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USMLE (Subject) / Hematology and Oncology (Lesson)

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• Platelet disorders Defects in platelet plug formation --> ↑ bleeding time (BT) Platelet abnormalities --> microhemorrhage: mucous membrane bleeding, epistaxis, petechiae, purpura, ↑ bleeding time, possibly decreased platelet count (PC)
• Bernard-Soulier syndrome Defect in platelet plug formation. Large platelets.↓ GpIb → defect in platelet-to-vWF adhesion. Abnormal ristocetin test that does not correct with mixing studies. Platelet count (PC): -/↓Bleeding time (BT): ↑PTT, PT: - - Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding.
• Glanzmann thrombasthenia Defect in platelet integrin αIIbβ3 (GpIIb/IIIa) → defect in platelet-to-platelet aggregation, and therefore platelet plug formation. Labs: Blood smear shows no platelet clumping. Platelet count (PC): -Bleeding time (BT): ↑PTT: - - Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding.
• Hemolytic-uremic syndrome Characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. - Typical HUS is seen in children, accompanied by diarrhea and commonly caused by Shiga toxin of enterohemorrhagic E coli (EHEC) (eg, O157:H7). - HUS in adults does not present with diarrhea; EHEC infection not required. Same spectrum as TTP, with a similar clinical presentation and same initial treatment of plasmapheresis. Platelet count (PT): ↓Bleeding time (BT): ↑
• Immune thrombocytopenia Anti-GpIIb/IIIa antibodies → splenic macrophage consumption of platelet-antibody complex.May be 1° (idiopathic) or 2° to autoimmune disorder, viral illness, malignancy, or drug reaction. Labs: ↑ megakaryocytes on bone marrow biopsyPlatelet count (PC): ↓Bleeding time (BT): ↑ Treatment: steroids, IVIG; rituximab or splenectomy for refractory ITP.
• Thrombotic thrombocytopenic purpura Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease) → ↓ degradation of vWF multimers. Pathogenesis: ↑ large vWF multimers → ↑ platelet adhesion → ↑ platelet aggregation and thrombosis. Labs: schistocytes, ↑ LDH, normal coagulation parameters.Platelet count (PC): ↓Bleeding time (BT): ↑ Symptoms: Fever, microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic symptoms. Treatment: plasmapheresis, steroids.
• von Willebrand disease Intrinsic pathway coagulation defect: ↓ vWF → ↑ PTT (vWF acts to carry/protect factor VIII). Defect in platelet plug formation: ↓ vWF → defect in platelet-to-vWF adhesion. - Autosomal dominant. - Mild but most common inherited bleeding disorder. - No platelet aggregation with ristocetin cofactor assay. Labs: - Platelet count (PC): –- Bleeding time (BT): ↑- PT: –- PTT: ↑/– Treatment: desmopressin, which releases vWF stored in endothelium.
• Disseminated intravascular coagulation Widespread activation of clotting → deficiency in clotting factors → bleeding state. Causes:- Sepsis (gram ⊝)- Trauma- Obstetric complications- Acute pancreatitis- Malignancy- Nephrotic syndrome- Transfusion Labs: schistocytes, ↑ fibrin degradation products (D-dimers), ↓ fibrinogen, ↓ factors V and VIII- ↓ PC- ↑ BT- ↑ PT- ↑ PTT
• Factor V Leiden Production of mutant factor V (G → A DNA point mutation → Arg506Gln mutation near the cleavage site) that is resistant to degradation by activated protein C. Most common cause of inherited hypercoagulability in Caucasians. Complications: DVT, cerebral vein thromboses, recurrent pregnancy loss.
• Protein C or S deficiency ↓ ability to inactivate factors Va and VIIIa. ↑ risk of thrombotic skin necrosis with hemorrhage after administration of warfarin.
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• Blood transfusion therapy Packed RBCs: ↑ Hb and O2 carrying capacity.- Use: acute blood loss, severe anemia Platelets: ↑ platelet count (↑ ~5000/mm3/unit)- Use: Stop significant bleeding (thrombocytopenia, qualitative platelet defects) Fresh frozen plasma: ↑ coagulation factor levels; contains all coagulation factors and plasma proteins- Use: DIC, cirrhosis, immediate warfarin reversal Prothrombin complex concentrate: contains factors II, VII, IX, and X, as well as protein C and S- Use: DIC, cirrhosis, immediate warfarin reversal Cryoprecipitate: contains fibrinogen, factor VIII, XIII, wWF, and fibronectin- Use: Coagulation factor deficiencies involving fibrinogen and factor VIII Blood transfusion risks: infection transmission, transfusion reactions, iron overload (may lead to 2° hemochromatosis), hypocalcemia (citrate is a Ca2+ chelator), hyperkalemia (RBCs may lyse in old blood units).
• Leukemia vs. lymphoma Leukemia:- Lymphoid or myeloid neoplasm with widespread involvement of bone marrow.- Tumor cells are usually found in peripheral blood. Lymphoma:- Discrete tumor mass arising from lymph nodes. Presentations often blur definitions.
• Reed-Sternberg cells Distinctive tumor giant cell seen in Hodgkin lymphoma - binucleate or bilobed with the 2 halves as mirror images ("owl eyes") - RS cells are CD15+ and CD30+ B-cell origin
• Burkitt lymphoma Non-Hodgkin lymphoma- Occurs in adolescents or young adults - t(8;14) translocation of c-myc and heavy-chain Ig - "Starry sky" appearance, sheets of lymphocytes with interspersed "tingible body" macrophages- High proliferation index respresented by Ki-67 fraction.- Associated with EBV- Jaw lesion in endemic form in Africa; pelvis or abdomen in sporadic form
• Diffuse large B-cell lymphoma - Occurs in older adults, but 20% in children - Alterations in Bcl-2, Bcl-6 - Most common type of non-Hodgkin lymphoma in adults
• Follicular lymphoma Non-Hodgkin lymphoma- Occurs in adults - t(14;18) – translocation of Ig and BCL-2 - Indolent course; Bcl-2- inhibits apoptosis- Presents with painless "waxing and waning" lymphadenopathy
• Mantle cell lymphoma Non-Hodgkin lymphoma- Occurs in adult males - t(11;14) – translocation of cyclin D1 and heavy-chain Ig, CD5+ - Very aggressive- Patients typically present with late-stage disease
• Adult T-cell lymphoma - Occurs in adults - Caused by HTLV (associated with IV drug abuse) - Adults present with cutaneous lesions- Especially affects populations in Japan, West Africa, the Caribbean - Lytic bone lesions, hypercalemia
• Mycosis fungoides/Sézary syndrome T-cell non-Hodgkin lymphoma- Occurs in adults Mycosis fungoides: - Skin patches/plaques (cutaneous T-cell lymphoma)- Characterized by atypical CD4+ cells with "cerebriform" nuclei and intraepidermal neoplastic cell aggregates (Pautrier microabscesses)- May progress to Sézary syndrome (T-cell leukemia)
• Multiple myeloma Monoclonal plasma cell ("fried egg" appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%). - Bone marrow >10% monoclonal plasma cells.- Most common 1° tumor arising within bone in people >40-50 years old Associated with:- ↑ susceptibility to infection- Primary amyloidosis (AL)- Punched-out lytic bone lesions on x-ray- M spike on serum protein electrophoresis- Ig light chains in urine (Bence Jones protein)- Rouleaux formation (RBCs stacked like poker chips in blood smear)- CRAB findings: hypercalcemia, renal involvement, anemia, bone lytic lesions/back pain - Numerous plasma cells with "clock-face" chromatin and intracytoplasmic inclusions containing immunoglobulin. Monoclonal gammopathy of undetermined significance (MGUS) – monoclonal expansion of plasma cells (bone marrow <10% monoclonal plasma cells), asymptomatic, may lead to multiple myeloma. No "CRAB" findings. Patients with MGUS develop multiple myeloma at a rate of 1-2% per year. Distinguish from Waldenström macroglobulinemia → M spike = IgM → hyperviscosity syndrome (eg, blurred vision, Raynaud phenomenon); no CRAB findings.
• Myelodysplastic syndromes Stem-cell disorders involving ineffective hematopoiesis → defects in cell maturation of nonlymphoid lineages.  Caused by de novo mutations or environmental exposure (eg, radiation, benzene, chemotherapy). Risk of transformation to AML. Pseudo-Pelger-Huet anomaly – neutrophils with bilobed nuclei. Typically seen after chemotherapy.
• Leukemias Unregulated growth and differentiation of WBCs in bone marrow → marrow failure → anemia (↓ RBCs), infections (↓ mature WBCs), and hemorrhage (↓ platelets). Usually presents with ↑ circulating WBCs (malignant leukocytes in blood); rare cases present with normal/↓ WBCs. Leukemic cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.
• Acute lymphoblastic leukemia/lymphoma Most frequently occurs in children; less common in adults (worse prognosis).- T-cell ALL can present as mediastinal mass (presenting as SVC-like syndrome).- Associated with Down syndrome. - Peripheral blood and bone marrow have ↑↑↑ lymphoblasts.- TdT+ (marker of pre-T and pre-B cells), CD10+ (marker of pre-B cells) - Most responsive to therapy- May spread to CNS and testes- t(12;21) → better prognosis
• Chronic lymphocytic leukemia/small lymphocytic lymphoma Age: >60 years. Most common adult leukemia. - CD20+, CD23+, CD5+ B-cell neoplasm. - Often asymptomatic, progresses slowly- Smudge cells in peripheral blood smear- Autoimmune hemolytic anemia Richter transformation – CLL/SLL transformation into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).
• Hairy cell leukemia Mature B-cell tumor.- Most commonly in adult males. - Cells have filamentous, hair-like projections (fuzzy appearing on LM).- Peripheral lymphadenopathy is uncommon. - Causes marrow fibrosis → dry tap on aspiration.- Patients usually present with massive splenomegaly and pancytopenia. - Stains TRAP (tartrate-resistant acid phosphatase) ⊕. TRAP stain largely replaced with flow cytometry. Treatent: cladribine, pentostatin.
• Acute myelogenous leukemia Median onset 65 years. - Auer rods; myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in APL (formerly M3 AML)- ↑↑↑ circulating myeloblasts on peripheral smear; adults. Risk factors: prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders, Down syndrome. APL: t(15;17), responds to all-trans retinoic acid (vitamin A), inducing differentiation of promyelocytes. DIC is a common presentation.
• Chronic myelogenous leukemia - Occurs across the age spectrum with peak incidence 45-85 years, median age at diagnosis 64 years.- Defined by the Philadelphia chromosome (t[9;22], BCR-ABL) and myeloid stem cell proliferation. - Presents with dysregulated production of mature and maturing granulocytes (eg, neutrophils, metamyelocytes, myelocytes, basophils) and splenomegaly.- May accelerate and transform to AML or ALL ("blast crisis"). - Very low LAP as a result of low activity in malignant neutrophils (vs benign neutrophilia [leukemoid reaction], in which LAP is ↑). - Repsonds to bcr-abl tyrosine kinase inhibitors (eg, imatinib, dasatinib).
• Langerhans cell histiocytosis Collective group of proliferative disorders of dendritic (Langerhans) cells. - Children, peak incidence 5-10 years Presentation:- Lytic bone lesions (mostly skull)→ Can cause recurrent otitis media if the mastoid bone is involved- Skin rash: brown to purple papules and/or eczematous rash- Bone marrow infiltration, splenomegaly, hepatomegaly - Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentations. - Cells express S-100 (mesodermal origin) and CD1a.- Birbeck granules ("tennis rackets" or rod shaped on EM) are characteristic.
• Polycythemia vera Chronic myeloproliferative disorder of a ↑ hematocrit. - May present as intense itching after hot shower. - Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities.- Responds to aspirin. - ↓ EPO (vs 2° polycythemia, which presents with endogenous or artificially ↑ EPO)- JAK2 mutation- ↑ RBCs, ↑ WBCs, ↑ platelets Treatment: phlebotomy, hydroxyurea, ruxolitinib (JAK1/2 inhibitor)
• Essential thrombocythemia Chronic myeloproliferative disorder, characterized by massive proliferation of megakaryocytes and platelets.  - Symptoms include bleeding and thrombosis.- Erythromelalgia may occur (headache, visual disturbances, acral paresthesias)- Acute gouty arthritis (due to high cell turnover)- Increased risk of fetal loss - Blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed.- JAK2 mutation (30-50%)- Thrombocytosis >600'000/µl
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• Myelofibrosis Chronic myeloproliferative disorder.Obliteration of bone marrow with fibrosis due to ↑ fibroblast activity. - Often associated with massive splenomegaly and "teardrop" RBCs. - ↓ RBCs, variable WBCs and platelets- JAK2 mutations (30-50%) - Hyperproliferative phase (early): thrombocytosis and leukocytosis- Pancytopenic phase (late): erythrocytopenia (→ anemia), leukocytopenia (→ infections), thrombocytopenia (→ petechial bleeding)
• Chromosomal translocations t(8;14): Burkitt lymphoma (c-myc activation) t(9;22) (Philadelphia chromosome): CML, rarely ALL t(11;14): Mantle cell lymphoma (cyclin D1 activation) t(14;18): Follicular lymphoma (BCL-2 activation) t(15;17): APL (M3 type of AML)
• Hodgkin lymphoma - Constitutional ("B") symptoms: low-grade fever, night sweats, weight loss- Localized, single group of nodes- Contiguous spread (stage is strongest predictor of prognosis)- Characterized by Reed-Sternberg cells (CD15+, CD30+ of B-cell origin)- Bimodal distribution – young adulthood and >55 years; more common in men except for nodular sclerosing type- Associated with EBV Treatment: ABVD regiment (Adriamycin, Bleomycin, Vinblastine, Decarbazine) Subtypes:- Nodular sclerosis: Most common- Lymphocyte rich: Best prognosis- Lymphocyte depleted: Seen in immunocompromised patients- Mixed cellularity: Eosinophilia, seen in immunocompromised patients
• Waldenström macroglobulinemia B-lymphocyte lymphoproliferative disorder with high levels of IgM  - hyperviscosity syndrome (eg, blurred vision, Raynaud phenomenon, vertigo) - bone marrow biopsy reveals infiltrates of lymphocytes, plasma cells, lymphocytes Distinguish from multiple myeloma: No CRAB signs- hypercalcemia- renal involvement- anemia- bone lytic lesions
• Hemoglobin C disease Single nucleotide change in a codon causes lysine (basic) to replace normal glutamic acid (acidic) at beta 6 position. - Normochromic-normocytic anemia- Splenomegaly- Target cells- Rod-shaped crystals in erythrocytes
• Erythrocytes - Carry O2 to tissues and CO2 to lungs. - Anucleate and lack organelles; biconcave, with large surface area-to-volume ratio for rapid gas exchange.- Life span of 120 days- Source of energy is glucose (90% used in glycolysis, 10% used in HMP shunt)- Membranes contain Cl-/HCO3- and transport CO2 from the periphery to the lungs for elimination Erythrocytosis = polycythemia = ↑ HctAnisocytosis = varying sizesPoikilocytosis = varying shapes Reticulocyte = immature RBC; reflects erythroid proliferationBluish color (polychromasia) on Wright-Giemsa stain of reticulocytes represents residual ribosomal RNA.
• Leukocytes Divided into granulocytes (neutrophils, eosinophils, basophils, mast cells) and mononuclear cells (monocytes, lymphocytes). WBC differential count from highest to lowest:- Neutrophils (~60%)- Lymphocytes (~30%)- Monocytes (~6%)- Eosinophils (~3%)- Basophils (~1%)
• Monocytes Found in blood, differentiate into macrophages in tissues. Large, kidney-shaped nucleus. Extensive "frosted glass" cytoplasm.
• Plasma cell Produce large amounts of antibody specific to a particular antigen. - "Clock-face" chromatin distribution and eccentric nucleus, abundant RER, and well-developed Golgi apparatus. - Found in bone marrow and normally do not circulate in peripheral blood.
• Fetal erythropoiesis Fetal erythropoeisis occurs in:- Yolk sac (3-8 weeks)- Liver (6 weeks-birth)- Spleen (10-28 weeks)- Bone marrow (18 weeks to adult) Embryonic globins: ζ and ε.Fetal hemoglobin (HbF) = α2γ2Adult hemoglobin (HbA1) = α2β2HbF has higher affinity for O2 due to less avid binding of 2,3-BPG, allowing HbF to extract O2 from maternal hemoglobin (HbA1 and HbA2) across the placenta.HbA2 (α2δ2) is a form of adult hemoglobin present in small amounts.
• Rh hemolytic disease of the newborn Rh ⊝ mothers; Rh ⊕ fetus - First pregnancy: morther exposed to fetal blood (often during delivery) → formation of maternal anti-D IgG. Subsequent pregnancies: anti-D IgG crosses the placenta → HDN in the fetus. - Jaundice shortly after birth, kernicterus, hydrops fetalis - Treatment: Prevent by administration of anti-D IgG to Rh ⊝ pregnant women during third trimester and early postpartum period (if fetus tests ⊕ for Rh). Prevents maternal anti-D IgG production.
• Hemoglobin electrophoresis On a gel, hemoglobin migrates from the negatively charged cathode to the positively charged anode. HbA migrates the farthest, followed by HbF, HbS and HbC.This is because the missense mutations in HbS and HbC replace glutamic acid ⊝ with valine (neutral) and lysine ⊕, respectively, impacting the net protein charge.
• Procoagulation Oxidized vitamin K → Reduced vitamin K (epoxide reductase)Reduced vitamin K acts as a cofactor of γ-glutamyl carboxylase to activate coagulation factors. Vitamin K deficiency: ↓ synthesis of factors II, VII, IX, X, protein C, protein S.Warfarin inhibits vitamin K epoxide reductase.Vitamin K administration can potentially reverse inhibitory effect of warfarin on clotting factor synthesis. FFP or PCC administration reverses action of warfarin immediately and can be given with vitamin K in cases of severe bleeding. Neonates lack enteric bacteria, which produce vitamin K. Early administration of vitamin K overcomes neonatal deficiency/coagulopathy. Factor VII – shortest half life.Factor II – longest half life.vWF carries/protects factor VIII.
• Anticoagulation Protein C –(thrombin-thrombomodulin complex in endothelial cells)→ activated protein CActivated protein C –(Protein S)→ cleaves and inactivates Va, VIIIa  Plasminogen –(tPA)→ plasmin → fibrinolysis: 1. Cleavage of fibrin mesh2. Destruction of coagulation factors Antithrombin inhibits activated forms of factors II, VII, IX, X, XI, XII.Heparin enhances the activity of antithrombin.Principle targets of antithrombin: thrombin and factor Xa.Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C.tPA is used as a thrombolytic.
• Platelet plug formation (primary hemostasis) 1. Injury- Endothelial damage → transient vasoconstriction via neural stimulation reflex and endothelin (released from damaged cell)2. Exposure- vWF binds to exposed collagen- vWF is from Weibel-Palade bodies of endothelial cells and α-granules of platelets3. Adhesion- Platelets bind to vWF via GpIb receptor at site of injury only (specific) → platelets undergo conformational change → Platelets release ADP and Ca2+ (necessary for coagulation cascade), TXA2→ ADP helps platelets adhere to endothelium4. Activation- ADP binding to P2Y12 receptors induces GpIIb/IIIa expression at platelet surface5. Aggregation- Fibinogen binds GpIIb/IIIa and links platelets Pro-aggregation factors: TXA2, ↓ blood flowAnti-aggregation factors: PGI2 and NO (released by endothelial cells), ↑ blood flow
• Thrombogenesis Formation of insoluble fibrin mesh. - Aspirin irreversibly inhibits cyclooxygenase-1, thereby inhibiting TXA2 synthesis.- Clopidogrel, prasugrel, and ticlopidine inhibit ADP-induced expression of GpIIb/IIIa by irreversibly blocking P2Y12 receptor.- Abciximab, eptifibatide, and tirofiban inhibit GpIIb/IIIa directly. Ristocetin activates vWF to bind GpIb. Failure of aggregation with ristoacetin assay occurs in von Willebrand disease and Bernard-Soulier syndrome.
• Iron deficiency ↓ iron due to chronic bleeding (eg, GI loss, menorrhagia), malnutrition, absorption disorders, GI surgery (eg, gastrectomy) or ↑ demand (eg, pregnancy) → ↓ final step in heme synthesis. Labs: - ↓ iron, ↓ ferritin- ↑ TIBC- ↑ free erythrocyte protoporphyrin- ↑ RDW- Microcytosis and hypochromasia (↑ central pallor) Symptoms: Fatigue, conjunctival pallor, pica (consumption of nonfood substances), spoon nails (koilonychia)- May manifest as glossitis, cheilosis, Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and dysphagia).
• Megaloblastic anemia Impaired DNA synthesis → maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm. RBC macrocytosis, hypersegmented neutrophils, glossitis. - Folate deficiency- Vitamin B12 (cobalamin) deficiency- Orotic aciduria
• Nonmegaloblastic anemia Macrocytic anemia in which DNA synthesis is unimpaired. Causes: alcoholism, liver disease RBC macrocytosis without hypersegmented neutrophils. Diamond-Blackfan anemia – Rapid-onset anemia within 1st year of life due to intrinsic defect in erythroid progenitor cells. (= Pure red blood cell aplasia)- ↑ % HbF (but ↓ total Hb).- Short stature, craniofacial abnormalities (eg, hypertelorism, micrognathia), and upper extremity malformations (triphalangeal thumbs) in up to 50% of cases.
• HbC disease Glutamic acid-to-lysine mutation in β-globin. Causes extravascular hemolysis. Patients with HbSC (1 of each mutant gene) have milder disease than HbSS patients. Blood smear in homozygotes: hemoglobin crystals inside RBCs, target cells.

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