CELL TYPE Eosinophil basophil

FUNCTION fight parasitic infections often indicates a hematologic disease such as CML

SIZE

APPEARANCE large orange granules dark purple to black irregular cytoplasmic granules that obscure nucleus; rarest type of WBC

normal count

lymphocytes monocytes

T and B cells; assoc w/ viral RBC is size of a nucleus of a resting infections lymphocyte travel to tissues where they has pseudopods and vacuoles in nucleus mature into macrophages, ID and phagocytose foreign particles, assists lymph in mounting an immune response by antigen processing; clump at site of injured BV to form plug and inhibit bleeding transport O2 130,000-400,000 plts/uL

platelet

erythrocyte (RBC)

6-8 microm.

anucleated biconcave cell filled w/ Hb that stain salmon pink under wrightgiemsa stain w/ zone of pallor covering 1/3 of their center

DISEASE CAUSES ANEMIA iron deficiency anemia hematological, nutrition, metabolic dx; kids: diet; young women: menstration; older: GI bleed (#1 cause); 2/3 found in RBCs, 1/3 in storage in BM, liver, spleen; causes: blood loss, inadeq diet, malabs., diversion to fetus during pregnancy/lactation, intravasc hemolysis, combo; prevalence: White women 18-44 and AA of both sexes; Poverty strong predictor for iron def b/c its found in red meats; clinical sx cont... growth/metabolism: can cause or contribute to thermal dysreg,gastric achlorhydria (which further impairs iron absorption); made worse by agents such as PPI

CLINCIAL FEATURES signs/sx: Fatigue,irritability related to exercise, HA, parasthesias, burning of the tongue (likely due to tissue cell iron def); Pica (unusual/obsessive food craving); pagophagia(craving for ice);Restless leg syndrome; Pallor; Glossitis; Stomatitis; Angular cheilitis (inflammation at corners of mouth);Hair loss mm activity/exercise tolerance:Iron-def study animals show poor exercise ability and exercise-related lactic acidosis; revealed swollen mito,distorted cristae though not known in humans nervous system changes: neuresthesias, papilledema, EKG abn.(ST and T changes) infants: Infants exhibit poor attn span, sensory response, and behavioral and develop.retardation; Monoamine oxidase activity involved in the metabolism of neurotransmitters is low in iron deficiency;

PATHOGENESIS plasma Fe clearance is rapid, inversely prop to plasma Fe conc; prop of Fe used for RBC prod increases as plasma levels fall; bone marrow: decreased/absent storage hemosiderin (do trasnfusion or parenteral iron to see)

MORPH/HISTO iron-dep enzymes: o As plasma iron falls, storage hemosiderin and ferritin disappear -> no longer available ->Results in decreased activity of cytochrome enzymes, succinic dehydrogenase & myoglobin; dysfxn of iron-containing enzymes disrupts the fxn of many noniron-containing enzymes, particularly effecting energy production and regulation; histo: atrophy of tongue & esophagus mucosa; and laryngopharynx, which gives rise to web formation and dysphagia

LAB

DX/ PROGNOSIS

TREATMENT oral therapy is tx of choice; reticulocytosis should increase w/in 1-2 wks, Hb w/in 3-4 wks later (b'cing normal w/in 3-4 mths); oral therapy: 15100 mg daily elemental iron as tolerated (less in elderly) w/o food (which inhibit abs); acid increases abs; IV therapy: reserved for severe oral intol or failure (iron dextra, iron sucrose, iron gluconate); rapid correction and assured availability, but risk of anaphylactic shock!

Microcytic, hypochromic RBCs (first multiple stool samples followed by they are anisocytosis followed by endoscopic/radiological procedures as ovalocytosis); Low plasma iron conc; warranted to look for GI bleed Low serum ferritin conc; increased serum transferrin (TIBC) concentration elevation; Depleted bone marrow iron stores; norm WBC count; thrombocytopenia

normochromic/normoc size of RBC and content of ytic anemia Hb NORMAL; causes: blood loss, hemolysis, decreased prod

underlying conditions: posthemorrhagic, hemolytic, sickle cell, RBC membrane damage, anemia of chronic disorders, aplastic/hypoplastic anemia, hyperplastic bone marrow blood loss; Epistaxis, hemoptysis, hematuria; uterine bleeding or GI bleeding can be overlooked or occult;Excessive menstrual bleeding often goes unrecognized unless the patient is asked about the duration of bleeding, presence of clots, cramps of the abdomen, overloading of tampons, or the high number of pads used; GI bleeding is usually an occult process; it may be recognized if it presents as hematochezia or melena before iron def occurs but if the stools appear normal or if bleeding is slow but persistent, iron deficiency anemia signs and symptoms may be the presenting sx

MCV b't 80-100

post-hemorrhagic anemia

Hct not reliable after acute bleeding; RBCs and plasma fall together and for 24 to 48 hours blood remains NC/NC; If adeq iron stores exist, a few days after blood loss reticulocytes are prod > raising MCV, seen in peripheral blood' If hemorrhage causes or occurs with iron def, MCV/MCH may begin to fall quickly and iron def confirmed by serum iron, TIBC, and ferritin or bone marrow stains; EVERY pt w/ iron deficiency should have occult GI blood test

Confirm bleeding as cause; Localize site and source of the blood loss; Transfuse as needed; Replacement of bleedinginduced deficiencies such as iron and supportive therapy to assist RBC production such as folate; Surgically or medically repair the problem

hemolytic anemia

hereditary: result of intraacq vary in severity corpuscular defects; strongly suggested by family hx of anemia, jaundice, cholelithiasis, or splenectomy;genetic defect:vast majority of RBC enzyme abn are G6-PDH deficiency and pyruvate kinase abn.; may not necessarily be early and in G-6-PDH deficiency only occurs after exposure to an oxidant drug acquired defects: extra-corpuscular -> physical agents/trauma, chems, infections, liver &kidney disease, cancer, collagen vasc & malignant abmediated diseases antibody-med: drug-dependent, collagen vascular, post-infectious, and malignant

Increased destr is evidenced by hyperbilirubinemia; increased prod evidenced by reticulocytosis; Using the presence of anemia to detect hemolysis will overlook most hemolytic destr.; anemia as evidence of hemolysis requires an RBC lifespan of 20 days or less (so there has to be a significant hemolysis for it to cause anemia) -> only revealed when destruction increases 6 - 8 fold norm b/c bone marrow can increase prod by same cap.;reticulocytosis and indirect hyperbilirubinemia are used to detect hemolysis: hemolytic process may be evident at an RBC of 40- 50 days; All these pts have a hemolytic disorder; patients may have hemolysis but not be recognizable by anemia if the bone marrow is able to respond with high rate of reticulocyt.

Spherocytes, elliptocytes, and sickle cells are seen in their respective diseases, target cells in Hb C or E disease o

Interview, examine and review blood smears on family members to confirm suspected hereditary nature

confirm hemolysis and cause; Remove offending agents, support with iron or folic acid where needed, admin. immune supp; splenectomy where required(since the spleen is the MC reticuloendothelial organ); Transfuse blood when necessary and w/ the proper tech; control excess iron

decreased RBC prod

anemia of chronic disorders (ACD), hypoplasia, or aplasia; ACD: occurs rapidly after onset of infection, inflamm or surgery; hypoplasia/aplasia:pancytopenia w/ abn. WBC/platelets; hyperplasia: bone marrow failure due to severe nutritional def (lack of B12, folate, Fe), failure of bone marrow stem cell mutation or dysplasia

dx of exclusion; treatment: hyperplastic: Replacement w/ iron, B12, or folate in def states;Withdraw MTX or other DNA synthesis inhibitors if present; When related to confirmed myelodysplasia, mitigate with EPO or treat with 5-aza-cytidine, decitabine, induction chemo or BMT

ACD: Carefully exclude other diagnoses or treat concurrent abn.; Aggressive therapy of underlying disease; Rarely req transfusion, unless to minimize comorbid medical conditions (like HF); hypoplastic/aplastic: Bone marrow most helpful in distinguishing underlying disorders; Remove offending agents; Support w/ testosterone or ESA; Aggressive immunosupp or chemo(like Tcell supp); Epigenetic modulators of methylation (try to effect expression of genes, but dont modify the actual gene); BMT (can be done in pts w/ matches of related people)

megaloblastic anemia disorders of DNA synthesis usually caused by def of B12 or folate and associated w/ megaloblastosis of BM cells; leads to abn large erythroid precursors and red cells; Nucleus remains immature while the cytoplasm matures creating nuclearcytoplasmic asynchrony;Characterized by both ineffective erythropoiesis and hemolysis; assoc w/ 30-50% decreased RBC survival; Granulopoiesis decreased by disintegration of granulocyte precursors in the marrow; B12 and folate are coenzymes for synthesis of thymidine -> def of these enzymes results in deranged/inadeq DNA synthesis w/ delay/block in cell division

Disease develops slowly, but when anemia is severe pts experience weakness, fatigue, palpitations, light-headedness & SOB and dypsnea on exertion; Severe pallor and mild jaundice cause sallow skin

Much more cytoplasm and RNA than DNA in the RBCs indicating more ready creation of intra-cytoplasmic organelles and cytoplasm than nucleus; Slowing of DNA replication in folate and B12 deficiency results from failure of conversion of dUMP to dTMP; DNA polymerase unable to distinguish dUTP from dTTP and incorporates the wrong nucleotide into the DNA ->Attempts to repair the DNA by replacing uridine with thymidine fail leading to DNA fragmentation and finally cell death path: with aniso- and poikilocytosis; Oval macrocytes; Immature erythroid cells; Hypersegmented large neutrophils (see pic);

Blood cells vary in size and shape; reticulocytes are low; macrocytic anemia with megaloblastosis (MCV > 100)Neutrophil nuclei are often hyperlobated; Platelets are slightly smaller in size and vary widely in size; Marrow: [cellular with striking megaloblastosis (increased hematopoietic precursors); Sideroblasts are increased in # with increased # of iron granules;Nuclear to cytoplasmic asynchrony in erythroid precursors (Cytoplasm matures normally while nuclear maturation is delayed); Granulocytes show giant metamyelocytes and band forms;all cells here are abnormal; Megakaryocytes are abnormally large with bizarre multilobate nuclei; Most precursors undergo apoptosis in the marrow (ineffective b/c the precursor RBC never get out of the bone marrow;] Macrophage iron is often increased; Cells from mouth, stomach, SI, and cervix may appear larger and more immature than normal; Megaloblastic changes can be confused for malignant transformation or dysplasia particularly in severe deficiency and even indist. in BM

WBCs and platelets may be slightly low, large platelet size; Bilirubin, iron and ferritin levels increased; LDH 1 and 2 increased; EPO levels slightly increased due to frustrated stimulus to make more RBCs; decreased reticulocytes

Coexisting microcytic anemia may mask most of the features of megaloblastosis -> peripheral blood may show microcytes and macroovalocytes; hypersegmented neutrophils will still be present; RBC folate usually quite low in folatedeficient megaloblastic anemia and it is low in 50 per cent of B12 deficient megaloblastic anemia ->so when you find someone who is B12 deficient, you also want to supplement their folate

folate deficiency

usually caused by antimetabolites or antimicrobial agents; due to either decreased intake, malabs., or increased requirement Nonhematological effects:Abn neural tube closure;Other congenital abnormalities of the heart, urinary tract, limbs and other sites; Vascular disease; Elevated homocysteine a risk factor for arterial and venous thrombosis, and atherosclerosis; (treatable with folate, B12, and pyridoxine) Colon cancer (Folic acid replacement of 400 mcg/ day reducesrate by 30 %)

decreased intake:Folate reserves are small and def develops rapidly in the undernourished; at risk: aged, the poor, alcoholics, hyperalimentation, renal failure/dialysis pts; Special nutritional circumstancesPremature infants particularly those with infection, diarrhea, or hemolytic anemia; Children on synthetic diet; Infants raised on folate-poor goats milk; Those whose food is excessively cooked, destroying folic acid; Special nutritional circumstance of alcoholism: depresses folate levels which acutely lower all types of blood cell prod;Can occur even if large amounts of replacement folic acid are given with alcohol

malabsorption: Celiac disease, nontropical sprue; atrophy of intestine from exposure to wheat gluten o Tropical sprue, responds to folate therapy though assoc MC with B12 deficiency than with folate deficiency o Regional enteritis, post-resection of extensive small bowel, leukemia or lymphoma of the intestine, and Whipple disease are other possible causes

increased req: Preg/ lactation; levels fall steadily during pregeven in pts w/ good nutrition;Increased cell turnover in exfoliative dermatitis such as psoriasis

lab features: Low serum folate level (earilest); RBC folate relates better to tissue folic acid level; reflects folate turnover over months diff dx: Macrocytosis also occurs in alcoholism, liver disease, hypothyroidism, aplastic anemia, some myelodysplasias, pregnancy, hemolysis, and of course B12 deficiency; Non-tropical sprue diagnosed by demonstration of malabsorption, atrophy on jejeunal biopsy; increasingly use of antibody panels paricularly IgA type antibodies and response to gluten-free diet to diagnose and confirm

Folic acid therapy of 1 to 5 mg/day; parenteral therapy is also available Tropical sprue involves 1 to 5 mg/day for at least 2 yrs and concurrent ax;Preg women must be given at least 400 mcg/day of folic acid; MTX toxicity can be relieved by folate or folinic acid

cobalamin(B12) def.

decreased uptake caused by impaired abs due to: gastrectomy: Iron def MC; B12 deficiency may develop w/in 2-5 yrs as B12 stores are used up so this doesnt occur immed.; Partial gastrectomy may result in low serum B12 and megaloblastosis as a result of mucosal atrophy in the remnant stomach or bacterial overgrowth in the afferent bowel loop;intestinal diseases: resection of the ileum; ileitis, Crohns; tropical or occasionally non-tropical sprue; B12 malabs 2ndary to hypothyroidism; pancreatic diseases: only source of dietary B12 is animal-based foods; Loss of pancreatic proteases results in the failure to destroy intermediate complexes that must be broken down for the cobalamin/intrinsic factor interaction; dietary B12 def Vegetarians, vegans; Breast-fed infants of vegan moms

clinical:Generalized: Megaloblastosis of platelet prod is only 10% of that expected RBCs;anemia;weight loss, asthenia, mild jaundice, and glossitis; neuro abn:May develop with megaloblastosis but not necessarily anemia; cannot be reversed when advanced;begins w/ parasthesias of hands, feet, trunk & vibratory sense and proprioception disturb.;most severe stage is spastic ataxia as a result of demyelination of dorsal and lateral spinal columns called combined system disease;Brain may also be affected manifesting as somnolence; altered taste, smell and vision at times associated with optic atrophy and associated with slow wave abnormalities of EEG; Dementia; psychotic depression; paranoid schizophrenia; radiological:MRI can demonstrate demyelination consistent with cobalamin deficiency; but occurs late and may not be reversible at that point

Serum B12 is low in most cases (and in vegans w/ norm tissue cobalamin) Serum folate may be higher in B12 def pts and when both cobalamin and tissue folate are low may show normal folate levels; Methylmalonic aciduria (MA) is evident/elevated only with EIM or B12 def;Elevated serum MA and homocysteine ->this ONLY occurs in B12 def -> rise before B12 levels fall into abnormal range; may distinguish early B12 deficiency from other abnormalities Schilling test measures urinary radioactivity after oral dose of radioactive cobalamin; complex and seldom used now Deoxyuridine suppression test:the failure of deoxyuridine to be suppressed indicates cellular folate or B12 deficiency; both too complex and not used

Extremely broad diff; overlooked by insidious onset, potential to be masked by folate supp in multivit;Anti-intrinsic factor antibody has low sensitivity but high specificity for B12 def;Anti-parietal cell antibody of lower sensitivity and specificity

remember always supplement folate acid when also treating for B12 def; Parenteral B12 to replace storage pool, primarily in the liver, largely repleted by 6 injections; Standard treatment schedule of 1000 mcg per day for some consecutive days; Longer replacement for suspected neuro probs; B12 supp availabe for injection or oral, subling pills or intranasal spray; Transfusion is required for profoundly low Hb/Hct or if extremely weakened or infected or with HF; Response to treatment:w/in 12 hrs, marrow begins to change from megaloblastic to normoblastic; After parenteral B12 elevated LDH, plasma bilirubin and iron will rapidly fall indicating improved erythropoiesis; Reticulocytosis begins on day 3 to 5 and peaks at day 10; Normalization of WBCs and plts with resolution of hypersegmentation by two weeks; Normalization of serum B12 and folate; Hb normal w/in 30- 60 days; Large folate doses can cause a reticulocytosis and partially correct the anemia of B12 def.

Pernicious anemia (type of B12 def) -> caused by loss of gastric parietal cells, and subsequent inability to absorb vitamin B12

Gastric or abn that disrupt usual gastric- can be inherited; assoc w/ HLA types A2,3 med processes: may manifest as failed B7,12 and blood group A intrinsic factor secretion from gastric atrophy; antibodies against parietal cells; CD4+ T-cells mediate PA; Pernicious anemia with blocking antibodies against intrinsic factor and associated with other autoimmune diseases including thyroiditis, type II diabetes, hypoparathroidism, hypoadrenalism, ulcerative colitis, and vitiligo

microcytic anemia

problem is you can't make Hb

seen in iron deficiency, chronic inflamm diseases (cancer, renal disease), thalassemias, sideroblastic/myeloproliferative dysplastic anemias, hemolytic anemia Presenting symptoms depend upon the rate of hemolysis and severity of anemia; aquired: older pts; hereditary; younger pts; sx: Pallorous mucus membranes (anemia);Fluctuating jaundice; Splenomegaly;Occurs in hereditary spherocytosis and elliptocytosis, some immune-mediated anemias but not sickle cell or G-6-P(D) deficiency; Suggests some acquired illnesses like CLL, other lymphomas and systemic lupus (SLE) Bleeding and petechiae suggest TTP, HUS, DIC and HELLP syndrome Butterfly malar rash, arthritis, and teno-synovitis suggest SLE Lymphadenopathy and splenomegaly suggest diagnosis of CLL or other lymphoma Mild jaundice with bilirubin up to 4 mg/dl may indicate hemolysis although gallbladder and liver disease must be excluded Norm RBC survival is 120 days; premature RBC destruction can be the result of intrinsic membrane defects, abnormal Hb, RBC enzymatic defects, immune-med destruction, mech RBC injury and the effect of hypersplenism; Hemolysis results from both hereditary and acquired defects of the red blood cell All hereditary hemolytic disorders are a result of intra-corpuscular defects and acquired defects are extra-corpuscular in nature Hemolysis causes release of Hb,LDH, increase in indirect bilirubinemia, increased urobilinogen (breakdown of bilirubin in urine) in the urine from Hb breakdown, and it incites compensatory bone marrow prod in form or reticulocytosis -> Mild anemia may occur if hemolysis is mild and the bone marrow can partially compensate;severe anemia occurs if hemolysis is more vigorous or the bone marrow is more significantly suppressed(Parvovirus B19 infection); morph: Polychromasia -> reflect reticulocytosis; Spherocytes -> indicate hereditary spherocytosis or AIHA;When the spleen eats away at the hemolytic markers, it may not destroy the RBC all together, but over time as the membrane is injured, it bc less distensible and more spherical; Schistocytes suggest MAHA which can be seen in TTP, HUS, DIC, or mechanical damage from valvular heart disease, vascular repair, or severe vascular disease; May reveal underlying malignancy like CLL or peripheralizing lymphoma

low MCV < 80

hemolytic anemia

premature destruction of RBC -> leads to anemia when the bone marrow is incapable of compensating for destruction-> Genetic conditions of Hb Sickle cell anemia;mixed sickle synds; Thalassemia ;Genetic conditions of RBC metabolism: G-6-PD def; Pyruvate kinase def;Genetic conditions of RBC membrane: Hereditary spherocytosis or elliptocytosis

RBC indices:Low MCV (microcytic hypochromic anemia) may be seen in hemolytic anemia which can occur in chronic intravascular hemolysis including PNH as a result of superimposed iron deficiency o High MCV:due to megaloblastic anemia though can occur in liver disease and other disorders or with reticulocytosis o So anemia is not the main thing were looking for, but any form of anemia may suggest hemolysis o High MCH and MCHC (hyperchromic) suggest spherocytosis Bone marrow->demonstrate erythroid hyperplasia Reticulocytosis:Seen in but not specific for hemolysis o Can be seen acutely in blood loss or after replacement of iron, folate, or B12 deficiency; LDH: Elevated LDH is a necessary but not specific laboratory abn in hemolysis; LDH isoenzyme 1 and 2 are elevated in hemolysis;(levels will return to normal very early w/ tx); serum haptoglobin: seen invariably;Indirect bilirubinemia in hemolysis is generally less than 4mg/dl

if survival of RBCs is decreased and we can directly demonstrate increased destruction, or increased production as compensation for destruction, we can support a diagnosis of hemolysis; Increased destruction is evidenced by hyperbilirubinemia and increased production is evidenced by reticulocytosis Using the presence of anemia to detect hemolysis will overlook most hemolytic destruction; anemia as evidence of hemolysis requires an RBC lifespan of 20 days or less Anemia as a result of hemolysis is only revealed when destruction increases to 6 to 8 fold normal because the bone marrow can increase production by the same capacity If reticulocytosis and indirect hyperbilirubinemia are used to detect hemolysis, hemolytic process may be evident at RBC lifespan of 40-50 d; All patients with reticulocytosis and indirect hyperbilirubinemia have a hemolytic disorder; patients may have hemolysis but not be recognizable by anemia if the bone marrow is able to respond with a high rate of reticulocytosis

diff dx: Ineffective erythropoiesis; shares features of hemolysis with RBC breakdown that occurs prior to cell release from the bone marrow; Thalassemia; Myelodysplastic syndrome; Megaloblastic anemia; B12 deficiency; Folate deficiency; treatment: Transfusion (Avoid in immune hemolysis but transfuse to alleviate cardiopulmonary stress in any hemolytic process or vaso-occlusive injury); discontinue offending meds; give folic acid; Splenectomy can control hemolysis in hereditary spherocytosis and refractory extravascular immune-mediated hemolysis

warm antibody autoimmune

Idiopathic;SLE;Evans syndrome; drugs;Chronic lymphocytic leukemia (CLL)

glucocorticoids are best-established therapy in immune-med hemolysis; IVIG can limit immune-mediated hemolysis acutely

cold antibody autoimmune

Idiopathic cold hemaggluttinin syndrome; mono and mycoplasma; Paroxysmal cold hemoglobinuria; Lymphoma Penicillin; hapten-mediate antibody against RBC; Alphamethyldopa Hemolytic disease of the newborn (Rh, ABO, etc); Hemolytic rxns to transfused blood, poor typing; Non-immunemediated hemolysis Non-immune-mediated hemolysis: drugs, toxins, trauma, MAHA, TTP, HELLP (hemolytic anemia, Elevated Liver enzymes, Low Platelet ct) found in preg women, infections (malaria, babesiosis, sepsis), membrane disorders, liver disease Only hemolytic anemia from an acquired mutation on the X chromosome in the phosphatidylinositol glycan complementation group A gene (PIGA), and enzyme essential for certain cell surface proteins; RBC, platelets and granulocytes are subject to damage by complement; CD 59 is Inhibitor of C3 convertase Decreased surface CD55, CD 59 and C8 prevents the spontaneous activation of (GPI linked proteins that regulate the alternative complement pathway; CD 55 is decay accelerating factor and C8 increased RBC destruction binding protein Glycosylphosphatidylinositol GPI

drug-related

allo-immune

Paroxysmal nocturnal hemoglobinuria (PNH)

called nocturnal b/c most of damage occurs at night; sx:Hemolysis, usually chronic without dramatic hemoglobinuria; Anemia (mild/mod);Thrombosis is leading cause of disease related death in PNH;3 to 5% develop acute myeloid leukemia or myelodysplastic syndrome;Assoc b'tPNH and aplastic anemia

aplastic anemia

pancytopenia due to primary hematopoietic failure;Autimmune mechs suspected; most idiopathic; Fanconis anemia: rare AR disorder caused by defects in a multiprotein complex that is required for DNA repair; Marrow hypofunction occurs early in life; often accomp by multiple congenital anomalies, such as hypoplasia of the kidney and spleen and bone anomalies, MC involving the thumbs or radii.

morph: Markedly hypocellular bone Dry taps will occur on aspiration; marrow with fat cells, fibrous stroma and therefore, must have bone marrow scattered lymphocytes and plasma cells biopsy

HEMOGLOBINOPATHIES divided into RBC disorders : and thalassemias RBC disorders result in inheritance of abn of RBC structure that result in clinical probs from abn Hb

Most not clinically evident; Only a genetic defect causing an abn structure few cause serious disease or # of one or more globin chains of Hb molecule

sickle cell disease (HbS) mainly in tropical African populations where incidence of the gene is as high as 40%; Found in some pops in aboriginal peoples of India, Middle East and Mediterranean; some protection against P falciparum malaria; AR disorder;heterozygotes carry sickle cell trait; homozygotes demonstrate sickle cell disease(a chronic hemolytic anemia & vasoocclusive disease); sequestration crisis occurs primarily in children and results in sequestration of RBCs in the reticuloendothelial system, mainly the spleen;leg ulcers from sickling causing deep, non-healing ulcers of the skin and SQ tissues;most of these pts dont survive to even develop renal failure

Homozygotes sickle daily while heterozygotes sickle only under unique circumstances; Hb S is a chain mutation and sickling typically does not manifest until after 6 months of age when Hb F has declined (Hb S density increases) Effects of chronic hemolysis: Anemia;jaundice from rapid heme turnover;cholelithiasis from excess bilirubin prod; aplastic crisis results in severe anemia because of shortened RBC survival and parvovirus-suppressed RBC prod;hemolytic crisis from sudden exacerbation of chronic hemolysis; Effects of vaso-occlusion:dactylitis (ischemia or infarction of bones of hands and feet causing swelling and pain);autosplenectomy (gradual infarction of the spleen due to excess splenic activity and ischemia);priapism;renal papillary necrosis from inhospitable renal medullary environment producing sickling; infarct crisis caused by increased sickling from stress(esp infection)

SNP w/ sub of valine for glutamine at 6th AA of chain; Hb S expresses its biochem instability by precipitating out of solution and forming microtubular arrays called tactoids ->RBC membrane stretches around tactoids creating long curved cell shapes called sickle cells and is very poorly deformable ->cant deform their structure like normal RBC > get stuck in BV;Tactoids formed only from deoxyg Hb S-> The greater the prop of Hb S containing cells, the greater the likelihood of sickling; therefore sickle cell is density dependent -> anything that decreases the density (like acute blood transfusion) can help

morph: Variable # ofirrversibly sickled Several co-existing mutations common cells; reticulocytosis; target cells; aniso- in African populations may minimize and poikilocytosis; Howell-Jolly bodies sickling-> called double heterozygosity (small nuclear remnants due to asplenia); Hyperplastic bone marrow with compensatory erythroid hyperplasia; Bone resorption with expansion of marrow and secondary new bone formation; gross:Splenomegaly in childhood; w/ time, splenic infarction, fibrosis and progressive shrinkage (autosplenectomy); infarctions may occur in multiple tissues

co-existing mutations that may help: Athalassemia and to lesser degree Bthalassemia cause lower RBC MCV that lowers the vaso-occlusive effects of Hb S-> so if you carry 1 Hb-S mut and 1 Athalassemia mut., youll have less disease manifestation than homozygote; Sickle-thalassemics have fewer vaso-occlusive events and generally live longer than homozygous sickle cell pts;Hereditary persistence of HbF decreases the density of Hb S so that sickling does not occur

treatment of HbS&HbSC:Vaso-occlusive crisis:IV fluids, antibiotics, oxygen, IV/oral narcotics, or NSAIDs, and blood transfusion for mod/severe episodes;hydroxyurea increases HbF and may work effectively as a preventive; Give O2 to improve O2 tension; Oral narcotics for pain in BV and bone marrow; Blood transfusion for mod/severe episodes only to dilute density of Hb, which decreases sickled Hb consequences Aplastic crisis: IVIG may be a direct therapy of parvovirus infection; IV fluids and blood transfusion for low blood volume; Splenic sequestration crisis, primarily in peds pts ->can rapidly go into circulatory collapse and require rapid fluid replacement; Analgesia, IV fluids, and when stabilized, splenectomy; Hemolytic crisis: IV fluids and blood transfusion;O2;IV or PO analgesia; Prophylaxis: Avoid crisis-prod factors: dehydration, anoxia, infection, circulatory stasis, and cooling of the skin surface; Good nutrition, hygiene, folic acid; Vaccination for pneumococcus, H. flu, meningococcus, Hepatitis B; Oral penicillin

Hb-SC

double heterozygocity; May inherit Hb S from one parent and Hb C from the other; occurs in 2-3% of AA; inherited AR trait;

Retinal damage from ischemia and The intracellular bodies of SC disease are vasc occlusion is often hybrids of the Hb S tactoids and the Hb severe;Severity is intermediate b't C crystalloids Hb S and Hb C disease asymptomatic but homozygotes and some heterozygotes have target cells with the Hb C crystals only seen occasionally sub of lysine for glutamic acid in Nterminal end of chain; forms bluntended intracellcrystalloids; Decreased RBC survival occurs but hemolysis is not as severe as in sickle cell and vaso-occlusive events uncommon If you look at a smear and see lots of target cells, think of this!

aseptic necrosis of femoral head is a complication

HbC

Prognosis quite good and usually does not require treatment

thalassemias:

result in defects in Hb chain synthesis of one or more of the globin chains, unbalanced Hb prod (abn. dimerization), ineffective erythropoiesis, hemolysis and varying degrees of anemia

genetic mutation may affect the , , , or chain or a combination of , , and chains but never and chains together

MC single gene disease trait in man; AR inheritance; Occur at high freq in Mediterr., Middle East, and SE Asian areas from India thru Malay Peninsula; Occur in large # in immigrant pops in US; Heterozygotes may have malaria protection; Anemia occurs from def of Hb prod and also, the relative excess of the other globin chain may damage the RBCs thalassemias result from mutations in the HBB gene on chrom 11 and are inherited as an AR trait; chain def results in chain excess causing RBC membrane defects and in high concs of toxic aggregates of alpha chains and hemolysis; gene clusters on the short arm of chrom 11 contain highlypreserved and predictable areas as well as highly variable areas; Gene deletions: Roughly 20 deletions have been described and are rare except for a 619 bp deletion common in India and Pakistan;Homozygotes have 0 thalassemia while those who are heterozygotes have + thalassemia with high chain production and increased hemoglobin A2

Consequences: Defective Hb prod resulting in reduced rate of globin chain synthesis ->Imbalance of globin chains( named for the chain that is deficiently produced);May result in damage to RBCs from the globin chains that are prod in excess

Thalassemia major; severe form of thalassemia; Freq blood transfusions for sx of anemia and to sustain norm growth/develop; maintain Hb of 10; folic acid; Iron chelation therapy to remove excess iron w/ various toxicities; vitamin C for chelation; Splenectomy to reduce transfusion requirements

B-thalassemia

a consequence of a pt mutation-> may occur w/in the gene itself, promoter, enhancer or other expression-controlling sites; Beta0 (0): no beta chain production-> thalassemia major generally requires two separate mutations affecting genes and globin synthesis; Beta+ (+): decrease in beta chain production; homozygotes have 0 and heterozygotes have + thalassemia; Heterogeneous with nearly 200 different characterized mutations; Primarily point and non-deletion mutations occur that affect transcription, processing or translation;

Beta0 (0): Manifests as elevated Hb F; hepatosplenomegaly from excess RBC destruction and extramedullary hematopoiesis; Beta+ (+):Primarily manifest by elevated level of HbA2; Each worldwide population effected is characterized by two or three common defects with a large number of rare mutations

Decreased Hgb production causes hypochromic, microcytic red cells; Ineffective erythropoeisis 70 to 85% of red cell precursors are destroyed due to membrane damage from insoluble alpha chain precipitates; Red cells released to circulation have inclusions and membrane damage causing extravascular hemolysis; Lots of RBC destroyed b/f they even get out of bone marrow, and if they do get out, they are microcytic; morph: Anisocytosis (marked variation is size); Poikilocytosis (marked variation in shape);Basophilic stippling (precipitated ribosomes); Inclusions are removed by spleen and not seen;Nucleated red cell precursors; Increased reticulocyte by lower than expected for severity of anemia because of ineffective erythropoiesis; Expansion of active bone marrow with resorption of bone and new bone formation; Extramedullary hematopoiesis with splenic enlargement also due to phagocytic hyperplasia; Hemosiderosis and 2ndary hemochromatosis due to ineffective erythropoiesis

Thalassemia intermedia:Wide variation in severity; treat those in need (Hb < 6) Thalassemia minor; mild to mod anemia; rare tx needed; Assoc w/ asthma and depression increase in this population Chelation therapy for iron overload; Iron damaging to heart; iron evident on T2 MRI and inferrable by serum ferritin but ferritin not as reliable; Iron chelators-> Deferoxamine by acute or continuous IV infusion; 2/3 excreted in urine; better with vitamin C; Deferiprone or Deferasirox are oral agents w/ urine and stool excretion respectively

A-thalassemia

Hgb A: 22-> 2 alpha and 2 beta chains; Hgb A2: 22->2 alpha and 2 delta chains; gene clusters on chromosome 16 contain three functional and several non-functional genes

globin chains are encoded by 2 closely linked genes on chrom 16 ->genes HBA1 and HBA2 are responsible for prod of 1 and 2 globin chains; Decreased Aglobin chains result in excess chains in adults and excess chains in newborns; Alpha0 (0) thalassemia:when both linked genes on the same chrom are defective and no A-chain is prod from that chrom; Alpha+ (a+) thalassemia occurs when one gene in a linked pair is dysfunctional o If one alpha locus is affected, normal Hb but low MCV and MCH; silent carrier o If two alpha loci affected, mild MC/HC anemia; alpha thalassemia trait; cis and trans positions o If three loci affected called Hb H disease with two unstable Hbs, Hb Barts (fetal) from tetrameric chains and Hb H (adult) from tetrameric chains; If all four loci affected, fetus dies in utero or shortly after birth, hydrops fetalis

Comparing the A1 and A2 variants of the A-globin genes; A2 prod 1.5 to 3X as much m-RNA; 1 exons are identical to one another and 2 exons are identical to each other but 1 differs in number and order of bases from 2 o Introns that separate and surround exons contain hypervariable regions and are highly polymorphic; globin introns contain single nucleotide polymorphisms and with characteristic hypervariable regions allow for tracing inheritance of thalassemia mutations

Hemoglobin Bart's (HbH)

() globin chains are found in both fetal and adult Hb and effect Hb prod in all ages ->Reduced A-chain prod in fetal setting increases the amount of gamma chains prod >Excess gamma chain prod leads to gamma tetramer production and hemoglobin Barts

Hb H results in MC/HC anemia with target cells and Heinz bodies on peripheral smear and splenomegaly

Delta-beta () thalassemia

In some patients no delta or beta globin chains are produced; Delta-beta+ results from production of an abnormal hemoglobin from an alpha chain combined with a non-alpha chain created by fusion of Nterminal portion of a delta chain and C-terminal portion of an alpha chain: called hemoglobin Lepore

MALIGNANT HEMATOLOGY

leukemia vs. lymphoma: Leukemia o Malignancy of hematopoietic cells o Starts in bone marrow, can spread to blood, nodes o Myeloid or lymphoid o Acute or chronic Lymphoma o Malignancy of hematopoietic cells o Starts in lymph nodes, can spread to blood, marrow o Lymphoid only o Hodgkin or non-Hodgkin

normal bone marrow:

LYMPHOPROLIPrimary lymphoid organs: FERATIVE NEOPLASMS thymus and bone marrow;2ndary lymphoid organs: lymph node and spleen; In bone marrow and thymus, you have progenitor lymphocytes that differentiate into other cell types -> you want to generate B cells that are capable of fighting specific infections

chronic lymphocytic leukemia (CLL)

a lymphoproliferative disorder caused by a clonal expansion of mature, longlived lymphocytes -> typically B cell in origin, and are functionally defective; is liquid-phase (i.e. bloodborn); epidem: western hemisphere: >95% are B-cell origin;MC in males, 2:1 M:F; Median age at diagnosis 6065 (more aggressive clinical course in younger folks);Increases with age; Virtually non-existent in children; Only leukemia NOT assoc w/ radiation; Strongest tendency for familial clustering among leukemias; Increased incidence of 2ndary solid tumors, particularly lung and gastrointestinal carcinomas (Due to immune surveillance defect,the immune system just doesnt detect it); asian: Predominantly T-cell origin; only 5% of all leukemias

usually presents in asymp pts; sx of leukostasis (sludging) are uncommon in CLL, (unlike CML and AML); sx: fever, night sweats, weight loss (B sx ->caused by massive cytokine release), adenopathy, hepatosplenomegaly; hypogammaglobulinemia; Anemia and thrombocytopenia in

Bone marrow architecture disrupted; infiltration can be 30-100% of all cells. Diffuse infiltrates of lymphocytes carry a worse prognosis; common diseases in CLL: RA, SLE, Hashimotos Thyroditis, Graves Disease; Unlike CML and other acute leukemias and lymphomas, no single specific molecular anomaly predominates

Morph:Lymph node diffuse effacement of nodal architecture with monomorphic

If you have a pt w/ CLL and they have anemia, look for colon cancer and a bleed, b/c thats the number 1 cause lymphocytes here look the same; May of anemia! have proliferation centers larger (w/ CLL pts, always check their tumor activated mitotically active lymphocytes in secretion tests); Cytogenetic loose aggregates which are abnormalities exist in >80% of cases, pathognomonic of CLL/SLL; May have and several types have prognostic smudge cells in peripheral smear; significance; FISH (fluorescent in situ Lymphocytic infiltrates in bone marrow, hybridization) Analysis allows spleen and hepatic portal tracts detection of cytogenetic variants; Lymphocytosis is the universal finding on peripheral blood smears: Immunophenotyping of CLL/SLL B-cell 5,000/mcL up to 500,000/mcL; neoplasm - positive for CD19 and CD20, Elevated peripheral smear white count CD 23 and CD 5 (CD5 is found on T-cells with absolute lymphocytes greater and a small subset of B cells) Negative for than 5,000; Smudge cells are CD10; Low-level expression of surface Ig common and raise suspicion of dx; About pts have low antibodies(hypogammaglobulinemia), even in early stage, w/ resulting bacterial & viral infection risk; Low titer monoclonal antibodies are common (this is a malignancy of the cells that make antibodies, so the antibody production will be low; Autoantibodies against RBC and platelet antigens are common, leading to autoimmune hemolysis and thrombocytopenia;

dx criteria: Sustained absolute peripheral blood lymphocyte count of 10,000/mcL or greater (Classical Criterion); Documentation of monoclonal B-cell phenotype lymphocytes by flow cytometry of blood or marrow, whatever the absolute lymphocyte count (Modern Criterion); flow cytometry: CLL cells express the pan-B cell antigens CD19 and CD20, along with CD5, a mature Tcell antigen ->only a few malignancies cause this, so its a good marker (either CLL and another type of lymphoma); Most cells are CD23+ and FMC7- ; Surface IgM (+/- IgD)is weakly + in 90%

Necessary to treat? pts w/ indolent disease may have normal life spans; Early stages=no benefit; you can do it and make their disease go away, but if they relapse, its harder to treat (the window of remission narrows every time you treat people, so take your time b/f you treat them the 1st time) ->older pts die of something else; conventional: Alkylating agent and steroids;Cytoxan, Vincristine, Prednisone (CVP) the same; Newest alkylating agent: Treanda (Bendamustine) -> longer response durations; Complete remissions in a small minority of patients; nucleoside analogs:Fludarabine, 2-CdA, DCF The Rai Staging System (USA) or The >Antimetabolites active against dividing binet staging system (Europe) for and resting cells; higher response rates staging/ prognosis; half of all CLL cases and duration than alkylator agents; exhibit V gene hypermutation Tumor lysis syndrome possible (renal consistent with postgerminal center failure, gout) ->b/c they work so fast; memory B cells -> pts w/ this have Fludarabine may induce AIHA; better prognoses than unmutated V monoclonal antibodies: Rituxan genes (even in early stage); (rituximab) (anti-CD20) in combo hypogammaglobulinemia common; w/alkylators and/or purine analogs, low have inbalance b't T4 helper cells and activity if used alone; Campath-1H T8 suppressor cells in advanced (alemtuzumab) (anti-CD52) now disease; approved for 1st line ; Prophylaxis for PCP and HVZ required; CMV surveillance imperative!

Evan's syndrome

Autoantibodies from CLL frequently target RBCs causing autoimmune hemolytic anemias (AIHA): Coombs +, Haptoglobin low, LDH high, Bilirubin high, Reticulocyte counts high Autoantibodies also target platelets: ITP (idiopathic thrombocytopenic purpura) AIHA + ITP = Evans Syndrome

steroids

Richter transformation

minority of CLL (or other low-grade B cell lymphomas) pts experience evolution into aggressive lymphoproliferative disorders -> Usually Diffuse Large Cell Lymphoma (DLL),rarely acute lymphocytic leukemia (ALL)

Presents with rapid clinical worsening: fever, weight loss, sweats, progressive lymphadenopathy, pain, enlarging spleen, rising LDH and 2M

tissue is the issue

Survival can be poor; treatment is with aggressive chemotherapy and/or radiation

Small lymphocytic leukemia (SLL)

is the solid-phase analog; may exist concurrently w/ CLL may arise de novo or evolve Pts. typically have weakness, from CLL; massive splenomegaly, but lymphadenopathy is typically minimal larger than typical CLL, have more abundant cytoplasm, clumped chromatin, and a single nucleolus Less CD5 positivity, CD23-, dense IgM expression Treatment is same as for CLL

prolymphocytic leukemia

Hairy cell leukemia

midd-aged white males

Typical lymphocyte morphology: hairy projections on cell surface Very rare, but accurate diagnosis important

On peripheral blood smear, leukemic cells have round, oblong or reniform nuclei with pale blue cytoplasm with hairlike projections; Pancytopenia is common; Bone marrow: diffuse infiltrate of leukemic cells enmeshed in extracellular matrix composed of reticulin fibrils that cannot be aspirated Cells stain for TRAP or tartrate-resistant acid phosphatase

distinct markers such as CD11c, CD25 and CD103; get dry tap on bone marrow aspirate -> so need bone marrow biopsy

High response rates to 2-CdA and DCF; Durable remissions are the norm!

large granular neutropenia, anemia, or lymphocytic syndrome frank red cell aplasial (LGL) Typically an indolent course despite monoclonal cells

2 variants: 1. T-LGL (CD3+, CD 56-), heterogeneous, but morphologically and clonally rearranged TCR genes; 2. clinically distinct from other indolent NK-LGL (CD3-, CD56+), lymphoproliferative neoplasms germline/non-rearranged TCR gene (CD56 is called the neural crest adhesion molecule) Often see rouleaux of RBC (aggregation of RBCs), hemolysis, massive splenomegaly, diffuse adenopathy, pancytopenia; Sausage-link retinopathy on funduscopic examination may be seen, along with microvascular ischemia and infiltrates rouleauz --->

may present in association with RA, splenomegaly, and/or Feltys Syndrome (RA + splenomegaly)

LGL cells normally comprise 10% of peripheral blood mononuclear cells, but may be increased in certain inflammatory conditions, in viral infections, or post-splenectomy

steroids, cytoxan, MTX, fludarabine, splenectomy, cyclosporine, G-CSF; May evolve into aggressive leukemia > thats why you follow these pts!

Waldenstrom's macroglobulinemia

aka Lymphoplasmacytic Lymphoma; Low grade malignancy of Blymphocytes that produce monoclonal IgM; hyperviscosity features (visual disturbances, headache, bleeding, vascular sludging, cardiopulmonary collapse) >this is why you would do plasmaphoresis

May require plasmapheresis to remove IgM if serum viscosity is elevated beyond 4 centipoise-> (normal 1.4-1.8 cP); Plasma cell disorder like myeloma

treated with chemo regimens as for CLL or other indolent lymphomas, and usually has a similar clinical course

PLASMA CELL

DYSCRASIA

( aka MULTIPLE MYELOMA)

diseases of elderly (65-70); AA 2x as likely to develop as caucasians; M:F is 2:1; viral assoc: HHV-8 & SV40, deletion of chrom. 13

High dose/stem cell eligible: Revlimid/Dexamethasone orally for 4 cycles, followed by high dose IV Melphalan chemo and autologous stem cell rescue; IV bisphosphonate (Zometa, Aredia) Non-transplant eligible: IV bisphosphonate (Zometa, Aredia); Revlimid/Dexamethasone orally; Melphalan/Prednisone/Thalidomide orally; Single agent, high dose Dexamethasone; Revlimid or Thalidomide maintenance;

Multiple myeloma

aka plasma dyscrasias

some asymptomatic, most have sx: bone pain from lytic lesions or compression fracture; fatigue from anemia; nausea from renal insufficiency; recurring infections (even meningococcal sepsis); mental clouding from hypercalcemia; peripheral neuropathy

Complex genetic events/genomic instability (translocations of 14q32 and deletions of 13); Marrow microenvironment changes: Induction of angiogenesis, suppression of cell med immune surveillance, paracrine signaling loops involving IL-6 and VEGF (Vascular Endothelial Growth Factor); Destructive bone lesions develop due to activation of osteoclasts; hypercalcemia from bone destruction; Migration of high conc. monoclonal antibodies into the gamma region of protein electrophoreses, hence the name Monoclonal Gammopathies;Marrow infiltration and eventual pancytopenia (just like in CLL, but picture is diff)

morph: Excentric nuclei near edge; Chromatin gives clockface nuclei; Has pale area near nucleus where the golgi apparatus is; Can cause lytic lesions in bone, and M protein spikes

do skeletal survey; bone Scans do NOTroutinely image myeloma lesions, xrays do; MRI, bone marrow biopsy/aspiration; FISH; SPEP/SIEP:(serum immunoelectrophoresis)/UIEP(urine immune..)-identify and quantify the monoclonal protein, M Spike -> Most common IgG, then IgA, then light chain; IgD and IgE uncommon, hard to identify M spike; If you see IgM think waldenstroms; beta-2 Microglobulin- an index of lymphocyte activation. A component of MHC Class I molecules; CRP: surrogate marker for IL-6(stimulator for myeloma growth); serum free light chain assay (FLC): used to monitor monoclonal protein level, sensitive to changes in tumor mass

Major Criteria o M Protein IgG>3.5 g/dL IgA>2.0 g/dL o Marrow plasmacytosis >30% o Plasmacytoma - use durie-salmon staging

adjunctive therapy: Radiation(Pain control, impending fracture,impending cord compression); Vertebroplasty/Kyphoplasty; Maintain Renal Function ->Avoid NSAIDs, IV Contrast; Bisphosphonates (Monitor renal function and osteonecrosis of jaw); EPO for anemia; PCP, HVZ, Fungal prophylaxis; IVIG for recurring infections; Plasmapheresis for symptomatic hyperviscosity complications from tx: Neuropathy from Revlimid, Thalidomide, Bortezomib, Vincristine, steroids;Bacterial and viral infections from chemo-induced neutropenia; Opportunistic infections (Zoster, PCP); Venous thrombosis from Dexamethasone, Thalidomide, and Revlimid; thrombocytopenia; Need for transfusions, growth factor support; Osteonecrosis of bone (jaw) from bisphosphonates

Smoldering myeloma

dx criteria: M protein: IgG<7g/dL or observation at 3 mth intervals w/ IgA<5g/dL skeletal surveys every 6 mths Either no bone lesions or limited lesions (<3) Marrow plasmacytosis <30% (less than 30% plasma cells in bone marrow); if you have more, thats diagnosis of multiple myeloma;at 15 years, you have 16% change of MGUS progressing ->this means that for pts w/ MGUS, you just monitor them -> if they start developing bone lesions or increasing the M protein levels, they are progressing to smoldering multiple myeloma o Most pts w/ MGUS will die of something else in their life

solidary plasmacytoma

higher chance of cure w/ radiation --> stage 1: observation, but will probably progress; stage 2/3: no tx is curavtive,

Monoclonal Gammopathy of Undetermined significance (MGUS) Amyloidosis Heterogeneous group of extracellular protein deposition diseases; can deposit in any tissue in body; De novo or in setting of MGUS/Myeloma/Wald.

usually asymp, possibly neuropathy

Emergence of a limited number of clonal plasma cells

dx criteria: M Protein: IgG<3.5 g/dL or observation at 6 mth intervals IgA<2.0 g/dL; Urine light chains <1g/24; Marrow plasmacytosis <10%; No lytic bone lesions Orthostatic vital signs/History and Physical; ABDOMINAL FAT PAD ASPIRATION for CONGO RED TISSUE STAIN; Bone marrow exam for usual studies and Congo Red stain; Electropheresis/immunofixation of serum and urine (just like myeloma); 24 hour urine for protein and creatinine clearance; PET/CTs, PFTs, Gastric emptying scan, EMGs Amyloid deposits are generally irreversible, so goal of therapy is to retard further deposition Treatment is similar to myeloma, but no optimal therapy exists; clinical trial enrollment is best Survival is usually poor; patients with renal deposits and nephrotic syndrome may benefit

Extremely Polymorphic; Unexplained marked weight loss/fatigue; Cardiomyopathy, orthostatic hypotension (due to deposition in the heart); macroglossia (huge tongue esp if you see teeth marks in tongue), periorbital edema (swollen eye); Nephrotic syndrome, hepatomegaly; Carpal tunnel syndrome (hemodialysis patients with elevated Beta-2 microglobulin)

Homogenous protein molecules aggregate into linear, nonbranching fibrils that form an ordered, characteristic Beta-pleated sheet pattern on x-ray diffraction analysis. (Responsible for apple-green birefringence under polarized light for Congo-Red stained tissues) ->xmas colors Diverse human proteins can form amyloid fibrils

POEMS syndrome

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin changes (hyperpigment, hypertrichosis) NON-HODGKIN'S LYMPHOMA

A form of a plasma cell dyscrasia that presents in younger patients (51) who have longer survivals than myeloma (median 8 years) Progressive neuropathy responds to myeloma therapy

MALIGNANT

The great paradox of malignant lymphomas: Low-grade = delayed treatment possible, eventual treatment effective, relapses are universal, remissions shorten with successive treatments, you start treatment, they must always be treated; High-grade = immediate treatment mandatory, initial remissions in 30-60%, many of which will be cured, but resistant disease or relapsed disease results in death in a short time

Non-hodgkin's lymphoma (NHL)

Characterized by malignant, clonal expansion of B cells, T cells, NK, or rarely, histiocytic/ dendritic cells; WHO Classification:precursor/mat ure, B or T/NK categories; Kids do NOT get indolent lymphomas( they do NOT get follicular, MALT, or any of those)

Indolent lymphomas are generally easily treatable, yet ultimately incurable;Clinical courses are marked by slow progression, repeated remissions/relapses with treatment, and even remarkably stable disease in the absence of treatment. Survivals 5-20 years!

Follicular NHL

MC of indolent lymphomas; typically older adults, typically stage IV disease (nodes everywhere, marrow involvement); commonly asymptomatic,

t(14;18) translocation ->results in overexpression of BCL2, an antiapoptotic gene (antagonizes apoptosis and promotes survival of follicular lymphoma cells), in 90% of cases

morph: lymph node shows nodular/diffuse growth pattern; Two principal cell types: o Centrocytes (small cleaved cells) irregular or cleaved nuclear contours and scant cytoplasm o Centroblasts larger cells with open nuclear chromatin , multiple nucleoli and modest amount of cytoplasm; Bone marrow involvement in 85% of cases with paratrabecular lymphoid aggregates; Splenic white pulp and hepatic portal triads freqinvolved

Pathologists grade FLs by numbers of progosis: Median survival is 7 9 years; centromeres per high power field (few Histo transformation occurs in 30 to = grade I/II, >15= grade III); On flow, 50% of follicular lymphomas, usually DLBCL malignancies o CD20+ only really seen in follicular lymphomas Grade III require more aggressive treatment than grade I/II Dont confuse Grade with Stage! Ex.- Stage IIIA, grade I Follicular B cell NHL, IPI low risk.

Marginal zone encompasses B-cell tumors lymphomas of NHL (MZL arising in the nodes, spleen of NHL) or extranodal tissues -> 3 types: o Extranodal MZL of MALT (mucosal associated lymphoid tissue; Nodal MZL; Splenic MZL

characterized by small, cleaved B lymphocytes that occupy an expanded marginal zone surrounding lymphoid follicles in LNs

CD5+, CD23- (compared to CLL, which is also CD5+ but CD23+)

MALT lymphomas

Bacterial- Helicobacter pylori with gastric MALT lymphomas ( this is the ONLY lymphoma that you treat w/ antibiotics, do NOT need radiation or chemo!)

occur at mucosal sites -> gastric, intestinal, lung, salivary, orbit, thyroid; Sites affected by inflammation: Sjogrens (salivary), Hashimotos (thyroid), AND o STOMACH: MC site, due to chronic inflammation with H. pylori ->presents w/ a gastric ulcer/mass, confined to stomach

70% of gastric MALTomas regress with antibiotics; Flagyl/Amoxicillin/Omeprazole +/-Biaxin

Nodal MZL

Usually behaves in an indolent fashion; Co-existing extranodal MALToma can be found in 30% of cases

IgM monoclonal gammopathy can be seen

Median survival is 10 years; treatment only for progressive disease

indolent T cell lymphomas: Mycosis fungoides/Sezary syndrome

Limited to skin in early stages as plaques or patches; Epidermal collections of atypical lymphocytes are known as Pautriers Microabscesses

Chronic illness, typically older patients, incurable

Advanced stage with nodal or organ involvement, and circulating clonal T cells in blood are called Sezary Cells >aka butt cells, look like cleft

Misdiagnosed as psoriasis commonly.

topical nitrogen mustard, electron beam XRT, UVA (psoralen with UV-A light), Sezary Syndrome treated with chemotherapy

primary cutaneous anaplastic large cell lymphoma (ACLC)

CD30+

aggressive B cell lymphomas: Diffuse Large B cell (DLBCL)

MC form of NHL; is a rapidly enlarging mass at a nodal heterogeneous disease; or extranodal site virtually median age: 60;slight M>F; anywhere in the body 3 subsets w/ markedly differing prognoses can be identified by cDNA microarray analysis ->1. GCB (germinal center B-celltype) ,best prognosis; 2. ABC (activated B-cell-type); 3. Type-3 Non-GCB, nonABC

path: transloc resulting in dysregulation of BCL6 resulting in overexpression which ultimately causes B-cells to be in an undifferentiated proliferative state. o 10 to 30% of DCBLs are associated with t(14;18) resulting in overexpression of BCL2 (as in follicular lymphoma);

morph: Diffuse growth pattern; Large cell size; Variability in nuclear appearance but MC vesicular nuclei with margination of chromatin to the nuclear membrane; Prominent nucleoli, single or multiple; Mod amt of pale or basophilic cytoplasm

Microarray analysis not ready for prognosis: rapidly fatal without RX; 40 40-50% cured with chemo (R-CHOP) general clinical use; the IPI is still used to 50% are cured, the rest die which is the best treatment for prognostication; 40% respond but relapse, usually in 2immunophenotyping: mature B-cells 3 years expressing CD19 and CD 20 w/ variable 10-20% primary refractory to expression of germinal center B-cell treatment markers such as CD10 and BCL 6 Bone marrow, nasosinus, or testicular involv increases risk for CNS involv Rituxan (MoAb CD-20) is an impadvance over chemotherapy alone

mediastinal (thymic) Typically young females, 20- Localized but bulky anterior large B cell lymphoma 40; Progression to mediastinal mass that may cause extranodal sites is common SVC syndrome (incl. kidneys, liver, spleen, CNS); Sclerosis/scarring is present;

BCL6 is a transcription factor gene capable of promiscuous rearrangement with multiple translocation partners

CD19/CD20+, SIg-

Distinct from typical DLBCL, resembles Cure rate 40-50% R-CHOP with radiation classical Hodgkins Lymphoma

Figure 3. Classical Burkitt lymphoma

Burkitt lymphoma

One of the most aggressive of all human malignancies! 3 types: 1. african (EBV, affects jaw); 2. sporadic (ileocecum, peritoneum); 3. assoc w/ HIV

Endemic form in African children with jaw or facial masses; Very acute onset, very rapid doubling time; Sporadic form of western world involves children and adults, typically with bulky abdominal disease, and CNS involvement is common

t(8;14), t(2;8), t(8;22) translocations all seen in Burkitts Lymphoma, in which a Ig light or heavy gene promoter is fused to the c-myc transcription factor ->14 is heavy chain locus; 8 is c-myc transcription factor --> mutation on chrom. 8 -> increased c-myc expression; the transcription factor is involved in multiple (15%) downstream gene expression targets, including proliferation, transformation , and apoptosis

morph: Affected tissues have a diffuse infiltrate of intermediate-sized lymphoid cells; Nuclei contain coarse chromatin, several nucleoli and mod amount of cytoplasm; High mitotic activity with numerous apoptotic cells; Starry sky appearance due to macrophages engulfing apoptotic cells
Kadin, M. ASH Image Bank 2003;2003:100692

60-80% cure rate with aggressive chemotherapy

Copyright 2003 American Society of Hematology. Copyright restrictions may apply.

Mantle cell lymphoma Worst of both worldscombines the worst attributes of both indolent and aggressive lymphomas: lack of curability, yet aggressive clinical course

Striking male predominance, 50-70 t(11;14) translocation on chrom 11 with yrs., advanced stage with marrow, overexpression of BCL-1, or cyclin D1, spleen, gut, peripheral blood, (unfavorable low/high grade lesion) lungs, Waldeyer ring, kidneys, prostate, CNS

morph: lymph nodes have nodular appearance (tumor cells surrounding germinal centers) or diffuse effacement; occasionally deeply clefted (cleaved) nuclear contours; Nuclei with condensed nuclear chromatin with inconspicuous nucleoli; Scant cytoplasm; ABSENT large cells resembling centroblasts and proliferation centers seen in follicular and CLL/SLL respectively; We have small lymphocytes here!; Looks very monomorphic, non-malignant

IgM monoclonal gammopathy in 25%. CD5+ ; Easily confused with CLL/SLL, but has the t(11;14) cyclin D1 gene expression; immunophenotyping: B cell markers CD 19 and 20 and high levels of surface Ig and usually CD5+ and CD23- which distinguishes it from CLL/SLL; High levels of cyclin D1

Median survival 3 years; breaks the great paradox b/c looks indolent, but behaves like high grade (aggressive) but can NEVER be cured -> this is an awful lymphoma; pretty rare

HIV-assoc lymphomas Typically B-cell aggressive subtypes, DLBCL or Burkitt. 2/3 are EBV-related and may carry c-myc oncogene translocations

PEL (body cavity lymphoma) presents with ascites or pleural effusions, associated with HHV-8, poor prognosis; CNS involvement is frequent

Treatment requires cytokine support (GCSF, EPO) and HAART

aggressive T cell lymphomas Tcell large cell hepatosplenic - T-Cell Lymphoma systemic anaplastic large cell seen in organ transplant recipients on immunosuppression CD30 (Ki-1)+, children and young adults, nodal/extranodal

Dont use rituxin as tx b/c theres no CD20+ here! worse prognosis than DLBCL; No good tx, try CHOP poor prog

overall excellent prognosis with CHOP

NHL in CHILDREN

Burkitt , T-lymphoblastic, large cell lymphomas; Follicular lymphomas rare

90% of Stage I/II Burkitt/Large Cell are cured; 70% of lymphoblastic cured; Stage III/IV require CNS chemoprophylaxis, possibly craniospinal radiation to low dosages

HODGKIN'S LYMPHOMA uncommon malignant lymphoma; Average age 30; 2 types: 1. nodular lymphocyte predominate HL (looks more like nonhodgkins); 2. classic hodgkin lymphoma (has below subtypes->)

Presentation with asymptomatic mass is typical, but can see the typical B symptoms: fever, night sweats, weight loss

Lymphoma? Uncertain for years, but cell of origin classically the ReedSternberg Cell, felt to be a monoclonal Bcell derived from germinal center; Bcell origin in most cases, and 30-50% of RS cells express the EBV protein LMP-1. Population studies show an increased incidence of HL in people with a diagnosis of infectious mononucleosis in prev 2 yrs. HL is defined pathologically by the demonstration of the RS Cell in an appropriate cellular background. The background ranges from small lymphocytes in LP HL to extensive collagen fibrosis in NS HL. Can be confused with a T-cell rich DLBCL!

RS cells are CD15+, CD30+, CD45-. No cytogenetic profile is characteristic; nodular LP: CD 20+, CD30-;Occurs in males, typically localized disease;asymp, no mediastinal involvement; Higher risk of subsequent B-cell NHL

Accurate staging is essential : CT scans of N/C/A/P, CBC, CMP, ESR, bone marrow biopsy (usually), formerly Gallium scans, now PET scans. ESRs are sensitive for relapse; TO TREAT RELAPSED/REFRACTORY HL/NHL: need High-dose chemo w/ stem cell rescue can salvage relapsed/refractory lymphomas; Better outcome if pts remain chemosensitive at time of relapse. 2-4 cycles of cytoreduction typically

Early Stage- 95% cure; Stage I/II; no bulky disease or B symptoms; 2-4 cycles ABVD chemotherapy with or without XRT Advanced- 85% cure; Bulky Stage II; Stage III/IV; B symptoms All require systemic, extended course (6-8 cycles ABVD) chemotherapy. XRT (radiation) only to sites of bulky disease. No survival advantage to consolidative XRT or HDCT/SCT; Nodular Lymphocyte Predominate HL may have the most favorable prognosis, >90% at 10 years, even with relapses; comp from HL tx: High rate of late toxicity; after 15 years(the risk of death from other causes exceeds risk of death from HL);Cardiovascular Disease (MI, pericarditis. cardiomyopathy); 2ndary solid Malignancies in radiation fieldBreast, lung, GI, thyroid, or sarcomas of soft tissue or bone. Latent period 5-10 years, but >30 years; Hypothyroidism; MOPP(see almost universal sterility); ABVD: Bleomycin lung injury; Adriamycin heart injury; increased risk of breast cancer in women

nodular sclerosis HL

MC subtype; 60-80%, younger pts, females with mediastinal mass

lymphocyte rich classic HL

mixed cellularity HL

2nd MC; 15-30% older pts, male predominance

Histo is diff than adults: LP (lymphocyte predominant) 10%, MC (multicellular) 30%, NS (nodular sclerosis) 40-70%

lymphocyte-depleted HL HL in children 5% of childhood cancers, uncommon before 10; M>F, especially if before 10yrs old; EBV assoc, MC in asians>caucasians>AA

this is it --> diff from adults: On-going growth and development; Longer expected life span after cure o late comp in kids: second cancers (AML, breast cancer, NHL); cardiomyopathy; premature closure of growth plates with XRT;subtle cognition impairment, and sterility ; Lots of breast cancer in young women who have thoracic radiation CAREFUL W/ RADIATION & CHILDREN: When you radiate centrally to adults, they may get some pulmonary fibrosis but nothing serious; When you radiate children, you fuse growth plates in their bones and the radiation has a much more profound effect than adults

ACUTE LYMPHOBLASTIC MC leukemia in children; LEUKEMIA (ALL) only 20% of all adult leukemias; Neoplasm is composed of immature B or T cells (lymphoblasts) ->85% are precursor B cells (BALL); usually 3 yrs old; Hispanic>Whites>Blacks; boys>girls; May have CNS and testicular involvement; T-ALL presents in adolescent males as thymic lymphomas but may present or evolve into leukemia ->starts in thymus!

Depression of marrow function>Anemia, neutropenia and thrombocytopenia; Mass effects from neoplastic infiltration of organs ->Bone pain from marrow expansion; Lymphadenopathy; Splenomegaly; Hepatomegaly; Testicular enlargement; T-ALLcompression of large vessels and airways in mediastinum; CNS manifestations HA, vomiting, nerve palsies from meningeal spread; TALLs have thymic masses in 50 to 70% likely to be associated with lymphadenopathy and splenomegaly

morph: Leukemic presentations >bone marrow is hypercellular with lymphoblasts o Lymphoblasts Nuclei with condensed chromatin, nucleoli absent, scant agranular basophilic cytoplasm (Myeloperoxidase negative, PAS + cytoplasmic material) o May have starry sky appearance (macrophages ingesting apoptotic tumor cells)

WBC Count at diagnosis- >50,000 Prognosis has improved remarkably associated with high risk with intensive induction-consolidationtranslocations; t(4;11), t(9;22); maintenance regimens, along with immunophenotyping (very imp): intrathecal CNS therapy; Goal- allow Mature B-cell Leukemia/Lymphoma children with good prognoses to be (Burkitt)-> CD20+, SIg, and c-myc spared more toxic and intensive (locus on 8) translocations with heavy treatment; Poor-prognosis groups chain locus 14 or light chain loci 2 or receive more intensive therapy to 22 increase the chance of cure; young o If liquid phase ->mature B cell children (1-9) do better than infants, leukemia older children, or adolescents; higher o Solid phase -> lymphoma;Terminal risk of tx failure in infants and CNS deoxynucleotidyl-transferase(TdT) involv.; girls have a slightly better expressed only in pre-B and pre-T prognosis than boys (related to lymphoblasts in 95% of cases; testicular relapses);survival rates for Distinguish between B and T cells with black and Hispanic children less than their specific markers: T-cells CD 1, whites; Pts req >4 weeks to achieve CD 2 CD 5, CD 7 and others depending remission have a poor prog upon stage of maturity; B-cells - Pan Bcell marker CD 19 along with others depending upon stage of maturity with CD10+ lymphoblastic leukemia antigen) CD = cluster designation

low/ standard risk: 3 drug induction with vincristine, glucocorticoids, and Lasparaginase, along with intrathecal therapy, CR 98-99%; High-risk: receive a 4th drug, typically Daunorubicin (an anthracycline); goal is to decrease the minimal residual disease burden rapidly, to prevent drug resistance and to prevent infiltration of leukemia cells into sanctuary sites; CNS treatment: only 3% of children have detectable disease at diagnosis, but 50-70% will eventually develop overt CNS leukemia if prophylaxis is not given, give XRT; Maintenance: consists of daily oral 6MP (mercaptopurine) and weekly oral MTX, with occasional boluses of vincristine and glucocorticoids. This continues until 2-3 years of continuous complete remission; STEM CELL TRANSPLANT: Peds: TOC for Ph+ ALL in first remission; Other high-risk children (induction failures or hypo-diploid presentations) may benefit -> If early relapse after remission, transplant. If late relapse after remission, excellent results possible with std chemotherapy/XRT, +/- later SCT; Adulthigh risk categories

B and T cell lymphoblastic lymphoma (LBL)

matter of semantics -> the distinction b/w ALL and LBL is based on the degree of marrow infiltration (>vs.<25%) and the presence of circulating blasts in peripheral blood M>F 2:1; Majority are Tlineage, advanced disease, and CNS involvement is

75% have an ant mediastinal mass and may present with SVC syndrome (dyspnea, wheezing stridor, dysphagia, facial swelling.

T-cell LBL:

diff dx: ALL vs. LBL: ALL: o No mass lesions o Peripheral blood + o BM > 20% blasts LBL (lymphoblastic lymphoma) o Mass lesions o Peripheral Blood o BM < 20% blasts

Workup can be a challenge due to risk of cardiac or respiratory arrest from sedation or anesthesia

ACUTE MYELOID LEUKEMIA (AML)

disease of adults (90%); risks: Benzene exposure, Chemo agents (alkylators, topoisomerase II inhib.), Myeloproliferative and Myelodysplastic disorders o Peds: Faconi anemia, Downs Syndrome, Schwachman-Diamond Syndrome

anemia, fever, infection, mucosal bleeding, bone pain; 1/2 w/ hepatosplenomegaly; Gum infiltrates, skin infiltrates (chloromas) with monocytic subtypes (M4 or M5); Lifethreatening DIC is seen with M3, APL; See mental clouding and hypoxia from sludging of microvasculature; compare picture to ALL (very similar)

FAB Classification relies on morphologic, cytochemical, and immunophenotypic criteria to define 8 major subtypes, M0M7. o Auer rods- cytoplasmic primary granules, detected on Wright stains or myeoloperoxidase stains, defines M1 or M2 biotypes o NSE stains (non-specific esterase) crucial for diagnosis of monocytic biotypes, M4 or M5; Know AML classifications; auer rods -->

Hyperviscosity Syndromes: WBC >100,000 leads to leukostasis -> treatment emergency, need leukopheresis to prevent sludging (NOT IN CLL, THOUGH!); Cytogenetic analysis by chromosomal banding, FISH, or PCR techniques confirm the diagnosis and provide prognostic information

prognosis: t(8,21) translocation, you have a better prognosis; young is better for tx and cytogenetics;

Remission Induction: 7 and 3 o 7 days of low-dose cytarabine by continuous infusion, 3 days of daunorubicin or idarubicin by bolus; Achieves remission in 80-90% children, good in others too; May have to be repeated if leukemia persists at day +14; o APL (M3) is treated much differently; Consolidation/Post-remission Therapy: (necessary to prevent relapse) In yount pts: High-dose cytarabine, 4 cycles; what about consolidation w/ transplant?Autologous: no benefit over high dose cytarabine; Allogeneic: graftvs.-leukemia benefit is offset by graft-vs.host disease morbidity/mortality; use allo-SCT in first remission for high risk cytogenetics, use standard consolidation for favorable cytogenetics

Acute proliferative leukemia (APL)

AML -> M3, unique; 10-15% of all AML, butMC in China, Mexico, and in the morbidly obese

APL blasts release proteolytic enzymes that induce a consumptive coagulopathy and fibrinolysis (i.e. DIC); fusion of the PML gene to the retinoic acid receptor (RAR), causing maturational arrest of myeloid cells. Can be overcome with ATRA (all-trans-retinoic acid)

Can be fatal due to induced DIC

Oral ATRA for APL leads to a 75-90% remission rate, far superior to 7/3. DIC is rapidly ameliorated by ATRA induced myeloid differentiation. But, hyperleukocytosis can result, leading to the ATRA Syndrome, characterized by fever, respiratory distress, pulmonary edema, effusions, hypotension, cardiac and renal failure. Rapid dosing of steroids can be life-saving; if relapse after all that, try Arsenic trioxide (has significant single agent activity as well as synergy with ATRA in APL); Must monitor electrolytes and EKG daily to avoid torsade de pointes, though

Myelodysplastic syndrome (MDS):

pre-leukemia disease b/c it almost always transforms into an acute myeloid leukemia; A group of clonal stem cell disorders characterized by maturation defects assoc with ineffective hematopoiesis ; High risk of transformation to AML; Disease of the elderly (mean age of onset is 70 years); Freq discovered incidentally while asymp

sx due to pancytopenia: weakness, infection, hemorrhage; classes: Primary (idiopathic); Secondary to previous genotoxic drug or radiation therapy (t-MDS) -> Appears 2 to 8 years after exposure, transformation to AML occurs more rapidly and frequently

morph: Bone marrow usually can cause sideroblastic anemia hypercellular at DX but may be hypo- or normocellular; Dysplastic diff affecting the erythroid, granulocytic, monocytic and megakaryocytic lineages;Peripheral blood smear may show Pseudo-Pelger-Huet cells (neutrophils with only 2 lobes and some lack any segmentation), giant platelets, macrocytes, and poikilocytes with a monocytosis; bone marrow: Erythroid series (Ringed sideroblasts-erythroblasts with iron-laden mito); Granulocytic (Decreased secondary granules, toxic granulation and/or Dohle bodies, PseudoPelger-Huet cells); Megakaryoctyes (single nuclear lobes or multiple separate nuclei (pawn ball megakaryocytes)

prognosis: Median survival varies from 9- 29 months but some may live for 5 years or more;Worse with: Increased blasts (increased progression to AML); Multiple clonal chromosomal abnormalities o Younger patients bone marrow transplant to live longer

MYELOPROLI-FERATIVE Common denominator in DISORDERS the myeloproliferative disorders are tyrosine kinase mutations (normally growth factors bind to surface receptors of normal progenitor cells and activate tyrosine kinases which turn on pathways promoting growth and survival)

CHRONIC MYELOID LEUKEMIA:

50-60s ages;

hepatomegaly and lymphoadenopathy from extramedullary hematopoiesis; Splenomegaly may produce a dragging sensation in abdomen or may get acute splenic infarct; Slow progression o After ~ 3 years, accelerated phase in 50% with increasing anemia and thrombocytopenia with additional cytogenetic abnormalities o After 6 to 12 months, accelerated phase terminates in a blast crisis (lymphoid or myeloid)

path: A chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9-> created by a reciprocal (9;22)(q34;q11) translocation call the Philadephia chromosome; directs the synthesis of a constitutively active BCRABL tyrosine kinase -> Drives GF-indep prolif and survival of bone marrow progenitors; does not interfere with differentiation resulting in mature cells

platelets increased;Hypercellular marrow with increased numbers of maturing granulocytic precursors and increased megakaryocytes; Sea-blue histiocytes scattered in bone marrow (macros with abundant wrinkled, green-blue cytoplasm); increased basophilia

Detection of the BCR-ABL fusion gene o Bone marrow transplant in young through PCR or chromosomal analysis; patients which is curative in 75% of median survival ~3 yrs cases performed during the stable phase o Imatinib, a BCR-ABL inhibitor, results in sustained hematologic remission in greater than 90% of patents; however, does not extinguish the CML stem cell o Its not curative, but very good treatment

POLYCYTHEMIA VERA (PCV)

an inapprop polycythemia w/ low EPO; Occurs in adults of middle age

sx due to hyperviscosity from increased RBC count; plethoric and cyanotic due to stagnation and deoxygenation of blood in peripheral vessels;HA, dizziness, HTN, and GI; Most ominous is thrombosis and hemorrhage (from stagnation);Gout (Increased breakdown of nucleated cells with uric acid production from purines); Increased histamine release from mast cells (b/c you have increased basophils, which go into tissues and bc mast cells); Pruritus after bathing (mast cells degranulate after change in skin temperature); Peptic ulcer disease ( Histamine stimulates gastric acid prod)

increased marrow production of RBC, granulocytes and platelets with SXs from RBC increase; assoc w/ mutations in the tyrosine kinase JAK2 gene leading to proliferation of hematopoietic cells independent of growth factors (less proliferative drive than CML); Erythropoietin levels are low

morph: Hypercellular marrow (trilineage) with only subtle increase in RBC progenitor; Mild organomegaly from congestion; Peripheral blood has basophilia and large platelets; Late in course of disease, extensive marrow fibrosis is present with extramedullary hematopoiesis in the spleen and liver leading to organomegaly

prognosis: Without Rx, death from bleeding or thrombosis occurs in months o With phlebotomy, ~10 year median survival o PCV evolves into a spent phase with development of myelofibrosis in 15 to 20% after ~ 10 years o Extramedullary hematopoeisis develops

ESSENTIAL Associated with JAK2 THROMBOCYTOSIS (ET) (50% of cases) or MPL (510% of cases) a receptor tyrosine kinase normally activated by thrombopoietin; Dysfunction of platelets leads to thrombosis and hemorrhage; >60 yrs but can be seen in younger pts

Erythromelalgia (a throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates)

Mild increase in bone marrow cellularity; Megakaryocytes are increased in number and in abnormally large forms;Delicate reticulin fibers in bone marrow;

Peripheral smears show abnormally large platelets with mild leukocytosis ;Modest extramedullary hematopoiesis with mild organomegaly

median survival of 12- 15 yrs

gentle chemotherapy

PRIMARY MYELOFIBROSIS

JAK2 mutation (so has same mutations as above but different clinical picture); Less common than PCV and ET; Age > 60 years

splenomegaly (extramed hematopoiesis), hepatomegaly; Progressive anemia and splenomegaly with leukoerythroblastosis

Hallmark of disease is development of obliterative marrow fibrosis; extensive deposition of collagen in the marrow by non-neoplastic fibroblasts which displaces hematopoietic elements >Likely caused by inappropriate release of fibrogenic factors (PDGF and TGF-B) from neoplastic megakaryocytes; Extramedullary prod is disordered resulting in severe cytopenias <-- pulmonary fibrosis

morph: hypercellular marrow of all lineages; Megakaryocytes are large, dysplastic and abnormally clustered; Peripheral blood may show leukocytosis and thrombocytosis; With progression, marrow is hypocellular and fibrotic with clusters of atypical megakaryocytes with hematopoietic elements in dilated sinusoids due to fibrosis o Late, fibrotic marrow is converted into bone, which is called osteosclerosis

Leukoerythroblastosis (premature release of nucleated erythroid progenitors and early granulocyte progenitors); Abnormally large platelets ; Basophilia ; Decreased white counts and platelets as disease progresses; AML transformation occurs in 5 to 20% o Bleeding, thrombosis, intercurrent infections are complications

teardrop cells (dacrocytes) ->

mean survival 3-5 yrs

LANGHERHANS CELL proliferative disorders of HISTIOCYTOSIS (Letter- dendritic cells or Siwe disease) macrophages; Usually occurs before age 2

Cutaneous lesions along with multiorgan infiltration

2 forms: 1. Eosinophilic granulomaproliferation of Langerhans cells admixed with eosinophils, lymphocytes, plasma cells and neutrophils, typically arises in bones;2.pulmonary Langerhans cell histiocytosis may be reactive proliferation in smokers

angerhans cells have abundant vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds Birbeck granules in the cytoplasm are pentalaminar tubules, with a dilated terminal end producing a tennis racket appearance -->

With chemo, 5 year survival is 50%

CLINCIAL DISEASES OF WBC

CONGENITAL NEUTROPENIAS