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USMLE STEP 2 CK REVIEW ~ HEMATOLOGY


TRANSFUSIONS
Blood Groups
o Blood Abs Produced in peyers patches M-cells transport A & B antigens to nearby B-lymphocytes
B-cells produce natural antibodies against antigens not present on RBC surface
o Type A A antigen on RBC surface & B antibody in plasma
o Type B B antigen on RBC surface & A antibody in plasma
o Type AB Both A & B antigens on RBC surface w/no antibodies in plasma universal recipient
o Type O Neither A nor B antigen on RBC surface w/both antibodies in plasma universal donor
o Rh Type RhC mothers exposed to Rh blood produce anti-Rh IgG MC during child birth
In subsequent pregnancies anti-Rh IgG can cross placenta & cause HDN
Prevent by giving mother Rh antigen Ig after delivery of first Rh baby

Transfusion Types
o PRBCs No platelets or clotting factors each unit | Hb by 1 g/dL & Hct by 4%
Mix w/NS to infuse faster dont mix w/lactated ringer's since Ca
2+
causes coagulation in IV line
Transfuse within 35 days to avoid hyperkalemia from cell lysis
o Platelet Transfusion Contraindicated in TTP/HUS, HIT, HELLP, ITP
Suspect following if | PC not seen post-transfusion alloantibodies, sepsis, hypersplenism
o Fresh Frozen Plasma (FFP) Contains all clotting factors but no RBCs, WBCs or platelets
Indications include sepsis, DIC, dilution, TTP/HUS, liver failure
o Cryoprecipitate Contains fibrinogen, vWF, factor VIII & XIII
Indications include vWD, Hemophilia, hypofibrinogenemia, DIC
o Whole Blood Only for massive blood loss rarely used

Hemolytic Transfusion Reactions
o Acute Hemolytic Transfusion Reactions (AHTR):
ABO incompatibility causing intravascular hemolysis 2
O
to complement activation
- Occurs immediately after transfusion MCC is clerical error
Symptoms Fever, chills, N/V, flank/back pain, chest pain, dyspnea
Complications ARF w/hemoglobinuria, hypovolemic shock or DIC
Treatment Stop transfusion & aggressively replace fluids to avoid shock & renal failure
o Febrile Non-hemolytic Transfusion Reactions (FNHTR):
Alloantibodies to WBC, platelets or other donor plasma antigens occurs <6hrs after transfusion
Symptoms Fever, rigors, facial flushing, headache, myalgia, hypotension
Treatment Stop transfusion if fever >38
O
C give antipyretics & anti-histamine
- If fever <38
O
C continue w/transfusion but + rate & give antipyretics
o Allergic Non-hemolytic Transfusion Reactions:
Alloantibodies (IgE) to proteins in donor plasma result in mast cell activation & histamine release
- MC in pts. w/history of multiple transfusions or multiparous women
Symptoms Urticaria fever can present as anaphylactic reaction in IgA deficient pts.
Treatment Stop transfusion & give IV Diphenydramine, Epinephrine, Corticosteroids
- If reaction mild slow transfusion rate & give Diphenhydramine
o Delayed Hemolytic Transfusion Reactions:
Due to alloantibodies to minor antigens such as Rh, Kell, Duffy or Kidd
Occurs 5-7d after transfusion antibody level at time of transfusion too low to cause hemolysis
- Antibody level later increases due to 2
O
stimulus & causes extravascular hemolysis
Symptoms Anemia & mild jaundice no specific treatment required

MICROCYTIC ANEMIAS
Iron Deficiency Anemia (IDA)
o Etiology:
Chronic bleeding Menorrhagia or GI bleeding R/O colon cancer in elderly pts. w/IDA
Dietary Cows milk or tea & toast diet MC in children & elderly

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| Iron requirement Pregnancy
o Clinical Presentation Pallor, fatigue, brittle nails w/koilonychia, DOE, tachycardia, palpitations
o Diagnosis + Ferritin (most reliable), | TIBC, | Transferrin, | RDW
o Treatment:
Iron Ferrous Sulfate/Gluconate/Fumarate continue for 3+ months until ferritin normalizes
- Oral iron should be taken w/citrus juice to enhance absorption
- Venofer IV iron if unable to tolerate or absorb oral iron
- If not responding to iron therapy obtain Hb electrophoresis to R/O thalassemia
Blood transfusion Only in severe cases or if comorbid cardiopulmonary disease

-Thalassemia
o -chain deficiency w/normal synthesis of -chains excess -chains bind & damage RBC membrane
o Thalassemia Major (Cooley's Anemia):
Homozygous -chain absent due to nonsense mutation (stop codon) MC in Mediterraneans
- Clinical manifestations begin at 6-12 months age when HbA normally replaces HbF
Clinical Presentation:
- Severe anemia & jaundice
- Stunted growth & development hypogonadal dwarf
- Gross splenomegaly due to extramedullary hematopoiesis
- BM expansion w/skeletal deformities crew cut skull, chipmunk facies, pathologic Fx.
- Pigmented gallstones evidence of | Hb catabolism
Diagnosis:
- Hb Electrophoresis | HbF (90-100%) & + HbA (0-10%)
- Skull XR Hair-on-end appearance
Treatment:
- PRBC transfusions Required frequently to sustain life
o If untreated death occurs within 1
st
few years of life 2
O
to progressive CHF
- Deferoxamine Fe chelation to prevent iron overload from frequent transfusions
- Allogenic BM Transplant
o Thalassemia Minor:
Heterozygous -chain underproduced
Asymptomatic or mild microcytic hypochromic anemia no treatment required
Hb Electrophoresis reveals | HbF & | HbA2 (>3.5%)
o Thalassemia Intermedia Involves both -globin genes w/intermediate severity anemia

-Thalassemia
o + Synthesis of -chains remaining -globin chains form abnormal Hb tetramers
o Carriers (silent) 1 -gene affected asymptomatic w/normal Hb & no treatment
o -Thalassemia Minor (trait) Mutation/deletion of 2 -genes - MC in African-Americans
Mild microcytic hypochromic anemia & no treatment needed
o HbH Disease (4) 3 -genes affected w/significant microcytic hypochromic anemia
Hemolytic anemia & splenomegaly treatment same as -thalassemia major
Hb electrophoresis reveals HbH
o Hydrops Fetalis/Hb Barts (4) All 4 -genes affected fatal at birth or shortly after

Sideroblastic Anemia
o Abnormality in RBC iron metabolism w/trapped iron in mitochondria of nucleated RBCs
o Etiology:
Hereditary X-linked defect in o-Aminolevulinic acid synthase gene
- Glycine + Succinyl CoA unable to form o-Aminolevulinic acid
- Rate-limiting step w/pyridoxine (B6) as cofactor
Acquired Alcohol, Pb, INH (inhibits B6), Chloramphenicol
o Clinical Presentation Anemia, hepatosplenomegaly, Fe overload syndrome
o Diagnosis:
Labs | Iron, | Ferritin, + TIBC
Histology Ringed sideroblasts in BM w/prussian-blue stain
o Treatment Remove offending agents & administer B6 if needed


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NORMOCYTIC ANEMIAS
Anemia of Chronic Disease (ACD)
o Anemia of underproduction due to impaired iron utilization can be normocytic or microcytic
Occurs in setting of chronic infection, cancer, inflammation or trauma
o Pathophysiology:
Release of inflammatory cytokines has suppressive effect on erythropoiesis
| Hepcidin from liver causes + release of iron from macrophages
EPO normal or slightly elevated but marrow unable to respond w/| erythropoiesis
o Diagnosis + Iron, + TIBC, + Transferrin, | Ferritin, | ESR, |CRP absent splenomegaly!
o Treatment Treat underlying process & do not give iron

Aplastic Anemia
o Pancytopenia caused by failure or destruction of myeloid stem cells in BM
o Etiology:
Idiopathic MCC & often T-cell mediated
Drugs Chloramphenicol, Sulfonamides, Carbamazepine, Benzene, Radiation, Alkylating-agents
Viral Parvovirus B19, EBV, CMV, VZV, HIV, HCV, HBV
Genetic Fanconis anemia or Shwachman-Diamond syndrome
o Clinical Presentation:
Anemia, fatigue, pallor, dyspnea absence of splenomegaly & LAD
Thrombocytopenia petechiae, easy bruising, mucosal bleeding
| Infections due to neutropenia
Complications can progress to acute leukemia
o Diagnosis:
Pancytopenia w/+ Reticulocytes
BM Biopsy Hypocellular w/fatty infiltration absent progenitors of all 3 hematopoietic lines
o Treatment:
Allogenic BMT Can cure 80-90% of pts. under age 50
Immunosuppressives Antithymocyte globulin, Cyclosporine, Prednisine 60-70% remission

MACROCYTIC ANEMIAS
Megaloblastic Anemia Vitamin B12 (Cyanocobalamin) Deficiency
o B12 is cofactor in 2 important reactions:
Conversion of Homocysteine to Methionine
Conversion of Methylmalonyl CoA to Succinyl CoA
o Etiology:
Pernicious anemia MCC in western hemisphere
- Auto-antibodies against gastric parietal cells causes achlorhydria & lack of intrinsic factor
- Parietal cells make IF which binds B12 & allows absorption by terminal ileum
Poor diet MC in vegetarians & alcoholics
- Main dietary source is meat/fish & B12 stores in liver enough for 3+ yrs
Chronic gastritis Leads to gastric mucosal atrophy
+ Absorption Gastrectomy, Crohn's, Ileal resection
Diphyllobothrium latum (fish tapeworm) Competes for B12
o Clinical Presentation:
Anemia, stomatitis & glossitis
Subacute-combined degeneration distinguishes B12 from folate deficiency
- Irreversible demyelination of spinal cord
- Posterior columns + vibration sense, proprioception & 2-point discrimination
- Pyramidal tracts hyperreflexia, spasticity, weakness, Babinski
- May cause urinary or fecal incontinence & impotence
Peripheral neuropathy usually symmetrical & affecting lower limbs > upper limbs
May lead to confusion, delirium or dementia
o Diagnosis:
| MCV >100, + B12 (<100 pg/mL), | Methylmalonic acid, | Homocysteine

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- | Methylmalonic acid seen only in B12 deficiency
Peripheral Smear Hypersegmented neutrophils & oval macrocytes
BM Biopsy Hypercellularity & nuclear-cytoplasmic asynchrony in RBC precursors
- Less mature nuclei than expected from development of cytoplasm
Schilling Test Determines cause of cyanocobalamin deficiency
- Administer IM dose of unlabeled B12 to saturate binding sites
- Give oral radioactive B12 & measure urine + plasma B12 to see absorption
- Next, give another oral radioactive B12 dose w/addition of intrinsic factor
o If no change in serum B12 after IF Malabsorption is cause
o If B12 | after addition of IF Pernicious anemia is cause
o Treatment Parenteral B12 once per month be cautious of hypokalemia & rebound thrombocytosis

Megaloblastic Anemia Folate Deficiency
o Folic acid stores limited & inadequate intake over 3-month period can cause deficiency
+ Dietary intake MCC of folate deficiency esp. elderly & alcoholics
Other Alcoholism, MTX, Phenytoin, pregnancy, hemolysis, hemodialysis
o Clinical Presentation Same as B12 deficiency but without neurologic manifestations
o Diagnosis + Folic acid & | Homocysteine
o Treatment Folic acid supplements

HEMOLYTIC ANEMIAS
Hemolytic Anemias (HA)
o Premature destruction of RBCs anemia results if RBC destruction > BM erythropoiesis
o Classification:
Hemolysis due to intrinsic RBC defects most cases inherited:
- Hb abnormality Sickle-cell, HbC disease, Thalassemias
- Membrane defects Spherocytosis, PNH (paroxysmal nocturnal hemoglobinuria)
- Enzymes G6PD deficiency, Pyruvate-kinase deficiency
Hemolysis external to RBC defects most cases acquired:
- Mechanical Prosthetic valves, microangiopathic hemolytic anemia (MHA)
- Infection Malaria, Clostridium
- Other Immune-mediated, medications or toxins
o Clinical Presentation Anemia, jaundice, hepatosplenomegaly, pigment gallstones
o Diagnosis:
+ Hb, + Hct, | Reticulocyte Count
| LDH released when RBCs destroyed
| Unconjugated/Indirect Bilirubin degradation of heme released from RBCs destruction
Intravascular Hemolysis:
- + Haptoglobin released hemoglobin immediately binds haptoglobin
- Hemoglobinuria & urine Hemosiderin
o Dark urine color indicates severe intravascular hemolysis
o Hemoglobin levels exceed reabsorption capacity of PCT
Extravascular Hemolysis:
- Haptoglobin normal Hb does not escape into plasma
- Absent hemoglobinuria & urine hemosiderin
- Direct Coombs Detects IgG or complement on RBC surface
o Add anti-IgG or anti-complement antibodies to pts. RBCs
o If RBCs agglutinate HDN, AIHA, AHTR
- Indirect Coombs Detects antibodies in serum that can recognize antigens on RBCs
o Mix pt. serum w/donor RBC & Coombs serum (human anti-Ig)
o If RBCs agglutinate used for cross-matching recipient serum w/donor RBC
o Treatment Treat underlying cause PRBCs if severe anemia

Sickle Cell Anemia
o Autosomal recessive, occurring when normal HbA replaced by mutant HbS
Intrinsic defect causing extravascular hemolysis

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o G6V HbS has uncharged Valine substituted for negative charged Glutamic acid at 6
th
position of -chain
o Deoxyhemoglobin + O2 causes HbS to polymerize causing RBCs to sickle
Sickled RBCs obstruct small vessels, leading to ischemia & painful crises
Precipitants acidosis, hypoxemia, | 2,3-DPG, | temperature, dehydration
o Classification:
Sickle Cell Trait Heterozygotes (HbAS) 60-65% HbA & 35-40% HbS
- Resistance to malaria, non-anemic w/normal CBC & normal life expectancy
- 1/12 Africans carry sickle cell trait also seen in Italians, Greeks & Saudi Arabians
HbSC Compound heterozygote mild anemia & spleen not always atrophic in adults
Sickle Cell Disease (SCD) Homozygous (HbSS) 90-95% HbS, 5-10% HbF & absent HbA
- Sickling occurs at pO2 of 80mmHg & life expectancy reduced by 25-30yrs
o Clinical Presentation:
Bone crises Bone infarction causing severe pain MC clinical manifestation
- Self-limiting lasting 2-7 days & involves multiple sites like tibia, humerus & femur
Aplastic crisis Provoked by viral infections MCC is Parvovirus B19
- Treat w/blood transfusion recovery in 7-10 days
Dactylitis Avascular necrosis of metacarpal & metatarsal bones
- Painful swelling of dorsa of hands & feet seen in infancy by 4-6 months
Splenomegaly Seen in childhood spleen no longer palpable by age 4
Autosplenectomy Repeated splenic infarctions spleen reduced to small, calcified remnant
- Results in Howell-Jolly bodies basophilic nuclear remnants in RBC
Splenic sequestration crisis MC in children w/intact spleens potentially fatal
- Sudden pooling of blood into spleen causing rapid splenomegaly & hypovolemic shock
| Infections Asplenia causes susceptibility to encapsulated bacteria H. influenzae, S. pneum.
- Osteomyelitis caused by Salmonella paratyphi
Avascular joint necrosis MC in femoral head & humeral head
Pigmented gallstones Due to | hemolysis
Priapism Erection due to vaso-occlusion sustained priapism >3hrs is medical emergency
CVA Due to cerebral thrombosis
Ophthalmologic Retinal infarcts & detachment, vitreous hemorrhage, proliferative retinopathy
Renal papillary necrosis w/hematuria Painless & seen in up to 20% of cases
Leg ulcers Vaso-occlusion of superficial leg vessels commonly in lateral malleoli
Acute chest syndrome Due to repeated episodes of pulmonary infarctions
- Mimics pneumonia chest pain, resp. distress, pulmonary infiltrates & hypoxia
CHF High-output heart failure may occur over time 2
O
to anemia
o Diagnosis Hb Electrophoresis
o Treatment:
Hydroxyurea | HbF production reduces sickling cytotoxic & may cause BM suppression
Painful crises Morphine + Fluids (to + viscosity) + O2
PRBC transfusion Only in severe cases CNS, cardiac or respiratory manifestations
Antibiotics If infection suspected Ceftriaxone or Cefotaxime
Preventative:
- Avoid high altitudes low oxygen tension can precipitate crisis
- Maintain fluid intake dehydration can precipitate crisis
- Vaccinations against S. pneumoniae, H. influenzae & N. meningitidis
- Penicillin prophylactically from 4 months until age 6

Hereditary Spherocytosis
o Autosomal dominant defect causing + spectrin levels MC hereditary HA
Intrinsic defect causing extravascular hemolysis
o + RBC membrane surface area without reduction in RBC volume necessitates spherical shape
Spherical RBCs become trapped & destroyed in spleen by macrophages
o Clinical Presentation:
Hemolytic anemia, jaundice, splenomegaly, calcium-bilirubinate gallstones
Aplastic crisis w/parvovirus B19 infection
o Diagnosis:
| Reticulocyte count, | MCHC, | RDW, | LDH

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Peripheral Smear Spherocytes w/no central pallor
C Direct Coombs Helpful for distinguishing from AIHA also has spherocytes
Osmotic Fragility Test RBC lysis in hypotonic saline
o Treatment Splenectomy w/vaccination against encapsulated organisms

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
o X-linked recessive enzyme deficiency intrinsic defect w/extravascular hemolysis
Precipitants infection, fava beans or drugs (Sulfa, Nitrofurantoin, Primaquine, Dimercaprol)
o Pathophysiology:
+ G6PD + NADPH & + Glutathion (GSH) | H2O2 | RBC susceptibility to oxidant stress
GSH neutralizes H2O2 preventing oxidization of Hb & formation of Heinz bodies
Heinz bodies attach to RBC membranes causing + flexibility & leads to splenic RBC sequestration
Bite cells form after splenic macrophages remove heinz bodies from RBCs
o Classification:
A-Variant G6PD deficiency Mild form seen in 10% of African-American men
- Hemolytic episodes usually self-limited & involves only older RBCs
o Younger RBCs spared & have sufficient G6PD to prevent RBC destruction
- Protection against malaria (P. falciparum)
Severe G6PD deficiency MC in Mediterranean populations
- Both young & old RBCs are G6PD-deficient results in severe HA
o Clinical Presentation Episodic HA, jaundice & dark urine
o Diagnosis:
Peripheral Smear Bite cells & Heinz bodies
G6PD assay Deficient NADPH do not test in acute crisis as reticulocytes have | G6PD levels
o Treatment RBC transfusions if necessary

Paroxysmal Nocturnal Hemoglobinuria (PNH)
o Acquired disorder caused by deficiency of GPI anchor protein intrinsic defect w/intravascular hemolysis
o Pathophysiology:
GPI links complement-inactivating decay accelerating factor (DAF/CD55) to cell membranes
DAF destabilizes C3 & C5 convertase adhering to membranes of RBCs, WBCs & platelets
+ GPI Unanchored DAF | Complement-mediated RBC lysis
o Clinical Presentation:
Hemoglobinuria respiratory acidosis during sleep causes | complement attachment
Venous thrombosis esp. hepatic vein (Budd-Chiari syndrome)
o Diagnosis:
| LDH & urine Hemosiderin
Flow Cytometry For CD55 (DAF) & CD59 proteins sensitive & specific for PNH
Ham's Test Pts. cells incubated in acidified serum triggering alternative complement pathway
- Results in lysis of PNH cells but not normal cells
Sugar Water Test Pts. serum mixed in sucrose hemolysis will occur in PNH
o Treatment:
Corticosteroids Initial therapy some do not respond
Eculizumab Inhibits complement effect on RBCs

Autoimmune Hemolytic Anemia (AIHA)
o Auto-antibodies toward RBC membrane antigens leading to RBC destruction
Ab type (IgG or IgM) determines prognosis, site of RBC destruction & response to treatment
Often mild & treatment rarely required only if hemolysis severe
o Warm AIHA:
IgG auto-antibody binds optimally to RBC membranes at 37C - MC than Cold AIHA
Extravascular hemolysis Spleen is primary site of RBC sequestration causing splenomegaly
Etiology:
- Primary Idiopathic
- Secondary CLL, lymphomas, SLE, viral infections or drug-induced
o Type I drug-induced Hapten-mediated Penicillin, Cephalosporins
o Type II drug-induced Immune-complex mediated Quinine, Sulfas, Rifampin
o Type III drug-induced True anti-RBC Ab Methyldopa

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o Cold AIHA:
IgM auto-antibody binds RBC membranes at cold temperatures between 0C5C
Intravascular hemolysis Due to complement activation & primary site of sequestration is liver
Etiology:
- Primary Idiopathic MC in elderly
- Secondary Waldenstrm's macroglobulinemia or infection w/Mycoplasma or EBV
o Clinical Presentation:
Anemia, fatigue, pallor, jaundice, dark urine
Cold AIHA cyanosis of ears, nose, fingers & toes
o Diagnosis:
Direct Coombs Anti-Ig Abs added to pts. RBCs will agglutinate if RBCs coated w/Ig
Cold Agglutinin Titer in Cold AIHA
o Treatment:
Warm AIHA Corticosteroids mainstay of therapy
- Splenectomy if unresponsive to steroids
Cold AIHA Avoid exposure to cold prevents bouts of hemolysis
- Immunosuppressants for severe cases Azathioprine, Cyclosporine, Cyclophosphamide
- Rituximab Anti-CD20 Ab may be beneficial

HEMOSTASIS
Phases of Hemostasis
o 1) Primary Hemostasis
Vessel injury results in collagen/subendothelial matrix exposure & release of vasoconstrictors
Blood flow impeded & platelets come into contact w/damaged vessel wall
- Adhesion Platelets adhere to subendothelium via vWF
- Activation Platelets activated causing release of ADP & thromboxane A2
- Aggregation These factors aggregate more platelets & form hemostatic plug
o 2) Secondary Hemostasis
Platelet plug reinforced by production of fibrin clot in secondary hemostasis
Extrinsic pathway Initiation of coagulation in vivo
Intrinsic pathway Amplification once coagulation has started
o 3) Resolution Fibrin stabilization & fibrinolysis

Extrinsic Coagulation Pathway
o Fast reaction caused by release of Tissue Factor from damaged endothelial cells
o Cascade involves factors 7, 10, 5 Defects cause | PT normal PT = 11-24 sec
o Pathway steps:
1) Tissue Factor cleaves VII VIIa (7a)
2) VIIa cleaves X Xa (10a)
3) Xa w/cofactor Va (5a) cleaves Prothrombin (II) Thrombin (IIa)
- Thrombin in return cleaves V Va (5a)
4) Thrombin cleaves Fibrinogen (I) Fibrin = Clot formation

Intrinsic Coagulation Pathway
o Slow reaction caused by contact activation involves factors 12, 11, 9, 8, 10, 5
Defects cause | PTT normal aPTT = 22-35 sec
o Vitamin K crucial for -carboxyglutamate residues on factors 2, 7, 9 & 10
o Pathway steps:
1) Contact activation cleaves XII (Hageman Factor) XIIa (12a)
2) XIIa cleaves XI XIa (11a)
3) XIa cleaves IX IXa (9a)
4) IXa w/cofactor VIIIa (8a) cleaves X Xa
- VIIIa formed when Thrombin cleaves VIII VIIIa
5) Xa w/cofactor Va cleaves Prothrombin Thrombin
- Thrombin in return cleaves V Va (5a)
6) Thrombin cleaves Fibrinogen Fibrin = Clot formation

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DISORDER OF PRIMARY HEMOSTASIS
Heparin-Induced Thrombocytopenia (HIT)
o HIT Type 1 Non-immune as Heparin directly causes platelet aggregation <48hrs after administration
Onset in 24-72hrs w/no thrombosis & no treatment needed may continue Heparin use
o HIT Type 2 Heparin induces antibody-mediated injury to platelets 3-12 days after initiating use
Ab recognizes complex of heparin & platelet factor 4 (PF4) leading to platelet activation
50% reduction in platelets within 5-15 days can develop in hrs if previously exposed to heparin
o Clinical Presentation:
Risk of thrombosis 30% bleeding complications uncommon
- Venous DVT, PE, limb gangrene, cerebral sinus thrombosis
- Arterial MI, stroke, acute limb ischemia, organ infarct
Heparin-induced skin necrosis w/LMWH
Acute inflammatory reactions fever, chills, flushing, etc.
o Diagnosis:

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C Serotonin Assay Donor platelets w/
14
C serotonin & heparin w/pts. plasma
ELISA for HIT-Ig More sensitive but less specific than serotonin assay
o Treatment:
Immediate discontinuation of Heparin do not substitute LMWH as 90% cross-reactivity
Alternative anticoagulation:
- Lepirudin Recombinant Hirudin avoid in renal disease
- Argatroban Thrombin inhibitor monitor w/aPTT & use caution in liver disease
- Danaparoid Inhibition of activated factor X

Immune Thrombocytopenic Purpura (ITP)
o Autoimmune anti-GpIIb/IIIa Abs (IgG) bind platelet surface & then removed by splenic macrophages
o Acute ITP Seen in children w/abrupt onset of bleeding & preceded by recent infection
Self-limited 80% resolve spontaneously within 6 months
o Chronic ITP Seen in adults, F>M = 3:1 w/insidious onset of bleeding & spontaneous remissions rare
Often ass. w/lymphoma, CLL, HIV, or SLE
o Clinical Presentation | BT, petechiae, ecchymoses, mucosal bleeding absent splenomegaly
o Diagnosis:
+ PC, | BT w/normal PT & aPPT
BM Aspirate | Megakaryocytes
Anti-GpIIb/IIIa antibodies
o Treatment:
Corticosteroids Prednisone initial therapy in most cases
IVIG + Platelet uptake & destruction by spleen by saturating reticuloendothelial binding sites
- Indicated if PC <20,000/mm
3
or if at risk of severe bleeding
- RhoGAM can be used as alternative in Rh pts.
Splenectomy Indicated in chronic ITP refractory to steroids 70-80% remission
Platelet transfusion Not beneficial but may be given during serious hemorrhagic episodes

Thrombotic Thrombocytopenic Purpura (TTP)
o Rare disorder of platelet consumption due to deficiency of ADAMTS 13 life threatening emergency
o Pathophysiology:
ADAMTS 13 is vWF metalloprotease involved in degradation of vWF multimers
- | vWF multimers | Platelet aggregation & thrombosis Platelet consumption
Leads to formation of hyaline microthrombi platelet thrombi occluding small vessels
- Can effect any organ & cause mechanical damage to RBCs causing schistocytes
o Clinical Presentation Thrombocytopenia, bleeding, fever, acute renal failure, altered mental status
o Diagnosis:
+ PC, | BT w/normal PT & aPTT no consumption of clotting factors
| LDH, + Haptoglobin, Schistocytes due to microangiopathic hemolytic anemia
o Treatment:
Plasmapheresis immediately Corticosteroids
Splenectomy Beneficial in some cases
Platelet transfusions Contraindicated due to microvascular thrombosis

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von Willebrand's Disease (vWD)
o Autosomal dominant deficiency or defect of vWF MC inherited bleeding disorder
vWF mediates binding of platelet GpIb to subendothelial collagen
Also carrier of factor VIII in blood associated w/antigenic protein of factor 8
o Classification:
Type 1 + Levels of vWF MC type
Type 2 Exhibits qualitative abnormalities dysfunctional vWF
Type 3 Autosomal recessive w/absent vWF very severe & least common
o Clinical Presentation:
| Bleeding epistaxis, bruising, gingival bleeding avoid use of Aspirin
- Menorrhagia affects >50% of women w/vWD
- No spontaneous hemarthrosis bleeding much milder than Hemophilia
o Diagnosis:
+ vWF, + Factor VIII antigen, | BT, | PTT & normal PC
+ Ristocetin-induced aggregation Ristocetin activates GpIb receptors on platelets
o Treatment:
Desmopressin (DDAVP) Induces endothelial cells to secrete vWF 1
st
line for type 1 vWD
- Type 2 may respond to DDAVP but not effective for type 3
Factor VIII concentrates Contains high-molecular-weight vWF
- Effective for type 3 vWD but given to all types after major trauma or during surgery
Cryoprecipitate Not recommended due to risk of viral transmission

Bernard-Soulier Disease
o Autosomal recessive disorder in platelet adhesion due to deficiency of platelet glycoprotein GpIb
GpIb responsible for binding platelet to subendothelial collagen via vWF
o Diagnosis | BT, + PC & abnormally large-sized platelets on blood film

Glanzmann's Thrombasthenia
o Autosomal recessive disorder of platelet aggregation due to deficiency in platelet glycoprotein GPIIb/IIIa
GPIIb/IIIa responsible for platelet to platelet aggregation via fibrinogen
o Diagnosis | BT & PC normal

DISORDERS OF SECONDARY HEMOSTASIS
Hemophilia A
o X-linked recessive deficiency or defect of factor VIII causing | bleeding predominately in males
o Clinical Presentation:
Hemarthrosis MC in knees but any joint can be involved
- Progressive joint destruction 2
O
to recurrent hemarthroses
- Maintaining normal factor VIII levels can minimize joint destruction
Hematomas, hematuria, hemospermia
| Risk intracranial bleeding any head trauma requires urgent evaluation
o Diagnosis | PTT & + Factor VIII
o Treatment:
Factor VIII concentrate For more severe cases mainstay of therapy
Desmopressin (DDAVP) For mild cases & can | factor VIII level fourfold
Analgesics For hemarthroses but avoid NSAIDs also immobilization of joint & ice packs

Hemophilia B
o X-linked recessive deficiency of factor IX also called Christmas disease
o Much less common than Hemophilia A but clinical features identical in both
o Treatment Factor IX concentrate DDAVP not beneficial

Disseminated Intravascular Coagulation (DIC)
o Abnormal activation of coagulation sequence leading to formation of microthrombi in vessels
Thrombi cause consumption of platelets, fibrin & coagulation factors leads to bleeding
o Activation of fibrinolytic mechanisms leads to hemorrhage bleeding & thrombosis occur simultaneously

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o Etiology:
Infection MCC esp. GN sepsis, but any infection can cause DIC
Obstetric Abruptio placentae, amniotic fluid emboli, retained dead fetus
- Placenta & uterus have | tissue factor levels
Tissue injury Major trauma, surgery, burns, fractures
Malignancy APL M3 or solid tumors esp. lungs, pancreas, prostate, GI
Other Shock, circulatory collapse, fat embolism, antiphospholipid Ab syndrome, snake venom
o Clinical Presentation:
Microvascular thrombosis:
- Skin focal ischemia, superficial gangrene
- Neurologic multifocal infarcts, delirium, coma, seizures
- Renal oliguria, azotemia, cortical necrosis
- Pulmonary ARDS
- GI acute ulcers & bowel infarction
- RBC microangiopathic hemolysis
Hemorrhagic diathesis:
- Skin petechiae, ecchymosis, oozing from puncture/incision sites
- Mucosal gingival oozing, epistaxis, massive bleeding
- Neurologic intracranial bleeding is common cause of death
- Renal hematuria
o Diagnosis:
| BT, | PT, | PTT, + PC, + Fibrinogen
D-dimers | Fibrin degradation products (FDP) due to activation of fibrinolytic system
Peripheral Smear Schistocytes due to mechanical RBC damage
o Treatment:
Hemorrhage FFP, Cryoprecipitate, Platelet transfusions
Thrombosis LMWH inhibits clotting & prevents consumption of factors
- Use is controversial & given only in rare cases where thrombosis dominates

Vitamin K Deficiency
o Several clotting factors depend on vitamin K as cofactor for synthesis in liver
Factors 2, 7, 9, 10 + Protein C & S Post-translational modification via gamma-carboxylation
Source leafy greens & synthesis by GI flora newborns lack flora & require vitamin K injection
o Etiology:
Antibiotics Suppress gut flora which supplies 50% of vitamin K
Diet TPN, poor diet, alcoholics
Malabsorption + Fat-soluble vitamin absorption
Warfarin Vitamin K antagonist via inhibition of epoxide reductase
o Diagnosis | PT & | PTT prolonged PT initial finding since factor VII has shortest life
o Treatment:
Vitamin K If INR between 4.5 to 10 w/no actively bleeding PT should improve within 24hrs
FFP Given simultaneously in severe bleeding

Coagulopathy of Liver Disease
o Seen in severe liver disease all clotting factors produced by liver except factor VIII
| Bleeding GI bleeds MC due to varices from portal HTN
o Etiology:
Liver disease + synthesis of clotting factors
Cholestasis causes + vitamin K absorption leading to deficiency
Hypersplenism splenomegaly due to portal HTN & causing thrombocytopenia
o Diagnosis | PT & | PTT no improvement w/vitamin K
o Treatment FFP contains all clotting factors





11
HYPERCOAGULABLE DISORDERS
Antithrombin III Deficiency
o Autosomal dominant inheritance or urinary losses in nephrotic syndrome
o Antithrombin slowly inactivates thrombin in absence of heparin
No response to heparin in AT III deficiency heparin requires presence of AT III
o Classification Type I = + AT levels & Type II = + AT activity
o Deficiency may result in resistance to unfractionated heparin LMWH must be used

Antiphospholipid Antibody Syndrome (APS)
o Hypercoagulable vasculopathy due to antiphospholipid Abs interfering w/coagulation cascade
o Classification:
1
O
APS Idiopathic occurs in absence of other disease
2
O
APS Associated w/any of the following:
- Collagen vascular disease esp. SLE
- Drugs Hydralazine, Procainamide, Phenytoin, IFN, Quinidine
- Infections HIV, TB, hepatitis C, infectious mononucleosis
Catastrophic APS (Ashersons syndrome) High mortality rate up to 50%
- Develops within 1 week of thrombotic occlusion in 3 organ systems
o Clinical Presentation:
Recurrent thromboembolic events DVT, PE, TIA, MI, renal vein thrombosis
Recurrent spontaneous abortions
Thrombocytopenia, hemolytic anemia, livedo reticularis
o Diagnosis Lupus anticoagulant, Anticardiolipin Ab, Anti-|2 glycoprotein-I Ab
o Treatment:
Thrombosis Lifelong anticoagulation w/Warfarin
- Target INR 2.0-3.0 for 1
st
venous event & >3.0 for recurrent or arterial event
Recurrent fetal loss Heparin/LMWH Aspirin given during pregnancy
Catastrophic APS Corticosteroids, Anticoagulation, Cyclophosphamide & Plasmapheresis

Protein C Deficiency:
o Autosomal dominant deficiency leads to unregulated fibrin synthesis Protein C inhibits factors V & VIII
o Homozygous Neonatal purpura fulminans
o Heterozygous Type I = + Protein C levels & Type II = + Protein C activity
o Acquired Warfarin, liver disease, sepsis, DIC
o | Risk of hemorrhagic skin necrosis following administration of Warfarin

Protein S Deficiency:
o Protein S is cofactor of Protein C deficiency causes + Protein C activity
o Type I + Free & total Protein S levels
o Type II + Protein S activity
o Type III + Free Protein S levels
o Acquired Liver disease, DIC, pregnancy, nephrotic syndrome, inflammatory diseases

Factor V Leiden:
o MCC of hereditary thrombophilia 5% of population are heterozygotes
o Factor V gene mutation (R506Q) results in resistance to inactivation of factor Va by activated Protein C
Causes unregulated Prothrombin activation leading to | thrombosis

Prothrombin Gene Mutation
o Mutation in 3 untranslated region G to A transposition in prothrombin gene promoter region
o Results in | levels of prothrombin causing | thrombin generation

Hyperhomocystinemia
o Genetic or acquired abnormality | homocysteine levels found in following:
B12/B6/folate deficiency, drugs - MTX, Phenytoin, Theophylline, CRF, hypothyroidism, malignancy
o Treatment Folate supplements can + plasma homocysteine by 50%


12
PLASMA CELL DISORDERS
Multiple Myeloma
o Primary neoplastic proliferation of single plasma cell line producing monoclonal immunoglobulin
95% produce M-protein 50% IgG, 20% IgA, 2% IgD or 0.5% IgM
15-20% produce free light chains found in either serum or urine as Bence-Jones protein
o Poor prognosis 5yr survival rate 10% & if treated median survival is 2-4yrs
o Epidemiology M>F, median age of diagnosis 68yrs, | risk in African-Americans
o Clinical Presentation:
| Bone resorption 2
O
to neoplastic release of RANKL causing osteoclast activation
- Bone pain MC in spine & ribs w/bony tenderness
- | Risk of pathologic fractures & + height due to vertebrae collapse
- Classic lytic lesions skull, spine, proximal long bones, ribs
- Hypercalcemia weakness, N/V, confusion, constipation, polyuria, polydipsia
BM suppression 2
O
to accumulation of abnormal plasma cells
- | Infections MCC of death & due to suppression of normal plasma cell function
o MC pathogens are S. pneumoniae & GNs
- Anemia weakness, fatigue, pallor
- Thrombocytopenia bleeding, petechiae, purpura
| Paraprotein 2
O
to abnormal production by plasma cells
- Renal failure MC is cast nephropathy
- Hyperviscosity headaches, stroke, angina, MI
- Amyloidosis accumulation of insoluble fibrillar protein in any organ tissue
o Cardiac diastolic dysfunction, arrhythmias, syncope, sudden death
o GI malabsorption, beefy large or laterally scalloped tongue
o Neurologic orthostatic hypotension, carpal tunnel, neuropathies
Extramedullary plasmacytoma Soft tissue mass of monoclonal plasma cells w/purplish color
Radiculopathy Can be due to vertebral fracture or extramedullary plasmacytoma
- Spinal cord compression in 15% - medical emergency
Acquired vWD Bleeding disorder due to absorption of vWF by plasma cells
o Diagnosis:
Serum Protein Electrophoresis (SPEP) Monoclonal protein spike in almost all cases
Urine Protein Electrophoresis (UPEP) Bence-Jones protein
Peripheral Smear Rouleaux formation hyperglobulinemia causes RBCs to stick together
Labs | ESR, | |2-microglobulin, | Ca
2+
, + PC, Anemia, Leukopenia
Radiographs Lytic bone lesions w/puched-out appearance
BM Biopsy More than 10% plasma cells confirms diagnosis
o Treatment:
Incurable Chemotherapy w/alkylating agents preferred initial therapy
Autologous Stem Cell Transplant (ASCT) For pts. <75yrs preferred over BMT
- Transplant candidates start Thalidomide & Dexamethasone
- Non-candidates start Melphalon, Prednisone & Thalidomide
Bortezomib Protease inhibitor useful for relapsed myeloma or combine w/other drugs

Waldenstrm's Macroglobulinemia
o Malignant proliferation of plasmacytoid lymphocytes chronic disorder of elderly w/median age 64yrs
Cells produce IgM para-protein very large & causes hyperviscosity of blood
o Clinical Presentation:
Lymphadenopathy & hepatosplenomegaly LAD not seen in MM
Weakness, fatigue, oronasal bleeding, weight loss, recurrent infections, dyspnea,
- Absence of bone lesions & no hypercalcemia helps distinguish from MM
Hyperviscosity syndrome due to | IgM thats mostly confined to intravascular space
- Headache, ataxia, retinal vessel dilation, rouleaux formation
CHF due to triad of anemia, hyperviscosity & plasma volume expansion
o Diagnosis:
M-spike IgM >5g/dL
Bence Jones proteinuria 10% of cases
BM Aspirate Reveals plasmacytoid lymphocytes

13
o Treatment:
Incurable Chemotherapy w/alkylating agents
Hyperviscosity syndrome Plasmapheresis

Monoclonal Gammopathy of Undetermined Significance (MGUS)
o Presence of serum M-protein in absence of any clinical manifestations of myeloma
MC in elderly affecting 3% of population >70yrs no treatment required
o Asymptomatic less than 20% develop MM after 10-15yrs
o Hematologic malignancy develops in <1% each year | risk if M-protein 15g/L or if IgA/IgM MGUS
o Diagnosis SPEP shows M-protein <30g/L & BM Biopsy reveals <10% plasma cells

LYMPHOMAS
Ann-Arbor Lymphoma Staging
o Stage I Confined to single lymph node
o Stage II Involvement of 2 or more lymph nodes, but confined to same side of diaphragm
o Stage III Involvement of lymph node regions on both sides of diaphragm
o Stage IV Dissemination to extralymphatic organs including BM
o Subtype A Absence of B symptoms
o Subtype B Constitutional symptoms unexplained fever, weight loss & night sweats

Hodgkin's Lymphoma
o Localized involvement of single group of lymph nodes w/contiguous spread to adjacent LNs
o Bimodal age distribution w/peaks at 15-30yrs & >50yrs EBV association in up to 50% of cases
o Histologic Classification:
Nodular Sclerosis (40-60%) Collagen banding & Lacunar cells only type MC in females
Mixed Cellularity (20-40%) Strong ass. w/EBV & large # of RS cells in pleomorphic background
Lymphocyte Predominant (10-20%) Few RS cells & many B-cells
Lymphocyte Depletion (1-10%) Lacking in mix of reactive cells & has worst prognosis
o Clinical Presentation:
Painless LAD cervical/supraclavicular (MC), axillary, mediastinal, inguinal
- Mediastinal mass often found on routine CXR
B-symptoms fever, night sweats & weight loss
Splenomegaly (50%) hepatomegaly
o Diagnosis:
LN Biopsy Reed Sternberg (RS) cells required to make diagnosis
- RS cells giant neoplastic cell w/B-cell origin CD15 & CD30
- Owls eye appearance two or more nuclei w/mirror image of halves
CXR & CT Detects LN involvement
Labs | WBCs & Eosinophilia - | LDH indicates adverse prognosis
- Presence of inflammatory cells distinguishes Hodgkin's from NHL
o Treatment:
Chemotherapy + Radiation = Cure rate >70%
ABVD Adriamycin, Bleomycin, Vinblastine & Dacarbazine
- ABVD preferred chemotherapy due to less adverse affects
BEACOPP Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone
Relapse or Resistance High-dose Chemotherapy + BMT

Non-Hodgkin's Lymphoma (NHL)
o Malignant transformation of B or T lymphocytes or their precursors in lymphatic system
Involves multiple, peripheral nodes & may spread to blood or bone marrow
o Twice as common as Hodgkin's NHL is 6
th
MCC of cancer-related deaths in USA
o B-cell Lymphomas (85%):
Burkitts Lymphoma
- Associated with t(8;14) & c-Myc activation MC in children & young adults
- African (Endemic) Type Massive jaw LAD & ass. w/EBV
- American (Sporadic) Type GI & para-aortic LNs hepatomegaly & abdominal masses

14
- Histology Starry-sky sheets of lymphocytes w/interspersed macrophages
- Very aggressive w/poor prognosis unless intense chemotherapy
Diffuse Large B-cell Lymphoma
- Predominantly B-cell origin 20% mature T-cell origin
- MC adult NHL 20% of cases seen in children
- High-grade, aggressive & presents as large extranodal mass
- Richters transformation 5% of CLL cases transform into DLBCL
Mantle Cell Lymphoma
- Associated with t(11;14) w/overexpression of cyclin D1 & bcl-1 activation
- Indolent course & MC in older males M>F = 4:1
Follicular Lymphoma
- Associated with t(14;18) causing bcl-2 overexpression an anti-apoptotic gene
- MC NHL w/mean age of onset at 55yrs painless peripheral LAD
- Indolent incurable & may transform into diffuse large cell lymphoma
o T-cell Lymphomas (15%):
Adult T-cell Lymphoma
- Aggressive w/cutaneous lesions due to HTLV-1 MC in Japan, West Africa & Caribbean
Mycosis Fungoides
- Cutaneous eczematoid lesions & erythroderma cribriform shaped CD4 lymphocytes
- Szary syndrome Late stage w/dissemination to LNs & blood
o Clinical Presentation:
Lymphadenopathy painless, firm, mobile & may rapidly enlarge
Retroperitoneal & mesenteric involvement hepatosplenomegaly
B-symptoms less common than in Hodgkin's
Oropharyngeal involvement (5-10%) sore throat & obstructive apnea
BM involvement may cause anemia, thrombocytopenia or neutropenia w/| infections
CNS involvement often seen in HIV pts.
o Diagnosis:
LN Biopsy Definitive biopsy any node >1cm present for >4wks & not attributed to infection
CXR May reveal hilar or mediastinal lymphadenopathy
CT Assess extent of spread & response to treatment
o Treatment:
Indolent Incurable Follicular & Mantle cell lymphoma
- Localized disease Radiation
- Advanced stage Chemotherapy Rituximab if B-cell origin
Aggressive Curable Diffuse large B-cell lymphoma
- Chemotherapy Rituximab if B-cell origin
- CHOP Cyclophosphamide, Hydroxydaunomycin (Doxorubicin), Oncovin (Vincristine), Prednisone
- CNS prophylaxis High-dose Methotrexate
- Relapse or Resistance High dose chemotherapy & BMT
Highly-aggressive Burkitts lymphoma Chemotherapy w/short intensive bursts
- High risk of tumor lysis syndrome upon treatment

LEUKEMIAS
Acute Myelogenous Leukemia (AML)
o Neoplasm of myelogenous progenitor cells | Myeloblasts due to failure of differentiation
o 80% of adult acute leukemias w/average onset at 65yrs accounts for 10-15% of childhood leukemia
o Etiology Idiopathic or 2
O
to myeloproliferative disorders, radiation, chemotherapy w/alkylating agents
o Classification:
M1 Myeloblastic without maturation
M2 Myeloblastic w/maturation
M3 Acute Promyelocytic Leukemia (APL)
- Accumulation of immature granulocytes called promyelocytes
- Associated with t(15;17) on retinoic acid receptor (RAR) gene
M4 Myelomonocytic
M5 Monocytic

15
o Clinical Presentation:
Anemia & neutropenia (even w/normal WBC) Leads to infections & fever
Thrombocytopenia ass. w/DIC in APL
Skeletal pain w/bony tenderness esp. sternum
Organ infiltration:
- Gingival hypertrophy & leukemia cutis
- Splenomegaly w/early satiety & LUQ fullness
- Roth spots & cotton wool spots
Leukostasis/Hyperleukosis syndrome medical emergency
- Large # of blasts interfere w/circulation leading to hypoxia & hemorrhage
- Can cause diffuse pulmonary infiltrates, CNS bleeding, respiratory distress or AMS
o Diagnosis:
Peripheral Smear Auer rods peroxidase cytoplasmic inclusions in myeloblasts
BM Aspirate Blast count >20% - normally <5%
Labs | LDH, | Uric acid, | PO4 released by leukemic blasts
o Treatment:
Chemotherapy To induce complete remission of AML rapidly fatal without treatment
- Ex. Cytarabine w/Anthracycline (Daunorubicin)
- Poor prognosis if low response to initial induction chemotherapy
Consolidation therapy To prevent recurrence
- Intensive consolidation chemotherapy
- BM/Stem cell transplantation autologous or allogeneic up to 50% cure rate
APL (M3) All-trans-retinoic acid (ATRA) vitamin A derivative that induces differentiation
- Treatment of M3 can release auer rods may lead to DIC & bleeding
Severe infections Consider acceleration w/hematopoietic growth factors ex. G-CSF
o Prognosis Remission rate of 70-80% if <60yrs & 50% if >60yrs 5yr survival rate 40%

Acute Lymphoblastic Leukemia (ALL)
o Malignancy of early lymphoid precursors BM replaced by Lymphoblasts
MC malignancy in children w/75% <6yrs age second peak at age 40
o Classification:
Pre-B-cell ALL Associated with t(12;21), TdT , CALLA , CD10
- MC subtype may spread to testicles
Pre-T-cell ALL TdT & CD10 negative
- Mediastinal mass can compress SVC, esophagus or trachea
o Clinical Presentation:
BM suppression anemia, thrombocytopenia & neutropenia
Fever, tender bones, LAD, hepatosplenomegaly, | infections
Meningeal signs headache, N/V, visual problems
o Diagnosis:
|| WBC seen in 50% of cases
Peripheral Smear | Lymphoblasts & PAS w/no granules
Cytogenetics Philadelphia (Ph) chromosome 25% of adult ALL cases
o Treatment:
Chemotherapy To induce complete remission w/undetectable leukemic blasts
- Dana-Farber Vincristine, Prednisone, MTX, Lencovorin, L-Asparaginase, Ara-C
- Consolidation continuing same chemotherapy to eliminate subclinical leukemic cells
- Intensification high-doses of different chemo. drugs to eliminate cells w/resistance
- Maintenance low-dose intermittent chemotherapy over 2-3yrs to prevent relapse
Imatinib (Gleevec) Add if Ph chromosome bcr-abl tyrosine kinase inhibitor
- bcr-abl fusion gene ass. w/chemotherapeutic resistance
Hematopoietic stem cell transplantation Potentially curative
o Prognosis:
Most responsive leukemia to therapy 80% long-term remission in children
- Higher cure rates in children due to + prevalence of bcr-abl fusion gene
Poor prognostic indicators Age <2 or >9, WBC >105/mm
3
or B-cell phenotype


16
Chronic Lymphocytic Leukemia (CLL)
o MC leukemia occurring after age 50 & MC leukemia in western world median age of onset 65yrs & M>F
o Monoclonal proliferation of B-cells morphologically mature but functionally defective
Mature B-cells do not differentiate into plasma cells causing hypogammaglobulinemia
Accumulation of neoplastic lymphocytes in blood, bone marrow, lymph nodes & spleen
o Small Lymphocytic Lymphoma (SLL) same as CLL except CLL has | peripheral blood lymphocytosis
o Prognosis Incurable but slow progression w/9yr median survival
o Clinical Presentation:
Asymptomatic often discovered on routine CBC due to lymphocytosis
B-symptoms (10%) weight loss, fatigue, fevers >38
O
C, night sweats
Lymphadenopathy (50-90%), splenomegaly (25-50%) & hepatomegaly (15-25%)
Richters transformation Aggressive transformation to DLBCL in 5% of cases
o Diagnosis:
CBC Lymphocytosis WBC 50,000200,000
Peripheral Smear Smudge cells leukemic cells "beaten up" in blood
Coombs Warm AIHA IgG mediated extravascular hemolysis causing splenomegaly
BM Aspirate Lymphocytes account for >30% of all nucleated cells
- 3 patterns of lymphocytic BM infiltration interstitial, diffuse - worst prognosis & mixed
o Treatment:
Chemotherapy & Ritxuimab Little effect on overall survival given for symptomatic relief
Corticosteroids & IVIG For autoimmune phenomena

Chronic Myeloid Leukemia (CML)
o Myeloproliferative disorder of granulocytic line w/no loss of ability to differentiate MC in adults 30-60yr
>90% w/Philadelphia chromosome t(9;22) causing bcr-abl fusion
bcr-abl ass. w/tyrosine-kinase activation leads to | cell division & inhibition of apoptosis
o Clinical Phases:
Chronic phase Easily controlled 85% diagnosed here
- Few blasts (<5%) w/slightly | eosinophils & basophils no significant symptoms
Accelerated phase Impaired neutrophil differentiation difficult to control
- Circulating blasts (10-20%) w/| peripheral basophils causing pruritis
Blast crisis Aggressive course blasts fail to differentiate & >20% in peripheral blood or BM
- Large foci of blasts in BM & extramedullary blast proliferation
- Evolution to acute leukemia 1/3 to ALL & 2/3 to AML
o Clinical Presentation:
Asymptomatic often discovered on routine CBC
Nonspecific fatigue, weight loss, malaise, excessive sweating, fever
Splenomegaly MC physical finding & due to extramedullary hematopoiesis
- 2
O
to splenic involvement early satiety, LUQ pain/fullness, referred shoulder pain
Bleeding & easy bruising due to platelet dysfunction
Pruritus due to | histamine from basophils
o Diagnosis:
Leukocytosis WBCs 50,000200,000 w/left shift toward granulocytes
+ LAP Differentiates CML from leukemoid reaction no splenomegaly, | LAP, infection
Peripheral Smear Immature granulocytes, Eosinophilia & Basophilia
Thrombocytosis Only leukemia w/|PC thrombocytopenia may be seen in accelerated phases
o Treatment:
Imatinib (Gleevec) Inhibits proliferation & induces apoptosis success + need for BMT
- Alternatives if unresponsive to Imatinib:
o Dasatinib Tyrosine kinase & src dual inhibitor
o Nilotinib Selective bcr-abl inhibitor
- Complete cytogenetic response (CCR) on Imatinib = 6yr survival >90%
o NOT achieving CCR on Imatinib = 6yr survival of 66%
- INF- Virtually obsolete after advent of tyrosine kinase inhibitors
Hydroxyurea For initial stabilization of WBC counts >20
Allopurinol & Antihistamines Symptomatic relief
BMT Curative


17
Hairy Cell Leukemia
o Mature B-cell leukemia seen in elderly mainly men
o Clinical Presentation Splenomegaly primary site for neoplastic cells
o Diagnosis TRAP & cells w/filamentous hair-like projections

MYELOPROLIFERATIVE NEOPLASMS
Polycythemia Rubra Vera (PRV)
o Malignant clonal proliferation of hematopoietic stem cells causing excessive erythrocyte production
| RBC mass occurs independent of Erythropoietin (EPO) median survival w/treatment 10-20yrs
o Clinical Presentation:
Hyperviscosity headache, dizziness, weakness, visual impairment, dyspnea
Bleeding epistaxis, gingival bleeding, ecchymoses, GI bleeds due to platelet abnormalities
Thrombosis DVT, PE, thrombophlebitis, | risk of stroke/MI due to | viscosity & abnormal PC
Erythromelalgia burning pain of hands & feet w/dusky color worsened w/heat
- Pathognomonic microvascular thrombotic complication in PRV & ET
Pruritus (40%) Cutaneous mast cell degranulation w/histamine release facial plethora MC
Splenomegaly (70%) hepatomegaly
PUD & GI-distress Due to gastric mucosal blood flow alterations from | viscosity
Gout Hyperuricemia due to | cell turnover
o Diagnosis:
Diagnostic criteria Must meet 3 major OR any 2 major + 2 minor
- Major criteria:
o | RBC mass >25%
o O2 saturation >92% no 2
O
erythrocytosis from hypoxemia or CO poisoning
o Splenomegaly palpable
o Clonal genetic abnormality other than bcr-abl fusion gene
o Endogenous erythroid colony formation in vitro
- Minor criteria:
o Thrombocytosis PC >400 x 10
9
/L
o Leukocytosis >12 x 10
9
/L
o BM biopsy revealing panmyelosis w/erythroid & megakaryocytic proliferation
o + EPO
Labs + EPO, | RBC, | Hb, | Hct, JAK2 mutation
o Treatment:
Phlebotomy Lowers Hct <45%
Myelosuppression Hydroxyurea or Recombinant INF- (rIFN-)
Symptomatic relief Aspirin, Allopurinol, Antihistamines

Essential Thrombocytosis (ET)
o Overproduction of platelets in absence of recognizable stimulus must R/O 2
O
thrombocythemia
2
O
Infection, inflammation, IBD, malignancy, hemorrhage, hemolytic anemia, post splenectomy
o Clinical Presentation:
Often asymptomatic headache, dizziness, syncope, thrombosis, bleeding, splenomegaly
Erythromelalgia burning pain of hands & feet w/dusky color worsened w/heat
- Caused by platelet activation leading to microvascular thrombosis
Complications | Risk of spontaneous abortion & risk of transformation to AML in <5%
o Diagnosis:
Labs | PC >600 also | K
+
& | PO4 due to release of platelet cytoplasmic contents
BM Biopsy Enlarged mature megakaryocyte
Peripheral Smear Hypogranular, abnormally-shaped platelets
JAK2 mutation acquired
Criteria for exclusion of ET:
- Absent bcr-abl fusion & no evidence of PRV, CML, IMF, MDS or BM fibrosis
- No reactive thrombocytosis from inflammation, infection, neoplasm or prior splenectomy
o Treatment:
Hydroxyurea 1
st
line for thrombocytosis

18
Aspirin Give low-dose if previous H/O thrombotic event or 1 cardiovascular risk factors
Splenectomy Not recommended due to | risk of bleeds & thrombosis

Idiopathic Myelofibrosis (IMF)
o Excessive BM fibrosis leading to marrow failure rare disorder w/average onset at 65yrs
o Pathophysiology:
Abnormal myeloid precursor produce dysplastic megakaryocytes that secrete FGF
- Fibroblast growth factors stimulate fibroblasts & stroma to deposit collagen in marrow
Fibrosis causes early release of hematopoietic precursors leading to:
- Leukoerythroblastic blood film primitive RBC & WBC in blood
- Migration causing extramedullary hematopoiesis leads to hepatosplenomegaly
o Clinical Presentation:
Anemia severe fatigue & pallor
Splenomegaly (90%) & hepatomegaly (70%) portal HTN
Weight loss, fever & night sweats 2
O
to hypermetabolic state
Bone & joint pain 2
O
to osteosclerosis & gout
o Diagnosis:
Peripheral Smear Teardrop RBCs, nucleated RBCs, immature myeloid cells
BM Biopsy Diagnostic fibrosis, atypical megakaryocytes, thickening of bony trabeculae
- Dry-tap in up to 50% w/BM aspirate
| ALP 2
O
to liver involvement & bone disease & | LDH 2
O
to ineffective hematopoiesis
o Treatment:
ASCT Potentially curative
EPO transfusion For anemia 30-50% respond to EPO
Hydroxyurea For splenomegaly, thrombocytosis, leukocytosis & systemic symptoms
- Alternatives INF- or Splenectomy
Other Thalidomide, JAK2 inhibitors, Etanercept

COMPLICATIONS OF HEMATOLOGIC MALIGNANCIES
Hyperviscosity Syndrome
o | Blood viscosity resulting from | serum Igs or | blood components in hyperproliferative states
Waldenstroms Macroglobulinemia accounts for 85% of cases
o Clinical Presentation:
Hypervolemia CHF, headache, lethargy, dilutional anemia
- + Cerebral blood flow headache, vertigo, ataxia, stroke
- Retina show vein engorgement & hemorrhages
| Bleeding due to impaired platelet function & absorption of soluble coagulation factors
Labs + ESR
o Treatment Plasmapheresis

Tumour Lysis Syndrome
o Metabolic complications resulting from spontaneous or treatment-related breakdown of cancer cells
o Labs | K
+
, | Uric acid & | PO4 + Ca
2+
due to binding w/ PO4
o Complications Lethal arrhythmia due to hyperkalemia & ARF due to urate nephropathy
o Prevention Allopurinol & aggressive IV hydration w/alkalinization of urine