenia during chemotherapy.

Þ Hydroxyurea
It is an antineoplastic drug, used in chronic myelocytic leukemia and polycythemia vera.
In terms of anemia, there are a lot of studies showing its benefits for sickle cell anemia.
Normally, sickle cells block the capillaries and cause anoxia in the tissues. Hydroxyurea
increases fetal hemoglobin levels and reduces the formation of sickle blood cells. Thus, it
prevents painful anoxic crises. Unfortunately, safety of hydroxyurea is not known, and we
should keep in mind that there may be a risk of bone marrow suppression.

Çıkmışlar

Which of the following drugs protect and accelerate myeloid engraftment after
autologous bone marrow transplantation and intensive chemotherapy?
GM - CSF

Which of the following is a human granulocyte colony stimulating factor (G-CSF) analog
and is indicated in patients receiving myelosuppressive anti-cancer drugs associated with a
significant incidence of severe neutropenia?
Filgrastim

Which of the statements below it / are correct for iron treatment?

(I)Iron dextran is an oral form of elemental iron.
(II)Oral ferrous iron formulations are more easily absorbed than the ferric forms.
(III)During parenteral iron treatment, hypersensitivity reactions may occur less than in
oral iron treatments.
Only II

<< 90 >>
PROTEİN SYNTHESİS İNHİBİTOR ANTİBİOTİCS-1

AYŞE PINAR YAMANTÜRK ÇELİK

PHARMACOLOGY

03.11.2020 (09.00)

NURSENA KÜÇÜKÖZYİĞİT
Özet başlığı olarak dersin programdaki adını yazdım ama hoca dersi anlatmaya Beta Lactam &Other Cell Wall & Membrane Active Antibiotics-1
slaytı 42. Sayfa penisilinlerin etkileşimleri ile başladı.

Penicillins are reducing agents. With Benedict, Fehling reagents and Clinitest tablets cause false
positive reaction in glucose determination in urine but do not affect glucose oxidase test

Many infectious disease we can say penicillin is first order if patient doesn’t have penicillin
allergy.Meningitis,osteomyelitis,arthritis,COPD,gonorrhea,bronchitis,nosocomial
pneumonia,pseudomonas infections,diphteria,surgical prophylaxis,infective endocarditis and
lyme disease.Lyme disease have some phases ,in early phase penicillins(especially amoxicillin and
aminopenicillins) the first option ,but tetracyclins they’re also first order especially doxycyclin.

Hoca dozu sınavda sormayacağını uygulanma yöntemini bilmemizin yeterli olduğunu söyledi.Okumak isteyen olursa diye slayttaki
kısmı ekledim.

Penicillin G: 1 million unit 0.6 g

Potassium penicillin G 1.7 mEq (65 mg) potassium per 1 million U (can cause cation toxicity)

Penicillin G i.m. and i.v. usually 25-50.000 U/kg 4-6 divided doses

Procain penicillin G: (depo penicillin)1.000.000 U almost 1 g 300.000-600.000 U i.m. 1 or 2 X with

12 hr interval Intravenous administration should not be done contraindicate

Acut genitourinary gonorrhea 4.800.000 U divided 2 i.m. from both sides of gluteal injection area
+ 1 g probenecid (oral) (unavailable in Turkey)

Benzathine penicillin G: To prevent rheumatic fever relapse 1.2 million U i.m. single dose
Intravenous administration should not be done contraindicate .For <27 kg body weight 600.000
U

Benzathine phenoximethyl penicillin per oral 50.000 U adult 50-100.000 U children 3 equally
divided doses

Methicillin i.m., i.v. 1 g every 4-6hr Easily deteriorates in acidic solutions (pH<5) like
glucose,should be avoided

Amoxicillin 25-50 mg/kg/day divided 3-4 oral /parenteral

Ampicillin 50-400 mg/kg/day divided 4 high doses parenteral

<< 91 >>
 BETA-LACTAMASE İNHİBİTORS

Clavulanic acid ,sulbactam and tazobactam have beta lactam rings but don’t have antibiotic
effect.

Avibactam is a structural class of inhibitor that doesn’t contain beta lactam core but maintains
the capacity to covalently acylate its beta lactamase targets.

• Although their antibacterial effects are negligible degree, they prevent bacterial
degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs
are effective against. Mostly effective against plasmid-encoded beta-lactamases
(gonococci, streptococci, E. coli, H. influenzae) Ineffective against inducible chromosomal
beta-lactamases (enterobacter ve pseudomonas) with the exception of avibactam.
• Acquired resistance to beta-lactamase inhibitor combinations is due to: beta-lactamase
hyperproduction.
• Combinations with beta lactamase inhibitors :amoxicillin+clavulanic acid ,
ticarcillin+clavulanic acid ,ampicillin +sulbactam ,cefoperazone+sulbactam
,ceftazidime+avibactam ,piperacillin+tazobactam.Sultamicillin(tek bir molekül emildikten
sonra sulbactam+ampicilline dönüşüyor,sulbaktam beta laktamazı inhibe etmesine ek
olarak ampicillinin oral biyoyararlanımını %80 ‘e çıkarıyor)
• Unwanted effects :cholestatic jaundince and acut hepatitis(penicillin+clavulanic
acid),allergy

CARBEPENEMS
İmipenem(prototype) Meropenem Ertapenem Pamipenem

Carbepenems posses the broadest spectrum of activity and greatest potency against Gram + and
gram – bacteria.

1)İmipenems:highly resistant to beta lactamases ,synthetic ,binds to PBP(penicillin binding

protein)

• Spectrum of activity:gram+cocci,gram-rods,*anaerobes,other antibiotic resistant

microorganisms(especially enterobacter and penicillin resistant pneumococci but
*ineffective against methicillin resistant staphylococcus)
• Pharmacokinetics:administered via intravenous route,*if meningitis is present it passes
into cerebrospinal fluid. Renal dehydropeptidase1
• Active imipenem-------------------------------------àinactiveimipenem!!nephrotoxic
• İf combine imipenem with cilastatin,it is indestructible with dehydropeptidase
(nephrotoxicity is prevented) and extends plasma halflife. ***cilastatin isn’t
antibacterial.İt’s inhibitor of dehydropeptides enzyme.

<< 92 >>
 • Unwanted effects: CNS toxicity at high serum levels ,confusion
,encephalopathy,*convulsion(especially epilepsy patient),skin flushing ,GİS
irritation,allergy,cross allergy with penicillins partially.

2)Meropenem:similar feature to imipenem.Difference between imipenem and

meropenem:meropenem *indestructible with renal dehydropeptidases and *less CNS toxicity.So
meropenem is used more often than imipenem.

3)Ertapenem:half life 4.5 hour(single dose per day i.v. or i.m.),protein binding 92%,excreted as
active drug in urine 92%, increased gram + activity,low antipseudomonal activity,*5% dextrose
shouldn’t be used as solvent,infusion at 0.9% NaCl.

MONOBACTAMS
Aztreonam(prototype) Carumonam Tigemonam

1)Aztreonam:*the beta lactam ring isn’t binded to another ring.

• Spectrum of activity:**resistant to beta lactamases* produced by gram – rods such as

klebsiella,pseudomonas,serratia.İneffective against gram + and anaerobs(*narrow
spectrum)
• Pharmacokinetics:i.v. or i.m.,excreted by secretion in the urine
• Unwanted effects:GİS complaints,vertigo,headache,hepatotoxicity rarely,skin
redness,***eusinophilia(especially in atopic patient ,rare but serious condition)
However ,no or seldom cross allergy with penicillins and other beta lactams(low
immunogenic potential)

ÇIKMIŞ SORULAR

1)Which of the following drug is a beta lactam antibiotic effective against most types of bacteria
resistant to penicillin and cephalosporins? İmipenem

2)Aşağıdakilerden hangisi beta laktamaz inhibitörüdür? Klavulanat

3)Tigesiklin hakkında hangisi yanlıştır?Monobaktam grubundandır.

4)Penisilinler hakkında hangisi doğrudur? Benzatin penisilin G intravenöz yapılmaz.

5)Aşağıdakilerden hangisi monobaktamdır? Aztreonam

6)İmipenem hakkında hangisi doğrudur? Beta laktamazlara ileri derecede dayanıklıdır.

7)Aşağıdakilerden hangisi uzun etkili (depo) penisilindir? Prokain penisilin

8) Aşağıdakilerden hangisi beta laktamaz inhibitörü değildir? Silastatin

9)Aşağıdakilerden hangisi metisiline dirençli stafilokok şuşlarına etkili değildir? İmipenem

İyi Çalışmalar

<< 93 >>
 OTHER CELL WALL & MEMBRANE-ACTIVE ANTIBIOTICS
Ayşe Pınar Yamantürk Çelik
Yusuf Burak Hatipoğlu
03.11.2020
*Vancomycin *Daptomycin (cell membrane-active)

*Teicoplanin *Bacitracin

*Telavancin *Fosfomycin

*Dalbavancin *Cycloserine

*Polmyxins (cell membrane-active)

These four are similar
molecules and peptide
antibiotics

VANCOMYCIN
+Bactericidal
+Glycoprotein
+Produced by Streptococcus orientalis (so it
is natural origin)
+Prevents transglycosylation in the cell wall
+It is not include beta-lactam chain.
Resistant development:
+D-Lactate substitutes for D-Ala, losing affinity in the binding region
+Plasmid-mediated (D-Ala yerine D-laktatın geçmesi sonucunda (plazmid aracılığıyla) binding
regionda afinite kaybı olur. Sonucunda vankomisine karşı direnç oluşur.)

Prophylaxis and treatment:

<< 94 >>
It is not a first order antibiotics.
Spectrum of activity:
*Resistant Gram (+)’s (except flavobacterium)
*Methicillin-resistant staphylococci
*Penicillin-resistant penumococci
*Clostridium difficile (pseudomembranous enterocolitis with oral administration)

Synergistic effect with aminoglycosides (used in enterococcal endocarditis)

Pharmacokinetics:
+Protein binding 10-50%
+Well distribution when administered parenterally
+Excreted in urine (almost unchanged)
+Dose should be adjusted in renal failure
+Monitoring of therapeutic serum drug level

Unwanted effects:
+Fever, chill
+Phelebitis
+Ototoxicity
+Nephrotoxicity
+Fast i.v. infusion causes widespread redness and shock(histamine release) → Red-man
syndrome

<< 95 >>
TEICOPLANIN
Prophylaxis and treatment:
+Similar to vancomycin, the difference is teicoplanin may be administered i.v. and i.m.(very
painful injection)
+Single dose per day
+No oral administration

TELAVANCIN
+Lypoglycopeptide, derived from vancomycin
+Gram(+) spectrum of activity
+i.v. slow infusion (all these peptide infusions should be slowly)
+Protein binding is very high and 90%
+Renal excretion
+GIS disturbances, taste disturbances
+Falsely elevated values for INR, PT anda PTT
+Used in skin infections

DALBAVANCIN
Lypoglycopeptide, synthesized from teicoplanin-like gylcopeptide
+Gram(+) spectrum of activity
+Biological half-life is 2 week
+Protein binding is very high and 93%
+i.v. slow infusion
+Symptoms resembling “red-man syndrome”
+Renal excretion
+Single dose per week
+Nausea, headache and diarrhea are common

<< 96 >>
+Used in skin infections
+ Falsely elevated values for INR, PT anda PTT

DAPTOMYCIN (CELL MEMBRANE-ACTIVE)

+Lipopeptide, produced by Streptomyces
roseoporus
+It is effective by depolarizing the cell membrane
(rapid cell death with potassium output)

Spectrum of activity:
+Resembles vancomycin but demonstrates faster
bactericidal activity in vitro
+Effective against bacteria resistant to vancomycin (enterococci and S. Aureus)

Pharmacokinetics:
+i.v. administration
+renal excretion

Unwanted effects:
+GIS disturbances
+Myopathy (creatine phosphokinase following)
+Nephropathy

Clinical use:
+Skin and soft tissue infections
+Sepsis
+Endocarditis
+Daptomycin akciğerde sürfaktan tarafından deaktive edildiği için pneumoniada kullanılmıyor.

<< 97 >>
BACITRACIN
+Polypeptide mixture of an antibiotics
+Affects the late period of synthesis of cell wall in Gram(+) organisms. (Inhibits the
dephosphorylation of the lipid carrier transfers peptidoglycan subunits.)
+In limited topical use due to significant nephrotoxicity (Wide area applications may cause
systemic toxicity.)

FOSFOMYCIN
+Inhibitor of cytosolic enolpyruvate transferase (formation of N-acetylmuramic acid, basic
molecule for peptidoglycan chain is prevented.
+Reduction in cell accumulation causes resistance
+Gram(+) and Gram(-) spectrum of activity
+Used in urinary tract infection(UTI)
+Renal excretion
+Oral and parenteral forms
+May be synergistic with fluoroquinolones, beta-lactams,aminoglycosides
+Rapid resistance and diarrhea with repeated dosing

CYCLOSERINE
+Structural analogue of D-alanine(antimetabolite)

Alanine racemase enzimini

inhibe eder.

+Prevents D-ala joining to peptidoglycan pentapeptide side chain

<< 98 >>
+Gram(+) and Gram(-) spectrum of activity
+Neurotoxicity: (tremor, seizure, psycosis) Used in resistance to other antituberculosis agents.

POLYMYXINS (CELL MEMBRANE-ACTIVE)

+Simple polypeptides containing fatty acids
+Polymyxin B and Polymyxin E (colistin) are used.
+Bactericidal against Gram (-) bacteria
+Break down the bacterial cell membrane
+Clinical use in topical therapy in resistant Gram(-) infections like enterobacter,pseudomonas
+If enter systemic vasculation:
Neurotoxicity: (paresthesia, vertigo, ataxia)
Acute tubular necrosis: (hematuria, proteinuria, nitrogen accumulation)
+Çaresiz kalındığında colistin tek başına veya kombine edilerek kullanılabilir.

Dose-Dose Interval-Administration Route:

+Meropenem: 1 gram for every 8 hours, i.v. administration

Oral yolla

<< 99 >>
Çıkmış Sorular:

Bakteri hücre duvarı sentezini önleyen aşağıdaki antibiyotiklerden hangisi beta-laktam halka içermez?

Cevap: Vancomisin

<< 100 >>

FEVER OF UNKNOWN ORIGIN-INTERNAL MEDICINE

04.11.20

LECTURER:PROF DR BÜLENT SAKA

NOTE BY:ALİ ÇÖL

Hocamız derse öncelikle bir vaka sunumuyla başladı.Bu kısmı Türkçe

anlattığından ben de notuma Türkçe olarak ekleyeceğim.

• 65 yaşında,erkek hasta,serbest meslek

SADECE BU ŞİKAYETLERE
• Şikayetleri son aylarda ortaya çıkan BAKARAK ETKİLENEN İKİ
ateş,öksürük,balgam,kilo kaybı,el ve SİSTEMİ GÖREBİLİRİZ:
ayaklarda uyuşukluk
SOLUNUM SİSTEMİ+SİNİR
• İnflamasyon+kilo kaybı yani Kaşeksi mevcut.
SİSTEMİ

Bu hikayeye baktığımızda Vaskülitler,emboli,septik

emboli,neoplastik,paraneoplastik hastalıklar fikir jimnastiği yaptığımızda
aklımıza gelebilecek şeyler.Fakat tabii ki daha fazla bilgiye ihtiyacımız var.

<< 101 >>

➢ Son iki aydır öksürük ve balgam devam etmekte.Normalde biz pnömoni
sürecinde 2 aylık bir öksürük beklemeyiz.Ancak tüberküloz olabilir fakat
tüberküloz da vasküler tutulumla pek uyuşmuyor.Bugün olsa COVID de
olabilir ama bu vaka daha eski.
➢ Tip 2 diyabet tanısı yeni konulmuş,bu eski bir vaka olup yeni tanı
konulmuş olabilir.Kırsalda yaşıyor senelerdir çok su içip çok idrara çıkıyor
ve ilk kez doktor yüzü gördüğünde türlü organ tutulumu,insülin yetersizliği
bir kenara beta adacık hücre yıkımı ve insülin yetersizliğiyle tanısı
konulmuş olabilir bu hastanın mesela.
➢ Veya sekonder diyabet yani pankreas malignitesine bağlı kaşeksi
gelişmiş de olabilir.

Yumuşak ödemin sebebi albümin

eksikliğidir,peki neden olur albümin
eksikliği?

o İştahsızlık
o Karaciğer malignitesi
o Aşırı katabolik süreç
o Nefrotik kayıp-proteinüri
o Ciltten kayıp,bağırsaktan kayıp

Bu akciğer sesleriyle belli ki alveolar bir

tutulum yok fakat interstisyel bir tutulum
olabilir.İnterstisyel tutulumda ileri evreye
kadar akciğer sesleri belirgin değildir.

Bariz bir şekilde arterlerinde obliterasyon var,bu hastada

vaskülit,emboli,ağır ateroskleroz ve Buerger hastalığı gibi tanılar ön
plana çıkıyor.

1 cm hepatomegali olabilir,belki
yağlanma vardır hastada normal.

Sinir sistemi muayenesi normal çıksa da

hatırlayalım hastada periferik nöropati
şikayetleri mevcuttu.

<< 102 >>

HASTANIN LABORATUVAR SONUÇLARINA GÖRE

✓ Mikrositer bir anemisi mevcut.

✓ CRP ESH yüksek.
✓ Lökositoz mevcut.
✓ Son 3 aylık şekeri gayet iyi,yani bu eski,komplikasyonlarla giden bir
diyabet olamaz.
✓ Böbrek iyi durumda,elektrolit imbalansı yok,karaciğerde bir
komplikasyon yok ve sentez kabiliyeti de iyi.
✓ Ciddi demir eksikliği var,ferritin yüksek ama bu yalancı akut faz
reaktanı zaten.
✓ B12,folik asit düşük 65 yaş için.
✓ Albümin ciddi düşük: 1.95 (4’ün altı düşüktür)
✓ Ya nefrotik proteinüri ya ağır bir katabolik süreç şu anda en olası
tanılarımız bu hastanın protein eksikliğiyle ilgili
✓ Hipergamaglobulinemi var,yani B hücre aktivitesi çok fazla bu
hastanın: Ağır bir inflamatuar süreçten geçiyor.

❖ Kalpte,aortta bir sorun görünmüyor

AC grafisinde
❖ Akciğerde görüyoruz ki yaygın bir
parankimal infiltrasyon paterni mevcut
❖ Görünen kemiklerde osteoporoz
göze çarpıyor.
❖ İdrar tahliline baktığımızda
görüyoruz ki proteinüri negatif,böylelikle
kararımızı veriyoruz:AĞIR KAŞEKSİ

❖ Ağız göz kuruluğu nedeniyle otoantikor sorgulandı,negatif bulundu ve

Sjögren böylece def edildi.
❖ EMG’de periferik duysal ve motor polinöropati saptandı.Bu direk sinir
tutulumu mudur,gerek doku gerek vasküler paraneoplastik bir durum
mudur hala bilmiyoruz.Tek bildiğimiz MSS tutulumu olmadığı.
❖ Hastada demir eksikliği var,erkek hastada demir eksikliği her zaman
araştırılmalıdır,kadında ise postmenopozal dönemde araştırılır.
❖ Endoskopileri normal gelen hastaya demir replasmanı tedavisi başlandı.

YAYGIN NODÜLER AC İNFİLTRASYONU

<< 103 >>

 ❖ Antibiyotik başlanmış fakat kültürlerinde üreme olmadığından 14 günde
kesildi.
❖ Human Albumin ile replasman yapıldı.
❖ Toraks grafisinde multipl LAP mevcut.

Granülomatoz hastalıklar bu hastada akciğer,vasküler ve periferik nöral

tutulum için çok anlamlı görünüyor.Nedir granülomatoz hastalıklar?

o Bruselloz,tbc,mantar enfeksiyonları
o Sarkoidoz,Cat Scratch disease
o PAN,Wegener
o Lenfomalar,paraneoplastik hastalıklar

❖ Tümör göstergeleri ve otoantikor negatif bulundu.

❖ Ekokardiyografi normal bulundu ve infektif endokardit dışlandı.
❖ Tüm bunlarla herhangi bir sonuca ulaşılamadığından PET istendi.PET’te
bilateral böbrek tutulumu bulundu.Biyopsi yapıldı ve nekrotizan
granülomatoz vaskülit tespit edildi.

BÖBREK AMPUL GİBİ PARLIYOR ARTERİYOLÜN DUVARI KALINLAŞMIŞ VE ONLARCA

İNFLAMATUAR HÜCRE MEVCUT

➢ ANCA negatif Wegener (evet olabiliyormuş,ben de şaşırdım) tanısı

konuldu.Siklofosfamid,metilprednizolon başlandı.
➢ Akut faz cevabı,organ tutulumları geriledi ve hasta taburcu edildi.

<< 104 >>

Arkadaşlar sunulan vaka burada son buldu.Bu vakayı bu kadar uzun koyma
sebebim oldukça öğretici ve mesleki bilgimize katkısı oluşuydu.Buradan
itibaren hocamız asıl ders konusunu İngilizce olarak anlattı ve ben de öyle
devam edeceğim.

HOW CAN WE DIAGNOSE FEVER OF UNKNOWN ORIGIN?

• Fever > 38.30C

THESE 3 CONDITIONS
•  3 weeks ARE UNIVERSAL RULES!
• 1 week impatient evaluation

In the previous cases in Turkey at the time of 1970s,1980s and 1990s cause of
FUO was %42-65 infectious diseases.

OUR LECTURER’S STUDY IN 2005

✓ 57 patients
✓ Median age was 44 years
✓ %46 males,%54 females
✓ %42 were due to infections
✓ %30 were due to inflammatory rheumatic diseases- 1/3 of this was Adult
Still’s disease
✓ %18 were due to malignancies
✓ %10 couldn’t be identified
✓ 12 had tuberculosis (%21) and 5 had brucellosis (%9).
✓ Mean fever period was 78.1 days (25 days-18 months).
✓ 48 patients (%84) had fever < 3 months.

Invasive diagnostic procedures:

- 50 invasive procedures.

13 Bone marrow biopsy

* 1 Hodgkin’s disease

* 1 adenocarcinoma (with metastasis)

12 Liver biopsy

<< 105 >>

 * 1 granuloma with caseification necrosis

* 3 granulomatous lesion

* 1 adenocarcinoma (with metastasis)

* 1 liver abscess drainage

6 Renal biopsy

* 3 lupus nephritis

* 1 necrotizing glomerulonephritis and amyloidosis

* 1 Wegener granulomatosis

* 1 glomerular mesangial proliferation and segmentary sclerosis

3 Temporal arterial biopsy

* 1 Temporal Arteritis

1 Muscle and nerve biopsy

* 1 Polyarteritis Nodosa

3 Lymph node biopsy

* 1 Tuberculosis

* 1 adenocarcinoma (with metastasis)

* 1 reactive LAP

They couldn’t diagnose 6 patients’ (%10) disease but in literature,it’s in

between %9-25

Geriatric patients in this study

11 patients (19%).

* Neoplastic disease, 5 patients (45%)

* Inflammatory Rheumatoid Disease, 3 pts (27%)

* Infections, 2 pts (18%)

* No diagnosis, 1 patient (9%)

<< 106 >>

Between 2010-2014,our lecturer started to use PET-CT to understand if it is
useful to diagnose the underlying disease in FUO.

• 52 patients
• Mean age; 54.2±19.5 years (18-93).
• 26 males (50%), 26 females (50%).

In this study,he saw the rate of infections are really decreasing (%36) but the
malignancies are increasing (%28)

➢ PET scan can show us the

correct areas with
hypermetabolic origin due to
malignancies and infections
with high sensitivity.

➢ You can see in 14 of 15

neoplastic patients, in 15 of 19
infection patients PET scan
showed mainly the correct
region.In tuberculosis,it showed
%100.

➢ In the inflammatory
rheumatic disease,we can see
it has a low sensitivity.

BURADAN İTİBAREN SLAYTTA HOCANIN OKUYUP GEÇTİĞİ FUO SEBEPLERİNİ

YAZACAĞIM,BİLGİ OLSUN DİYE VERİLDİ VE ÖNEMLİLER FAKAT SORU DEĞERLERİ
OLDUĞUNU DÜŞÜNMÜYORUM.

<< 107 >>

INFECTIONS INFLAMMATORY
RHEUMATOID DISEASES :
Türkiye -Tuberculosis
(~50%)* Adult Still’s disease
Polymyalgia rheumatica
Europe
Temporal arteritis
- Infective endocarditis Rheumatoid arthritis
- Abscess Rheumatic fever
Inflammatory bowel
❖ Tuberculosis patients disease
mostly showed Reiter's syndrome
extrapulmonary Systemic lupus
and/or erythematosis
disseminated Vasculitis
involvement.

NEOPLASTIC DISEASES: DRUGS:

Chronic leukemias Penicilins Sulfonamids

Lymphomas
Carbapenems Cephalosporins
Metastatic cancer
Nitrofurantoin Rifampin
Hypernephroma
Colon cancer Isoniazide Erythromycine
Hepatoma
Allopurinole Clofibrate
Myelodysplastic syndrome
Pancreatic cancer
Sarcomas Heparin etc.

DIAGNOSIS
- History taking and medical drug list Treatment must:

-Physical examination depend on the etiology.

- Concurrent physical examination with be multidisciplinary study.

- Rutine /specific laboratory analysis,PPD.

- Imaging methods/serologic analysis
/immunologic diagnostic methods.
- Invasive procedures

<< 108 >>

ÇIKMIŞ SORULAR VE SORU DEĞERİ OLANLAR:
Hocamız gençlerde enfeksiyon,yaşlılarda neoplazinin FUO’nun asıl sebebi
olduğundan bahsetti ve ayrıca neoplazinin şu anda daha yükselişte
olduğundan.Aynı zamanda yeni kullanılan PET-BT’nin de FUO sebebini
bulmadaki önemine vurgu yaptı.

Question: A patient with FUO presented with ****** lymphopenia,high ESR,high

CRP,LAP,caseification********What is the most probable diagnosis?

Answer: Tuberculosis

✓ Sorunun yarısı görünse de kazeifikasyon nekrozu gibi spesifik şeyler

tüberküloza işaret ediyor.

Question:How is the FUO defined?

Answer: Fever 38.3 for at least 3 weeks without any diagnosis after 1 week of
hospital examination.

https://open.spotify.com/track/6n3HGiq4v35D6eFOSwqYuo?si=m9L284Y8Thuh
c_Ad6YHOKA

<< 109 >>

TRANSFUSION PRİNCİPLES

04.11.2020 – 12:00 Sevgi Kalayoğlu Beşişik Akide Acar

If possible DO NOT TRANSFUSE !!!

Transfusion rule in practice

 Transfusion is not a treatment only a supporting management type.

 If you can treat underlying disease with medicament do not transfuse such as a patient with
low hemoglobin level because of low iron or B12 vitamin deficiency can be treated with drug
or nutritional factors. if the patient can’t recover despite medicament and show symptoms
then transfusion can be done
 In bleeding patient with hypotension to replace volume try to give fluid such as isotonic NaCl
 An experienced and talented surgeon or anesthetist would not need transfusion or a few
transfusion :)
 Red Blood Cell Transfusion

Sources of Red Blood cell (RBC) units

Phlebotomy is a procedure in which a needle is used to take blood from vein.

• Complement seperation from individual unit of whole blood

The majority of RBC units are manufactured by routine seperation of donated units of whole blood
(typical volume 450 to 500 mL) into various components by centrifugation. Please don’t use whole
blood because whole blood include every blood component.

• RBC Apheresis

A donor who has a sufficiently high hematocrit is connected to a apheresis device that separate red
blood cells from other blood constituents. The other cellular and plasma constituents are
infused back to the donor. In practice as a source of RBC we use whole blood because apheresis
is expensive. Both collection method is provide adequate RBC for transfusion.

Storege Procedures 2 -4 oC

-Plastic storage bag permit seperation of components while preserving sterility and Preservative
solution are used to prolong the shelf life.

-Storege bags is important, they made from polyvinyl chloride (PVC) . Anticoagulant- Preservative (A-
P) solutions are added. For bioavailability of RBC This additive solutions is added include dextrole
(not salt?), anticoagulant citrate, adinine , phosphate. They improve RBC shelf life.
- RBC can storage only in Blood Bank refrigerator, during transfering to clinic cold transfer bag is used
-Current generation additive solutions - 42 day ( six week) storage

Specialized Modification and Products: (Leukoreduction)

Every blood products include a few leukocyte this leukocytes are important in transfusion related
reaction so we need to reduce their number this procedure is called as Leukoreduction,
leukofiltration.

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 If blood Bank give Blood without
Leukoreduction bedside
Leukoreduction is used

• The Adverse Events Eliminated by Leukoreduced Products

Each unit of whole blood or packed RBCs contains approximately 2 to 5 ×1019 leukocytes contributing
to a number of adverse effects. Leukocyte reduction filters can achieve a 3-4 log reduction in the
leukocount of the unit and eliminate.

 HLA aloimmunization and platelet refraction

 Transmisson of cytomegalovirus (CMV) . In turkey %95 people are CMV seropositive. In those
donor leukocyte have latent CMV , transfusion without Leukoreduction cause CMV infection
in immunosuppressive patient. We have to give Leukoreduced RBC.
 Febrile nonhemolytic transfusion reactions. Leukocyte producing some chemokine, they are
contributing to fever . Some patient are continuously resiving transfusion such as
thalassemia major Leukoreduced RBC should be given those patient to prevent fever.
 İnflammatory and immunologically mediated events

Populations who needing routinely Leukoreduced blood products

o Chronically transfused patients

o Patients with previous FNHTRsFebrile Nonhemolytic Transfusion ReactionPatient undergoing cardiac
surgery
o All recipients ( or potential recipients ) of solid organ or hematopioetic cell transpalant
o CMV seronegative at risk patients for whom seronegative component are not supplied

Irradiation to prevent transfusion-associated graft-versus-host disease

(ta-GVHD)

-İrradiation is used to kills the donor leukocyts especially T lenfocyt and NK cell they are targeting all
tissue cells which are foreign to donor leukocyte such as liver , skin, mucosa, hematopoietic cell.
Patient came after one or two week later with skin, mucosa lesion , pancytopenia , liver dysfunction
so we have to prevent GVHD by irradiation RBC Prior to transfusion by subjecting them to 2500 cGy
of irradiation. Blood does not become radioactive after irradiation and not present any danger to
recipient.
-irradiated RBCS have a storage limit of 28 days from either a cesium-137 or cobalt-60 blood
irradiator or x-rays using a standalone machine

Patient groups requiring irradiated components

o Recipients of intrauterine or neonatal exchange transfusion, premature neonates

o Individuals with congenital cell-mediated immunodeficiency states
o Individuals treated with specific types of potent immunosuppressive therapies (purine
analogs. antithymocyte globulin [ATG].

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 o Recipients of hematopoietic stem cell transplant (autologous or allogeneic)
o Individuais with Hodgkin lymphoma (any stage of disease) .
o Individuals at risk for partial HLA matching with the donor due to directed donations.
HLA-matched products, or genetically homogeneous populations. → Because healthy
recipient is ignoring coming donor T lenfocyt but donor T lenfocyt can recognize recipient
as foreign cell result is ta- GVHD Do not transfuse from a relative !!!

Frozen red cells

It is a rarely used method. We don’t use it in Turkey. easy but expensive

- RBC units can be frozen in 40 percent glycerol

-Can be storaged at -80°C for up to 10 years
-in order to meet the transfusion needs of recipients with very rare red cell phenotypes (eg,
Bombay phenotype) . There some network to find this type rare blood
-to transfuse individuals who have developed multiple alloantibodies directed against
common RBC blood group antigens
-for individualsn with immunoglobulin A (lgA) deficiency who have circulating ant-lgA
antibodies

Washed red cells

-It is used to reduce or eliminate complications associated with the small amount of residual
plasma in the unit. It is used in conditions like:
-Severe or recurrent allergic reactions (eg, hives)
-for individualsn with immunoglobulin A (IgA) deficiency who have circulating anti-gA
antibodies . In a patient like that immunoglobulin A different RBC should be given , it is not
possible to find immunoglobulin A defficient donor so washed red cell can be used ,
-iIndividuals at risk for hyperkalemia

• Administrating The Transfusion

Don’t forget Informed consent. Patient should sign it.

It should be obtained from the intended recipient before all non- emergency administration of blood
components . It is a description of the risks, benefits, and treatment alternatives; the opportunity for
the intended recipient to ask questions

• Don’t forget Jehova's witness refuse blood transfusion. Yehovah's Witnesses believe that the
Bible prohibits ingesting Blood and that Cristians should therefore not accept blood transfusion
or donate or store their own blood for transfusion.

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 • Pre-transfusion considerations
*Patient identification - be ensure that the intended transfusion is given to the intended
recipient
*Premedication - Is not recommended routinely to prevent febrile nonhemolytic or allergic
transfusion reactions . If patient developed those reaction you should give Premedication
* Inspection of the unite -All units should be visually inspected before transfusion to see any
coagulation or opening of the bag

• Venous access
Adequate venous access is necessary for RBC transfusion .All RBC units must be transfused
through a standard 170 to 260 micron filter (contained as an integral part of a standard infusion
set) designed to remove clots and aggregates.

• Blood warmers

Stored blood cell is 4 oC this is cold but it is diluted in

body so we don’t need to warm the blood. But in some
condition we have to warm the blood such as:

Exchange transfusion in infant

When the patient has clinically significant cold

agglutinins ( Cold agglutinins are autoantibodies produced by a
person's immune system that mistakenly target red blood cells (RBCs).
They cause RBCs to clump together when a person is exposed to cold
temperatures and increase the likelihood that the affected RBCs will be
destroyed by the body)

Blood rate grater than 50m/kg/hour

Massive transfusion (50% of body volume)

Trauma situation

Cardiopulmonary bypass surgical procedures

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 • Compatible Fluids
RBC should not mix with any solution to prevent lysis No intravenous solutions or
medications except 0.9 percent (isotonic) sodium chloride for injection, should be
administered through the same tubing concurrently with the RBC units.
• Infusion rate

infusion rates for adults are 1 to 2 ml per minute (60 to 120 mL per hour) for the first 15 minutes and
then as rapidly as tolerated. The complete infusion should not exceed four hours

• Effectiveness of RBC transfusion

One unit of whole blood or RBC in a 70-kg- non-bleeding adult responsive to transfusion should
increase the Hcg about 3% or the Hb about 1 g/dl

• Post-transfusion monitoring

The post-transfusion hemoglobin level may be accurately measured as early as 15 minutes following
transfusion, as long as the patient is not actively bleeding.

 Platelets Transfusion Therapy

Hemostasis depends on an adequate number of functional platelets, together with an intact

coagulation (clotting factor) system.

COLLECTION

• Pooled platelets (different donors)

-A single unit of platelets can be isolated from every unit of donated blood by centrifuging the blood
within the closed collection system to separate the platelets from the red blood cells (RBCS)

This is a two step procedure

* 1 unit of platelet is produced from a unit of whole blood.

* 4 - 6 of these units from different donors are pooled together in a single pack. One unit platelet
increases platelet count 5×103

• Apheresis (single donor) platelets

Platelets can also be collected from volunteer donors in a one- to two-hour apheresis procedure,
Platelet unit is collected from a single donor and Other blood componenets plasma and RBCS are
giving back to the donor.

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ABO, Rh, and HLA matching

 Do not prefer ABO-incompatible platelet products

 Platelets concentrates also contain a small number of RBCS that express Rh antigens on their
surface (platelets do not express Rh antigens). If possible prefer Rh matching donor. If platelet
transfusion is not effective think about alloimmunization

Alloimmunization: Platelets express Class i HLAS, which can be recognized by the recipient's immune
system as foreign and anti-HLA antibodies would be produced to destroy those platelets. In thise
patient HLA matched platelets should be given. ABO and HLA compatible platelets appear to cause a
greater platelet count increment in the recipient.

 Both pooled and apheresis platelets contain some white blood cells (WBC) that were collected
along with the platelets.

Dose and infusion rate

Normal platelet count is 150.000-450.000 /mm 3 . In

spontaneously bleeding patient it is 20.000 . We should know Remember
platelet count for adequate platelet transfusion to prevent
bleeding .

A standard dose of platelets for prophylactic therapy in adults is

approximately one random donor unit per 10 kg of body weight
which translates to four to six units of pooled platelets or one
apheresis unit. . For an average-sized adult, six units of pooled
platelets or one apheresis unit of platelets are transfused over
approximately 20 to 30 minutes.

Platelet storage : Room temperature storage

-Platelets storage is different than eritrocyt because cold induces clustering of von Willebrand factor
receptors on the platelet surface and morphological changes of the platelets, leading to enhanced
clearance by hepatic macrophages and reduced platelet survival in the recipient.
-Platelets is agitated in a device called as agitator because if they are not agitated they will get
activiated
-The shelf Ilife of platelets stored at room temperature is generally only five days

Indication For Platelet Transfusion

When platelet transfusion is needed?

• Actively bleeding patient have Thrombocytopenia keep platelet counts > 50.000/microt.
• Preparation for an invasive procedure
• Prevention of spontaneous bleeding use prophylactic platelet transfusion to prevent
spontaneous bleeding in most afebrile patients with platelet counts below 10,000/microL
due to bone marrow suppression

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  Plasma transfusion

Fresh Frozen Plasma (FFP)

It is frozen at -18 to -30*C within eight hours of collection

*Convalescent plasma - Convalescent plasma is plasma prepared from individuals who have
recovered from infection with a specific pathogen such as Covid-19

Indications

• Vitamin K dependent coagulation factor replacement

-Elevated INR(international normalized ratio-PT) due to vitamin K antagonist therapy
-Elevated INR due to other causes of vitamin K deficiency
-Coagulopathy of liver disease , liver transplant
- Disseminated intravascular coagulation (DIC)
• Replacement of specific coagulation factors
- inherited factor XI, II, V. VII, X deficiency. Other factor deficiency is treated by factor
replacement
• Plasma exchange : patient’s own plasma is taken and FFP is given in some conditions such as
thrombotic thrombocytopenic purpura

Dose and İnfusion Rate

 The plasma volume in adults is approximately 40 mL/kg. The typical dose of given plasma is
approximately 10 to 15 mL/kg (ie, approximately three to five units) in most adults
 Standard units of plasma (FFP, PE24, Thawed Plasma) have a volume of approximately 200 to
250 mL . This dose (ie. 750 to 1250 ml of plasma) represents a significant volume challenge
 Heathy Individual 2 to 3 mL/Kg/hour (le, approximately one unit in 15 hours).
 Individual with volume overload or heart failure 1 mL/kg/hour (ie, approximately one unit in
approximately four hours ). Be Careful !!
 Individual undergoing plasma exchange 60 mL/minute, this can be raised to 100 mL/minute if the
situation warrants end this rate is tolerated by the patient's veins.

Plasma Transfusion and AB0 Matching

Identical Plasma Compatible Plasma
Type A Type A Type AB
Type B Type B Type AB
Type 0 Type 0 Type A, B or AB
Type AB Type AB
Plasma contains anti-A and anti-B antibodies depending upon the blood group. Our body
also has antibodies to A and/or B antigens according to our blood group. Patients should
only receive plasma that does not contain an antibody which could attack the antigens
present on their own red cells such as Group A recipients have A antigen on their red cells,
so they can’t receive group O or group B plasma as the anti-A will attack their red
cells. Plasma components of any RhD type can be given regardless to the RhD type of the
recipient.

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ANEMIA AND CONTROL PROGRAMS AS A PUBLIC HEALTH
PROBLEM/ AYŞE EMEL ÖNAL 04.11.2020 10.00 Hazırlayan: Behram BOZ
(Hoca slaytı okudu, vurguladığı bir kısım ya da eklediği bir şey olmadı. Çıkmışlarda daha çok demir
eksikliği ve talasemi ile alakalı sorular var. Sadece bir tane soru “Demir Gibi Türkiye” projesiyle
alakalı.)

• Anemia is the reduction of red blood cells in the blood and hemoglobin in blood. Anemia is
defined as hemoglobin below 13 g / dl in men, 12 g / dl in women and 11 g / dl in pregnant
women.

• The most common causes of anemia;

• red blood cell production is below normal.

• or there is more than normal destruction and loss of red blood cells.

• In some hereditary blood diseases, distorted red blood cells are made.

• Iron deficiency anemia is the most important cause of low red blood cell production.

• Iron deficiency anemia is the most common type of anemia in the community.

• Vitamin B12 deficiency and folic acid deficiency cause anemia (megaloblastic anemia).
• The hereditary blood disorder thalassemia is among the most common diseases, especially in
Mediterranean countries such as Turkey.

• Beta thalassemia type is also called Mediterranean anemia.

• Iron deficiency and thalassemias are hypochromic microcytic anemias.

• Beta thalassemia is a preventable disease due to its prevalence, detection of carriers,

genetic counseling and prenatal diagnosis, and is therefore an important disease for Public
Health.

• Iron deficiency anemia is important for public health since it is a preventable disease by
regulating nutrition and providing iron and folic acid preparations by detecting deficiency
early.

• Anemia is the most common blood disorder in the world and Turkey, and one-fourth of the
world population is affected by iron deficiency anemia.

• The highest prevalence is in infants and pregnant women, followed by women of

childbearing age. It is also common in the elderly.

• Iron deficiency anemia is 1-2% in adults and 12-17% over 65 years of age.

• Iron deficiency anemia is more common in developing regions where nutritional deficiencies
are higher. However, iron deficiency anemia is also a problem in developed countries.

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• According to WHO, 50% of women and children in developing countries and 25% of men
have iron deficiency anemia.

• In Turkey, approximately 50% of children in the 0-5 age group, 30% of school age children,
iron deficiency anemia is seen in 50% of lactating women.

• The most common causes of iron deficiency anemia are blood loss, malnutrition, and
inadequate iron absorption.

• There are 3-4 grams of iron in our body. 2 g of this is found as hemoglobin iron, 1 g is storage
iron (ferritin, hemosiderin), the rest is found in tissues and transport iron.

• Reduction of erythropoiesis results from absolute iron deficiency or functional iron

deficiency.

• There is no storage iron in absolute iron deficiency.

• In functional iron deficiency, storage iron is normal or increased, iron cannot be

supplied for erythroid precursors.

• Iron deficiency anemia has hypochromic microcytic anemia and low serum ferritin.

INCREASE IN IRON NEED

• blood loss (gastrointestinal tract)

• bleeding diathesis (tendency to bleed or bruise easily)

• bleeding from the respiratory system

• bleeding of the urogenital system

• as a result of repeated examinations or blood donations

• with rapid growth in infants, children and adolescents

• with pregnancy, birth and lactation

INSUFFICIENT IRON INTAKE

• It is caused by malabsorption;
o helicobacter pylori-associated autoimmune gastritis
o subtotal gastrectomy
o celiac disease
o frequent antacid
o proton pump inhibitor use

• Intravascular hemolysis and hemoglobinuria may also cause anemia.

• The mutation of tmprss6 gene with increased plasma hepcid and the genetic defect in iron
transporter enzyme may cause iron malabsorption and disuse.

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SYMPTOMS OF IRON DEFICIENCY ANEMIA
• Paleness

• Palpitation

• Fatigue

• Dizziness

• Headache

• Glossitis (soreness of the tongue, or more usually inflammation with depapillation of the dorsal
surface of the tongue)

• Stomatitis (inflammation of the mouth and lips, any inflammatory process affecting the
mucous membranes of the mouth and lips)

• Dysphagia

• Pica (earthenware) [psychological disorder characterized by an appetite for substances that are
largely non-nutritive, such as ice (pagophagia), hair (trichophagia), paper (xylophagia)]

• Pagophagia (eating ice)

• Restless leg syndrome (overwhelming urge to move your legs, it can also cause an unpleasant
crawling or creeping sensation in the feet, calves and thighs; no known cause, may occur due
to imabalance of the brain chemical dopamine)

CONTROL OF IRON DEFICIENCY ANEMIA

• Five basic applications are important in the control of iron deficiency anemia. These are;

1-Determination of the prevalence of anemia

2-Public nutrition education

3-Iron support

4-Control of viral, bacterial and parasitic diseases

5-Measures to enrich food with iron (flour should be enriched with ferrous sulfate or ferrous
fumarate).

• Prevention and control of iron deficiency anemia during infancy and childhood is absolutely
necessary. At birth, the baby is born with iron stores sufficient for the first 6 months
and the storage iron levels gradually decrease 6 months after malnutrition.

• When the baby reaches three times the birth weight, the baby needs to reach double in the
iron storage.

• 100 ml of breast milk contains 0.8 mg of iron and its absorption is 50%. (In normal diet, adult
absorption of iron is 10%).

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• The most important iron source in the body is iron (20 mg) which is released by the
destruction of old erythrocytes.

MAIN CAUSES OF ANEMIA IN INFANTS AND CHILDREN

• Starting additional foods before 6th month, giving breast milk along with additional foods
before 6th month

• Not to start additional nutrients from the 6th month, due to lack of knowledge, iron source
foods are not given in sufficient time and the bioavailability of the foods given is low.

• Failure to meet the increasing iron need with rapid growth

• Inadequate iron stores when the baby is born (due to low birth weight, umbilical intervention
before the completion of placental blood transfer at birth)

• Inclusion of tea in chid nutrition, high pytates (cereals and legumes), grains (tea, coffee),
oxalate (spinach) in diet, very little or no meat in diet, insufficient vitamin C intake.

FOOD CONTAINING IRON

• Liver, red meat, chicken and fish meat

• Egg

• Grape and molasses

• Dried legumes (soaking reduces the effect of phytates)

• Dried fruits such as dried apricots, raisins, dried mulberries

• Green leafy vegetables (spinach, chard)

• Nuts, peanuts and sesame seeds

FOOD CONTAINING PHYTATE

• Whole grains and legumes contain compounds called phytate, which adversely affect the
absorption of both non-iron (plant-derived iron). Apart from whole grains and legumes, this
compound can be found in nuts, seeds, bread, rice, peas, cereals and soy products.

• Phytate-containing foods such as whole grains and legumes are also very important sources of
non-hem iron. In other words, their consumption also increases iron intake and therefore
does not cause a significant deficiency.

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TANNIN

• Due to the presence of a compound called tannin in coffee and tea, iron absorption may
deteriorate. Tannin is a type of polyphenols and has a strong inhibitory effect on iron
absorption.

• Other beverages with tannins (other than tea and coffee) are red wine, cider and beer.

• However, they can be protected from their inhibitory effects by not drinking these beverages
two hours before and after an iron-rich meal.

OXALATE
• Oxalate is an oxalic acid salt or ester that reduces iron absorption in the body.
• Spinach is rich in non-hem iron but contains oxalates. This explains why there is too much iron
in spinach but less absorbed..

• However, the effects of oxalates can be prevented by consuming these foods with foods rich
in vitamin C, such as meat and oranges and broccoli.

• In addition to spinach, oxalates are also found in beets, cabbage, tea, chocolate, basil, parsley
and thyme.

FOODS AFFECTING IRON ABSORPTION

• Foods that prevent iron absorption: Tea, coffee, milk and dairy products, spinach, corn,
wheat, some medicines.

• Foods that increase iron absorption: Vit C-containing foods, meat, fish, amino acids in non-
meat nutrients (leafy vegetables, eggs, milk, etc.).

• A standard diet contains 10-15 mg of iron.

• Only 1-1.5 mg of this is absorbed.

IRON CONTENT OF FOOD

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IRON ABSORPTION OF THE FOOD

TEA & MILK INTAKE AND IRON ABSORPTION

IRON DEFICIENCY ANEMIA CONTROL IN TURKEY

!!Note!!: I think this webpage is more explanatory about the topic.

Iron-Like Turkey Project Circular 2004/21

Count: 21

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T. C. MINISTRY OF HEALTH General Directorate of Maternal and Child Health and Family Planning, 19
February 2004, ANKARA

Issue: B100AÇS0140000 Subject: Iron-Like Turkey Project

As it is known, approximately half of all deaths in our country

are seen in children under the age of 5 and malnutrition is the
main cause of these diseases. Again in this age group,
nutritional problems, growth and developmental retardation,
anemia, vitamin deficiencies, iodine deficiency diseases and
dental caries are seen.

Iron deficiency anemia, which is vital for all age groups,

generally occurs in 50% of children and pregnant women in the
0-5 age group.

In order to solve this important public health problem, our

ministry has; to raise awareness of the society about iron
deficiency, to ensure that:

• babies receive breast milk for the first 6 months and to continue breastfeeding until the age
of 2 by switching to appropriate and adequate amounts of nutrients at the end of the 6th
month
• providing free iron support to every baby between 4-12 months for prophylactic purposes
• providing the recommended treatment for infants with iron anemia

This project was initiated as “protection, promotion and

support of breastfeeding in order to minimize health problems
related to iron deficiency”.

For every 4 months old baby, free iron preparation is started

orally (4 drops at a time).

For 6 months old baby → recommended dose = 1 mg/kg/day.

Ferro Sanol drops → 9 drops per day, one bottle is enough for
three months.

Ferrum drops → One bottle is enough for 5 months of use.

!!Note!!: Full-term healthy babies receive enough iron from

their mothers in the third trimester of pregnancy to last for the
first four months of life. Infantswho are exclusively breastfed are at increased risk of iron deficiency
after four months of age. The AAP (American Academy of Pediatrics) clinical report, “Diagnosis and
Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children 0 Through
3 Years”, recommends giving breastfed infants 1 mg/kg/day of a liquid iron supplement until iron-
containing solid foods are introduced at about six months of age. When you add solid foods to your
baby's diet, continue breastfeeding until at least 12 months. (link)

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Premature babies born with a weight below 2500 gr → should be started at the 4th month (2 mg/kg/
day and once daily for 5-6 months).

If palmar paleness is detected in the baby between 12-14 months, Hb measurement is made and
if anemia is diagnosed, each baby is prescribed iron preparation (3mg/kg/dose for 3 months).

Infants who are treated with anemia are followed up 1 month after the initiation of medication.

Any infant and child whose Hb value is less than 7 g and Htc value is less than 21% is referred
to the hospital urgently.

The best absorption in the treatment with iron preparation is the first week. After the hemoglobin
concentration has returned to normal, treatment should be continued for two to three months until
the serum ferritin level reaches 30 μg/dl, or the amount of depot iron increases to 250-300 mg.

In addition, vitamin A, zinc and riboflavin supplements should be considered for 6-18 months.

Each pregnant woman is prescribed 100 mg iron + 350 mcg folic acid at the end of the third
month.

In adults, a daily dosage of 100-200 mg of iron preparation is sufficient.

Iron deficiency anemia should be confirmed by erythrocyte microcytosis (MCV <80 fL),
hypochromia status and low serum ferritin (limit value 12-15 mg / L).

EFFECTS OF IRON DEFICIENCY ANEMIA ON HUMAN HEALTH

• Weakness in physical and learning capacity
• Irritability, low concentration
• Forgetfulness
• Decreased resistance to infections
• Burning sensation in the tongue (glossitis),
• Fractures of the lips (angular stomatitis)
• Fragile, straight nails (spoon nails)
• Hair Loss
• Skin pallor
• Weakness
• Dizziness, headache, tinnitus
• Anorexia or abnormal appetite, difficulty swallowing, esophagitis
• Progression of significant health problems

o Tachycardia, heart enlargement, shortness of breath

o Mental retardation

o Motor developmental retardation

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 o Conduct disorder (grumpy, restless, maladaptive, crying, child not sleeping at night)

o Psychological developmental delay

THALASSEMIA

• Hemoglobin production is under the control of genes, and thalassemia occurs when a familial
genetic defect results in the failure or disruption of one of the globin chains that
make up hemoglobin.

• Hb: Hem + Globin

• Hem: It consists of 4 pyrrole rings and one iron atom.

• Globin: It consists of 2 different pairs of globin.

• Which of the globin chains cannot be synthesized or whose synthesis is reduced, thalassemia
is called by its name. For example, changes in beta globin synthesis lead to beta
thalassemia disease, and changes in alpha globin synthesis cause alpha thalassemia.
• At least 365,000 thalassemia patients are born and treated in the world every year.
approximately 1,300,000 thalassemia carriers in Turkey and has 4,500 thalassemia patients.

• Carrier frequency is 2.1% (1.3 million carriers) in Turkey. Carrier is also called thalassemia
minor. The thalassemia patient is also called thalassemia major.
• One out of every 50 people in Turkey (Antalya, Adana and one out of every 10 people in
Southeast Anatolia) is a carrier for the disease.

• Beta thalassemia carriage 13% in Antalya, 6.4% in Edirne, 6.4% in Urfa, 5.1% in Aydın, 4.6% in
Antakya, 4.8% in İzmir, Muğla 4.5% in Istanbul and 4.5% in Istanbul. Mediterranean, Aegean
and Thrace regions are the regions with high transportation.

• Carrier thalassemias are mild bloodless and do not benefit from iron therapy.

• Diagnosis of thalassemia carriage is made by complete blood count and hemoglobin

electrophoresis. HLPC (High pressure liquid chromatography), PCR (molecular chain
reaction) can also be performed.

• Hemoglobin and MCV values are low in whole blood count. In hemoglobin
electrophoresis, A2 and/or F is elevated.

• Normally A1 Hb is 97-98%, A2 Hb is 2-3%, Fetal Hb <1%.

• According to the World Health Organization,

thalassemia and abnormal hemoglobin
carrier frequency in the world is 5.1% and
there are approximately 250 million carriers.

• Hemoglobin disorders are common in most

of the tropical countries.

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• In addition, the frequency of recessive inherited diseases increases in regions where
consanguineous marriage is common.

• Related studies have been initiated by Muzaffer Aksoy thalassemia in Turkey in 1957. The
first studies showing the incidence of thalassemia were made by Arcasoy and Çavdar.
Carriage rate of the disease was reported to be 2.1% for Turkey. Different incidence rates
have been determined in different regions of the country (between 0.6-12%).

• In the world, the prevalence of beta thalassemia is high in the Mediterranean countries, the
Middle East, Asia, Southeast China, the Far East countries as well as the North African coast
and South America.

• The highest carrier frequency was reported in Cyprus (14%), Sardinia (10.3%) and
Southeast Asia (13).
• It is estimated that around 1.5% of the world's population (80-90 million people) has beta
thalassemia carriers.

MICROSCOPIC IMAGE OF RED BLOOD CELLS IN THALASSEMIA

TRANSPORT

THALASSEMIA MAJOR

• Also known as Mediterranean anemia. It is a very serious

blood disease that starts at 3–4 months and requires
continuous blood transfusions. These children cannot
do enough hemoglobin for themselves.

• Weakness, paleness, loss of appetite, restlessness,

liver,spleen and heart enlargement result in abdominal

<< 126 >>

 swelling, frequent fever changes in the skeletal system, changes in bones starting from the
face and head bones and typical facial appearance, dark urine (a sign of destruction of red
blood cells), delay in growth (anemia can both slow a child's growth and delay puberty.),
yellowness (skin or eye flux takes a yellowish color)

• These patients have to receive regular

treatment throughout their lives. The
treatments are difficult and expensive. Life
depends on blood transfusions and iron-
binding therapy administered every 3-4
weeks. Support treatment (splenectomy,
vitamins, minerals), treatment of
complications, bone marrow
transplantation may be necessary.

• Iron in the diet is reduced.

• 1mg / day folic acid is recommended.

• Hepatitis A and B vaccines are given.

**8 mayıs dünya talasemi günü***8 mayıs dünya talasemi günü***8 mayıs dünya talasemi günü**

The aim of Public Health is to identify the carriers. Therefore, carriers should be made aware.
Especially in consanguineous marriages, the risk of having a sick child is high.

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PREVENTION
1. Community education: The community should be educated about beta thalassemia and informed
about the risks of consanguineous marriages.

2. Detection of carriers: Screening of all relatives of patients and carriers with blood tests, especially
in areas with high rates of carriage, and informing couples to marry.

3.Genetic counseling: If both spouses are carriers, spouses should be counseled, referred to genetic
diagnosis centers and necessary tests completed before pregnancy (sample mutation analysis).

4. Prenatal diagnosis: In case of marriage of two carriers, couples should consult a doctor in the early
period of each pregnancy (first 2 months) and have the necessary examinations done. If two carriers
get married, the prenatal diagnosis can be made in the following weeks.

Today, the birth of a thalassemic child can be prevented by prenatal and preimplantation
(in vitro fertilization) diagnostic methods.

İNGİLİZCE ÇIKMIŞLAR
1)What laboratory examination is not required to diagnose iron deficiency?

Hemoglobin electrophoresis

TÜRKÇE ÇIKMIŞLAR
1)Aşağıdakilerden hangisi T.C. Sağlık Bakanlığı'nın yürüttüğü 'Demir gibi Türkiye" Projesinin
hedeflerinden bir değildir?

Cevap : Demirle suların zenginleştirilmesi

2)Demir eksikliği anemisinin epidemiyolojisi ile ilgili aşağıdaki seçeneklerden hangisi yanlıştır?

Cevap : Gelişmiş ülkelerde hiç görülmeyen sağlık sorunudur.

3)Akdeniz Anemisi aşağıdaki hangi hastalığa verilen isimdir ?

Cevap : Talasemi majör

4)Demir eksikliği anemisi için aşağıdakilerden doğru olanı işaretleyiniz.

Cevap : Hipokromi, mikrositoz, düşük ferritin

5)Toplum icinde talasemi kontrolunde yapılması gerekenleri iceren seceneği işaretleyiniz.

(I) Halkın eğitimi

(II) Taşıyıcıların tespiti

(III) Genetik danışma

(IV) Prenatal (doğum oncesi) tanı

(V) Besinlerin demirle zenginleştirilmesi

Cevap : I, II, III, IV

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