HEMAT-ONCOLOGY

DR.SRINATH.CHANDRAMANI
Asst. Prof & ICU in-charge
K.J. Somaiya Medical College,
Mumbai

Hematology
Hematology is the study of Blood and its
constituents.
Considering that blood is the vital fluid in the body
which is delivering Oxygen, nutrition, antibodies,
clotting factors and at the same time transporting
back carbon dioxide and the metabolic waste
products; hematology is a vital science.

Decoding Hematology

Hematological Disorders can be classified on

the basis of the cell line they dominantly
affect into :
A. RBC related disorders
B. WBC related disorders
C. Coagulation related disorders.

RBC Physiology

RBC Disorders

Iron deficiency Anaemia

Most common cause of microcytic,

hypochromic anaemia.
Nutritional Deficiency along with
menorrhagia make IDA Femalepredominant disease
Clinical features

Iron deficiency Anaemia

Lab investigations
RBC indices
Treatment
Oral vs. Parenteral iron therapy

Differential diagnosis

Prognosis

Sideroblastic Anaemia

What is a Sideroblast ?
Where are they present ?
ALA synthase + Pyridoxal phosphate
2 forms Genetic vs. Acquired
D/d of Sideroblasts.
Response to B6 supplementation.

Other Hypoproliferative states

CAUSE
APLASTIC ANAEMIA

PATHOPHYSIOLOGY
EXPLAINED NEXT

CHRONIC RENAL FAILURE DECREASED EPO, IRON DEFICIENCY

RA/SLE, ETC

DECREASED EPO (IL-MEDIATED)

HYPOTHYROIDISM

DECREASED EPO SYNTHESIS DUE TO LOW

TISSUE OXYGEN DEMAND
FAMILIAL EPO RECEPTOR DEFICIENCY / RESISTANCE
PROTEIN ENERGY
MALNUTRITION

GENERAL DEBILITY

Aplastic Anaemia
Commonest cause is Idiopathic
Post-Viral
Drug induced
Chemotherapy/radiotherapy induced
Role of steriods
Role of ATG
Role of Bone Marrow transplant (BMT)

Megaloblastic Anaemia
B12 & Folate deficiency
Etiology Diet, Parasites, drugs,
Malabsorption syndromes.
Clinical features
D/D of Macrocytic anaemia
Treatment

Myelodysplastic syndrome

Pre-malignant condition Acute leukamia

Radiation only & main risk factor
Genetic cases recorded
Old age presentation
Types
Commonly Pancytopenia
Diagnosis
Treatment
Prognosis

Hemolytic Anaemia

Cytoskeletal defects

Spherocytosis / Elliptocytosis
Spectrin defect
Mild hemolytic anaemia
Auto-Hemolysis
Splenomegaly
Splenectomy curative

Enzyme deficiency
RBC metabolism 80% by HMP shunt
Glutathione needs to be in reduced form
In G6PD, Glutathione in in oxidised state, leading
to hemolysis.
Since reserve is sufficient, hemolysis only occurs
when there is oxidative stress.
Following drugs are contra-indicated in G6PD
states.

Hemoglobin defects

HBS Sickle cell disease Glu Val at 6.

Clinical features Auto-splenectomy
Emergencies
Diagnosis
Treatment
Prognosis

Thalassemia
Normally Embryonic Hb at 6 weeks
Fetal HB from 11 weeks
Adult HB from 38 weeks
HbA 80-90%
HbA2 14-15%
HbF 0-5%
4 genes code alpha-chain
2 genes code beta-chain.

Alpha-Thalessemia
1 gene defect
2 gene defect
3 gene defect
4 gene defect

asymptomatic
HbH trait
alpha-thal
Hydrops fetalis

Beta-thalessemia
1 gene defect 2 gene defect Gene mutation -

B-Thal minor
B-thal major
Intermedia

Beta-thalessemia

Clinical presentation
Diagnosis
Treatment
Role of chelating agents

Paroxysmal Nocturnal Hemoglobinuria

Acquired intra-corpuscular defect

Decay accelarating factor (DAF) defect
Lysis due to complement mediation.
Usually follows aplastic anaemia
Hemoglobinuria only in 1st urine sample
Precipitating factors
Diagnosis Acid HAM test, Sucrose lysis, CD59 & DAF
detection by flow cytometry.
Treatment & Prognosis

Auto-immune Hemolytic anaemia

POLYCYTHEMIA
Defined as increased RBC in circulation
RBC mass differentiates spurious cases
Hb > 17.5 or PCV > 50 is diagnostic.
Presents incidentally or as
Hyperviscosity syndrome.

Approach to Polycythemia

Polycythemia rubra vera

Commonest of all myeloproliferative
disorders.
Monoclonal proliferation of
pleuripotent stem cells in absence of
physiological stimuli is characteristic.

Polycythemia rubra vera

Pathophysiology MpL mediated (Modified

thrombopoietic factor)
Etiology unknown
Clinical features : Massive splenomegaly,
Erthromelalgia, Aquagenic pruritis, Gout,
Gastritis, thrombotic events.

PRV

Diagnostic criteria of PRV

Raised red cell mass
Massive splenomegaly
Normal Arterial Oxygen concentration
BM not essential.
JAK-2 mutation, Increased LAP score,
Uric acid, B12 levels are supportive.

PRV

Aim of therapy
Treatment options
Hydroxyurea, Chemotherapy, Aspirin.
Radioactive phosphorus 32.
Anagrelide
Allogenic BMT
Prognosis

Test 1
Includes :
RBC disorders

 Totipotent stem cells

Myeloblast (recognisable precursor)

Promyelocyte
Myelocyte

Metamyelocyte
Band forms
Mature WBC

WBC PHYSIOLOGY

WBC DEFECTS
Deficiency Quantitative vs. Qualitative
Quantitative : Neutropenia, Lymphopenia
Qualitative : Chediak Higashi syndrome
Leucocyte Adhesion defect
Oxidation defects
Immune deficiency states

Qualitative defects
Chediak Higashi syndrome
Chemotactic defects.
Associated delayed lysosome release
Recurrent infections
Leucocyte Adhesion defect
Margination defect
Delayed falling of umbilical stump
Oxidation defects
Nitroblue Tetrazolium test
Dihydrorhodamine oxidation test

WBC excess states - Benign

Leucocytosis
Lymphocytosis
Eosinophilia
Infectious Mononucleosis
Leukamoid reaction

Normal eosinophil 150-350/mm3

Eosinophilia Mild 350-1500
Moderate 1501-5000
Severe - >5000

Eosinophilia

Classification:
1. Loefloes syndrome/ Simple pulmonary eosinophilia
2. ABPA
3. Drug induced
4. Tropical eosiniphilia
5. Churg Strauss syndrome
6. Hypereosinophilic syndromes
7. Chronic/ Prolonged pulmonary eosinophilia
8. Acute eosinophilic pneumonia

Infectious Mononucleosis

Characterised by increase in Macrophagemonocyte count mimicking leukamia.

Differentiated by Absence of Blast cells
Follows EBV infection
WBC > 20000.
Paul Bunnel reaction/ Heterophile antigen
D/D CMV / Cat scratch disease
Complete recovery in 2 months.

Leukamoid reaction
Parameter
Clinical features
WBC
NAP score
Anaemia
Platelets
Splenomegaly
BM infiltration
Blasts
Karyotyping

Leukamoid react
Underlying cause
Usually <1,00,000
Elevated
Rare,
non toxic look
6-7 lacs.
Absent
None
< 5%
Normal

Leukamia
No apparent caus
>1,00,000
Reduced
Common,
toxic look
> 10 lac
25-50%
Present
> 5%
Abnormal

WBC excess states - Neoplastic

Leukamia
Myeloproliferative states
Lymphoma
Multiple Myeloma &
Paraproteinemias

Leukamias
Leukamias are malignant neoplasms of
hematopoietic system, arising in the bone marrow,
that flood the circulating blood or other organs.
Classified on basis of cell type involved and state
of maturity of leukamic cells :
AML, ALL
CLL, CML

Acute Myeloblastic leukemia

Common in young and middle age

FAB classification
Auer rods & lower Nuclear : cytoplasm
Chemotherapy Duanorubicin, Cyotosine
arabinoside, Etoposide, Thiogaunine.
80% remission but only 30% 5 yr survival. BMT
improves remission to 50%.
ATRA (all trans retinoic acid) oral For M3.

ALL

Commonest in children.
Presents as hepatosplenomegaly & LNs.
Classification (Working classification)
CNS infiltration is almost certain. Hence
intrathecal methotrexate/ Radiation is
mandatory.

ALL

Chemotherapy 3 phases :
Adriamycin, Vincristine,
Prednisolone and L-Asparaginase.
Oral Methotrexate/Mercaptopurine& prednisolone.

Poor prognosis Philadelphia chr.

All translocations have worse prognosis.
L2 & L3.

CML
Myeloproliferative disease
90% have Philadelphia chromosome
50% of PH ve have ABL-BCR defect.
Alpha-interferon
Busulphan/Hydroxyurea
Leukapheresis
Splenectomy

CLL
Most common variety of leukamia
Treatment only if symptomatic.
Coombs positive anaemia
Chlorambucil / cyclophoshamide
Fludarabine

Hairy cell Leukamia

Lymphoproliferative B-cell disorder
CD25 & FM C7 hairy cells
Tatrate resistant acid phosphatase staining
High LAP score
Vasculitis
Interferons
Splenectomy

Lymphomas
Lymphomas are malignant proliferation
of the lymphoid system.
Classified into :
Hodgkins (HL)
Non-Hodgkins (NHL)

Hodgkins disease
Progressive, painless lymphoid enlargement
Reed sternberg cell
4 types : Lymphocyte predominant
Nodular sclerosis
Mixed cellularity
Lymphocyte depleted

Hodgkins disease
Lymphadenopathy cervical > mediastininal >
axillary >
Alcohol induced worsening
Pel Ebstein fever
LN biopsy diagnostic
Type A and B symptoms
Chemotherapy & Radiotherapy
Prognosis

Non-Hodgkins Lymphoma

70% of all lymphomas

Non contiguous LN spread
ENT and GIT commonly involved
Chr. Alterations common
BM involvement is stage 4 disease
CHOP regime / Rituximab CD 20
Poor curability
HIV

Plasma cell dyscrasias

Monoclonal gammopathies :

Multiple myeloma
Waldenstorms macroglobulinemia
Heavy chain disease
MGUS

Multiple Myeloma
M-Band in serum
Defective immunity
Long pre-clinical phase
Hypercalcemia/ Hyperviscosity syndrome
Renal insufficiency in 50%
Urine BJ/ Tom Harsfall protein

Conditions with BJ positive

Primary Amyloidosis
Waldenstorms Macroglobulinemia
Malignant lymphoproliferative disorders
Idiopathic BJ proteinuria

MGUS only observation.

Waldenstorms alpha chain disease, jejunal
biopsy is diagnsotic.

Transfusion Facts

Whole blood and components

PCV
FFP
Platelets
Cryoprecipitate

Crystalloids/ Colloids/ Flourocarbons

Transfusion related disorders

Infections
Chelation
Iron overload

Test 2
Includes :
Wbc disorder
Transfusion medicine

Platelet & Coagulation Physiology

Hemostasis achieved by 2 pathways:
A.Primary Primary adhesion
White Thrombi
Mainly in arteries (mi)
Platelet activation
Hence antiplatelets more
Platelet aggregation
effective

B. Secondary - Intrinsic Pathway

(coagulation Minor
Prolongs APTT
cascade)

Blocked by Heparin
(Binds all except vii a)

Extrinsic Pathway
Major
Prolongs P.t.
Blocked by Warfarin
(ii, vii, ix, x)

Platelet function depends on both quantity and quality

Quantity
<1,00,000 observe
<50,000 on trauma/minor
<20,000 serious risk

Quality
Bleeding time sensitive index
1mm deep x 9 mm puncture
Forearm B.P. cuffs 40 mm
B.T>15 mins 20 mins at risk of
bleeding
Not good for pre-op due to high
diurnal variations

Platelet disorders
Quantitative : Thrombocytopenia
Thrombocytosis

Qualitative : Described ahead

Causes of thrombocytopenia
A. Decreased production of platelets C. Increased destruction of circulating platelets
Non immune
Bone marrow aplasia
DIC
Tumour infiltration/ fibrosis
Vascular prosthesis, cardiac bypass
Drug induced
HUS
Sepsis
B. Increased sequestration
Vasculitis T.T.P
Splenic enlargement due to
Immune mediated
tumour invasion
Autoantibodies to platelet antigen
Splenic enlargement due to portal
Drug associated
hypertension
Circulating immune complexes
-SLE
-ITP
-Bacterial sepsis
-viral agents

ITP

Auto-immune destruction
Post infectious
Variable presentation
IC bleed dreaded
Transfusion
IVIG, Plasmapheresis
Rituximab

TTP
Platelet vessel wall disorder
Defect in metalloprotease ADAMS-13
Etiology

- Pregnance, Malignancy,
High dose chemotherapy, - Milomycin C
HIV, Drugs Ticlopidine
- Rarely inherited deficiency recurrent TTP
autosomal recessive

TTP

Dissemminated Intravascular coagulation (DIC)

DIC is widespread activation of the coagulation pathway by various factors. This
leads to consumptive coagulopathy leading to hypofibrinogenimia,
thrombocytopenia. Accompanied by secondary fibrinolysis, it can lead to subtle
to life threatening bleeding, especially through skin and mucous membrane.
ETIOLOGY OF DIC
A. Increased tissue factors
Obstetric causes :Abruption ,Amniotic fluid embolism
Malignancy Mucinous adenocarcinoma
Frost bite, Burns, Gunshot Wounds
Hemolysis
Fat embolism

B. Endothelial damage
Aortic aneurysm
Acute glomerulonephritis
Hemolytic uremic syndrome
C. Infections
Bacterial Streptococci, Pneumococci, Meningococci, GramNegative
Viral Arbovirus, HIV, Varicella, Rubella
Mycosis Acute Histoplasmosis
Parasitic Malaria, Kalaazar
Ricketssiel Rocky Mountain spotted fever
D. Misc
Snake bite

HIT
HIT is of two types:
TYPE 1
1. Occurs because of initial platelet aggregation by heparin
2. It is transient, mild
3. Does not require treatment or discontinuation of Heparin
TYPE 2
1. Occurs due to its activity of inactivating factor x a and other factors
2. It interacts with platelet factor 4 and forms antibody complexes
3. These platelets are rapidly cleared by the microphages and
Reticuloendothelial system
4. It is sever and may lead to fatal bleeding
5. It requires early recognition and Heparin disconitnuation

Qualitative platelet disorders

Congenital
Bernard-Soulier, Thromboasthenia
Disorders of ADP secretion

Acquired
Drugs NSAIDS, Aspirin, etc
Uremia

Summary Disorders of primary pathway (platelet-related)

Platelet adhesion
Von Willebrands factor deficiency
Absence of Gp I/ix
Platelet aggregation
Glanzmanns thromboasthenia
( Gp ii b/ iii a deficiency/ dysfunction)
Defects of platelet release
Drug induces Aspirin Cox inhibition
Congenital defects
Uraemia
Platelet coating (Penicillin/ paraproteins)
Defects of platelet coagulant activity
Scotts syndrome.

Von Willebrand Disease

Autosomal inheritance
Interferes with platelet adhesion GpIb
Types
Clinical presentation
Treatment :
Desmopressin, Cryoprecipitate

Coagulation Cascade

Disorders of secondary hemostatic pathway

Prolonged PTT
No active bleeding XII, HMWK deficiency
Mild bleeding IX Christmas factor
Mod. To severe VIII Hemophilia B
Prolonged PT
Vit. K deficiency early
Liver failure
Factor vii deficiency
Warfarin administration

Disorders of secondary hemostatic pathway

Both prolonged
Vit. K-Late (involves common pathway)
High/Prolonged Heparin administration
Warfarin, Dysfibrogenemia
Factor II, V, X deficiency
Not corrected by plasma
Coagulation inhibitors e.g. Anticoagulant Ab
(especially chronic factor replacements)
Clot solubility in 5M urea XIII deficiency
Rapid clot lysis 2 plasmin inhibitor

Hemophilia

A&B
X-linked recessive
Presentation
Treatment
Prognosis

Hyper coagulable states

Inherited Defective Coagulation inhibition
1. Factor 5 mutation (Leiden 5)
- Resistance to protein c
2. Protein S, Protein C deficiency
- Thrombin with thrombomodulin
stimulates protein C, which inhibits 8a
Autosomal dominant
More venous thromboembolism
and 5a
- Supported by Protein S
3. Antithrombin 3 deficiency
- Neutralises all clotting factors except 7 a
4. Prothrombin gene mutation
Impaired clot stability
1. Dysfibrogenemia
2. Plasminogen deficiency
3. TPA deficiency
4. Plasminogen activator inhibitor excess (PAI-1)
Unknown mechanism HyperHomocystinemia

Hyper coagulable states

Acquired
Physiological states
Pregnancy
Obesity
Post operative Immobilizations
Old age

Pathological states
Malignancy
Nephrotic syndrome
Lupus Anticoagulant
T.T.P
Estrogen excess
Hyperlipidemia
Diabetes Mellitus
Congestive heart failure
Paroxysmal nocturnal hemoglobinuria
(PNH)

Antiphospholipid syndrome
It is a characteristic syndrome presenting as
thrombotic events, presence of aCL, 2glycoprotein 1.
Has all types IgM, IgG, IgA
Automimmune is IgG3, Drug induced is IgG1

At least one clinical criterion and one laboratory criterion must be present for a patient to be
classified as having APS.
The clinical criteria are as follows:
Vascular thrombosis
One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or
organ
Thrombosis may involve the cerebral vascular system, coronary arteries, pulmonary system,
arterial or venous system in the extremities, hepatic veins, renal veins, ocular arteries or
veins, or adrenal glands.
Pregnancy morbidity
One or more late-term (>10 weeks' gestation) spontaneous abortions
One or more premature births of a morphologically healthy neonate at or before 34 weeks
gestation because of severe preeclampsia or eclampsia or severe placental insufficiency
Three or more unexplained, consecutive, spontaneous abortions before 10 weeks gestation
Laboratory criteria: Patients must have (1) medium to high levels of immunoglobulin G (IgG) or
immunoglobulin M (IgM) anticardiolipin (aCL), (2) antibeta-2 glycoprotein I, or (3) LA
on at least 2 occasions at least 12 weeks apart

BMT
Autologous
Allogenic
Procedure
Role of CSFs
Peripheral Autologous stem cell
transplant