USMLE (Subject) / Hematology and Oncology (Lesson)

USMLE First Aid

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• Thrombocytes - Involved in 1° hemostasis- Small cytoplasmic fragments derived from megakaryocytes- Life span of 8-10 days- When activated by endothelial injury, aggregate with other platelets and interact with fibrinogen to form platelet plug - Contain dense granules (ADP, Ca2+) and α granules (vWF, fibrinogen, fibronectin)Alfa granules contain vwF, fibrinogen, fibronectin - Approximately 1/3 of platelet pool is stored in the spleen - Thrombocytopenia or ↓ platelet function results in petechiae.- vWF receptor: GpIb- Fibrinogen receptor: GpIIb/IIIa- Thrombopoietin stimulates megakaryocyte proliferation.
• Neutrophils Acute inflammatory response cells. Numbers ↑ in bacterial infections. Phagocytic. Multilobed nucleus. - Specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin. - Azurophilic granules (lysosomes) contain proteinases, acid phosphatase, myeloperoxidase, and β-glucuronidase. - Hypersegmented neutrophils (6+ lobes) are seen in vitamin B12/folate deficiency.- ↑ band cells (immature neutrophils) reflect states of ↑ myeloid proliferation (bacterial infections, CML).- Important neutrophil chemotactic agents: C5a, IL-8, LTB4, kallikrein, platelet-activating factor.
• Macrophages - Phagocytoses bacteria, cellular debris, and senescent RBCs.- Long life in tissues.- Name differs in each tissue type (eg, Kupffer cells in liver, histiocytes in connective tissue, Langerhans cells in skin, osteoclasts in bone, microglial cells in brain). - Differentiate from circulating blood monocytes.- Activated by γ-interferon (from Th1 cells). - Can function as antigen-presenting cell via MHC II. - Important component of granuloma formation (TB, sarcoidosis). - Lipid A from bacterial LPS binds CD14 on macrophages to initiate septic shock.
• Eosinophils Defend against helminthic infections (major basic protein).- Bilobate nucleus.- Packed with large eosinophilic granules of uniform size.- Highly phagocytic for antigen-antibody complexes. - Produce histaminase, major basic protein (MBP, a helminthotoxin), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin. Causes of eosinophilia: parasites, neoplasia (eg, Hodgkin lymphoma), asthma, allergic processes, Churg-Strauss syndrome, chronic adrenal insufficiency, myeloprolierative disorders
• Basophils Mediate allergic reaction. - Densely basophilic granules contain heparin (anticoagulant) and histamine (vasodilator) (vs histaminase in eosinophils).- Leukotrienes synthesized and released on demand. - Basophilia can be a sign of myeloproliferative disease, particularly CML (vs eosinophilia in Hodgkin lymphoma).
• Mast cells Mediate allergic reaction in local tissues. Involved in type I hypersensitivity reactions. - Contain basophilic granules and originate from the same precursor as basophils but are not the same cell type. - Can bind the Fc portion of IgE to membrane. - Activated by tissue trauma, C3a and C5a, surface IgE crosslinking by antigen (IgE receptor aggregation) → degranulation → release of histamine, heparin, tryptase, and eosinophil chemotactic factors. - Cromolyn sodium prevents mast cell degranulation (used for asthma prophylaxis).
• B cells Part of humoral immune response. - Originate from stem cells in bone marrow and mature in marrow.- Migrates to peripheral lymphoid tissue (follicles of lymph nodes, white pulp of spleen, unencapsulated lymphoid tissue) - When antigen is encountered, B cells differentiate into plasma cells (which produce antibodies) and memory cells. - Can function as APC via MHC II.
• T cell Mediate cellular immune response. - Originate from stem cells in the bone marrow, but mature in the thymus. - Differentiate into cytotoxic T cells (express CD8, recognize MHC I), helper T cells (express CD4, recognize MHC II), and regulatory T cells . - CD28 (costimulatory signal) necessary for T-cell activation. - Most circulating lymphocytes are T cells (80%).
• ABO hemolytic disease of the newborn Type O mother with a type A, B, or AB fetus - Pre-existing maternal anti-A and/or anti-B igG antibodies cross placenta → HDN in the fetus - Mild jaundice in the neonate within 24 hours of birth. - Usually less severe than Rh HDN. - Treatment: phototherapy, exchange transfusion
• Acanthocyte ("spur cell") Liver disease, abetalipoproteinemia (states of cholesterol dysregulation)
• Basophilic stippling Lead poisoning, sideroblastic anemias, myelodysplastic syndromes, thalassemias. Seen primarily in peripheral smear vs ringed sideroblasts seen in bone marrow. Aggregation of residual ribosomes.
• Dacrocyte ("teardrop cell") Bone marrow infiltration (eg, myelofibrosis), thalassemias. RBC "sheds a tear" because it's mechanically squeezed out of its home in the bone marrow
• Degmacyte ("bite cell") G6PD deficiency
• Echinocyte ("burr cell") End-stage renal disease, liver disease, pyruvate kinase deficiency Different from acanthocyte; its projections are more uniform and smaller.
• Elliptocyte Hereditary elliptocytosis, usually asymptomatic; caused by mutation in genes encoding RBC membrane proteins (eg, spectrin)
• Macro-ovalocyte Megaloblastic anemia (also hypersegmented PMNs), marrow failure
• Ringed sideroblast Sideroblastic anemia. Excess iron in mitochondria. Seen in bone marrow with special staining (Prussian blue), vs basophilic stippling in peripheral smear.
• Schistocyte Microangiopathic hemolytic anemias, including DIC, TTP/HUS, HELLP syndrome, mechanical hemolysis (eg, heart valve prothesis). Fragmented RBCs (eg, helmet cells)
• Sickle cell Sickle cell anemia. Sickling occurs with dehydration, deoxygenation, and at high altitude.
• Spherocyte Hereditary spherocytosis, drug- and infection-induced hemolytic anemia. Small, spherical cells without central pallor.
• Target cell HbC disease, asplenia, liver disease, thalassemia
• Heinz bodies Seen in G6PD deficiency. Oxidation of Hb -SH groups to -S--S- → Hb precipitation (Heinz bodies), with subsequent phagocytic damage to RBC membrane → bite cells.
• Howell-Jolly bodies Seen in patients with functional hyposplenia or asplenia. Basophilic nuclear remnants found in RBCs. Howell-Jolly bodies are normally removed from RBCs by splenic macrophages.
• α-Thalassemia α-globin gene deletions → ↓ α-globin synthesiscis deletion (--/αα) prevalent in Asian populationstrans deletion (-α/-α) prevalent in African populations (offspring don't develop HbH or hydrops fetalis because mutations occur on separate chromosomes) 1 allele deletion (αα/α-): α-thalassemia minima. No anemia (silent carrier). 2 allele deletion (α-/α-; trans) or (αα/--; cis): α-thalassemia minor. Mild microcytic, hypochromic anemia; cisdeletion may worsen outcome for the carrier's offspring. 3 allele deletion (α-/--): HbH disease. Very little α-globin; excess β-globin forms β4 (HbH). Moderate to severe microcytic hypochromic anemia. 4 allele deletion (--/--): Hb Barts; excess γ-globin forms γ4. Hydrops fetalis; incompatible with life.
• β-Thalassemia Point mutations in splice sites and promotor (eg, Kozak) sequences → ↓ β-globin synthesis. In contrast to α-globin chain genes, the 2 β-globin chain genes are expressed postnatally only, and therefore there is only postnatal disease. - Prevalent in Mediterranean populations. β-thalassemia minor (heterozygote): β chain is underproduced. Asymptomatic, ↑ HbA2 (>3.5%) on electrophoresis.β-thalassemia major (Cooley anemia, homozygote): β chain is absent → Severe microcytic, hypochromic anemia with target cells, teardrop cells, basophilic stippling, and increased anisopoikilocytosis requiring blood transfusion (2° hemochromatosis). - Marrow expansion ("crew cut" on skull x-ray) → skeletal deformities. "Chipmunk" facies.- Extramedullary hematopoiesis → hepatosplenomegaly- ↑ risk of parvovirus B19-induced aplastic crisis- ↑ HbF (α2γ2), HbA2 (α2δ2)- Hemolysis causes jaundice and ↑ risk of pigment (bilirubin) gallstones- Disease becomes symptomatic only after 6 months, when fetal hemoglobin declines.- Congestive heart failure (CHF) is most common cause of death.
• Lead poisoning Lead inhibits ferrochelatase and ALA dehydratase → ↓ heme synthesis and ↑ RBC protoporphyrin, ALA. - Also inhibits rRNA degradation → rRNA aggregates (basophilic stippling). Symptoms:- Lead lines on gingivae (Burton lines) and on metaphyses of long bones on x-ray- Encephalopathy - Abdominal colic - Drops – wrist and foot drop- Children – exposure to old houses with chipped lead paint → mental deterioration- Adults – environmental exposure (eg, batteries, ammunition, construction) → headache, memory loss, demyelination Lab findings:- Sideroblastic anemia (microcytic)- Basophilic stippling on peripheral smear- Elevated venous lead level and serum zinc protoporphyrin level Treatment: Dimercaprol and EDTA- Succimer used for chelation in kids
• Sideroblastic anemia Disorder in which the body has adequate iron stores, but is unable to incorporate the iron into hemoglobin. Causes: - Genetic (eg, X-linked defect in ALA synthase gene)- Acquired (myelodysplastic syndromes)- Reversible (alcohol is most common; also lead, vitamin B6 deficiency, copper deficiency, isoniazid, chloramphenicol) Lab findings:- ↑ iron, normal/↓ TIBC, ↑ ferritin- Ringed sideroblasts (with iron-laden, Prussian blue-stained mitrochondria) seen in bone marrow- Peripheral blood smear: basophilic stippling of RBCs Treatment: Pyridoxine (B6, cofactor for δ-ALA synthase)
• Folate deficiency Causes: - Malnutrition (eg, alcoholics)- Malabsorption- Drugs (eg, methotrexate, trimethoprim, phenytoin)- ↑ requirement (eg, pregnancy, hemolytic anemia) Findings:- ↑ homocysteine, normal methylmalonic acid- No neurologic symptoms (vs B12 deficiency)
• Vitamin B12 (cobalamin) deficiency Causes:- Insufficient intake (eg, veganism)- Malabsorption (eg, Crohn disease)- Pernicious anemia- Diphyllobothrium latum (fish tapeworm)- Gastrectomy Findings:- ↑ homocysteine, ↑ methylmalonic acid- Neurologic symptoms: reversible dementia, subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis): spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction.- Historically diagnosed with the Schilling test, a 4-stage test that determines if the cause is dietary insufficiency vs malabsorption.- Anemia 2° to insufficient intake may take several years to develop due to liver's ability to store B12 (as opposed to folate deficiency).
• Orotic aciduria Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect in UMP synthase.- Autosomal recessive. Presents in children as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12.  Findings:- Orotic acid in urine- No hyperammonemia (vs ornithine transcarbamylase deficiency – ↑ orotic acid with hyperammonemia). Treatment: uridine monophosphate or uridine triacetate to bypass mutated enzyme
• Intravascular vs extravascular hemolysis Intravascular hemolysis:- ↓ haptoglobin, ↑ LDH, ↑ schistocytes, ↑ reticulocytes on blood smear.- Characteristic hemoglobulinuria, hemosiderinuria, and urobilinogen in urine.- May also see ↑ unconjugated bilirubin.- Causes: mechanical hemolysis (eg, prosthetic valve), paroxysmal nocturnal hemoglobulinuria, microangiopathic hemolytic anemias Extravascular hemolysis:- Macrophages in spleen clear RBCs.- Spherocytes in peripheral smear (most commonly hereditary spherocytosis and autoimmune hemolytic anemia).- No hemoglobinuria/hemosiderinuria.- ↑ unconjugated bilirubin, which can cause jaundice.
• Anemia of chronic disease Inflammation → ↑ hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport) → ↓ release of iron from macrophages and ↓ iron absorption from gut. - Associated with conditions such as rheumatoid arthritis, SLE, neoplastic disorders, chronic kidney disease. Findings:- ↓ iron, ↓ TIBC, ↑ ferritin- Normocytic, but can become microcytic Treatment: Address underlying cause of inflammation, judicious use of blood transfusion. Consider EPO (eg, chronic kidney disease)
• Aplastic anemia Bone marrow failure due to hematopoietic stem cell deficiency (CD34+). Causes:- Autoimmune- Radiation and drugs (eg, benzene, chloramphenicol, alkylating agents, antimetabolites)- Viral agents (parvovirus B19, EBV, HIV, hepatitis viruses)- Fanconi anemia (DNA repair defect causing bone marrow failure); also short stature, ↑ incidence of tumors/leukemia, café-au-lait spots, thumb/radial defects- Idiopathic (immune mediated, 1° stem cell defect); may follow acute hepatitis Findings:- ↓ reticulocyte count, ↑ EPO- Pancytopenia characterized by severe anemia, leukopenia, and thrombocytopenia- Normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap). Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection. Treatment: withdrawal of offending agent, immunosuppressive regimens (eg, antithymocyte globulin, cyclosporine), bone marrow allograft, RBC/platelet transfusion, bone marrow stimulation (eg, GM-CSF).
• Hereditary spherocytosis Extravascular hemolysis due to defect in proteins interacting with RBC membrane (eg, ankyrin, band 3, protein 4.2, spectrin).- Mostly autosomal dominant inheritance. Results in small, round RBCs with less surface area and no central pallor (↑ MCHC)→ premature removal by spleen Findings:- Splenomegaly- Complications: Pigmented gallstones, aplastic crisis from parvovirus B19 infection Labs: - ↑ osmotic fragility on glycerol lysis test- Normal to ↓ MCV with abundance of cells, hyperchromia Treatment: splenectomy
• G6PD deficiency Most common enzymatic disorder of RBCs. Causes extravascular and intravascular hemolysis.- X-linked recessive- African, Mediterranean, and Asian descent Defect in G6PD → ↓ glutathion → RBC susceptibility to oxidant stress.Hemolytic anemia following oxidant stress (eg, sulfa drugs, antimalarials, infections, fava beans). Findings:- Back pain- Hemoglobinuria a few days after oxidant stress.- Jaundice Labs: blood smear shows RBCs with Heinz bodies and bite cells (degmacytes)
• Pyruvate kinase deficiency Defect in pyruvate kinase → ↓ ATP → rigid RBCs → extravascular hemolysis.- Autosomal recessive- In glycolysis, pyruvate kinase converts phosphoenolpyruvate into pyruvate irreversibly. This step is required in the degeneration of glucose into pyruvate to generate ATP (major anaerobic pathway). In the absence of pyruvate kinase, RBCs are deficient in ATP. This leads to a disturbed cation gradient among the RBC membrane, resulting in hemolysis. Increases levels of 2,3-BPG → ↓ hemoglobin affinity for O2.  Findings: - Hemolytic anemia in newborn- Splenomegaly, icterus, pallor, fatigue, weakness- In rare cases: lethal hydrops fetalis- Peripheral smear: Echinocytes
• Paroxysmal nocturnal hemoglobinuria Acquired mutation of PIGA gene that encodes a GPI anchor for decay-accelerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59) in the cell membrane → ↑ complement-mediated intravascular RBC/WBC/platelet lysis.- Acquired mutation in a hematopoietic stem cell. - ↑ incidence of acute leukemias- Associated with aplastic anemia Findings: - Triad: Coombs ⊝ hemolytic anemia, pancytopenia, venous thrombosis- Venous thrombosis in unusual areas (eg, hepatic, cerebral, abdominal veins)- Patients may report red or pink urine (from hemoglobulinuria)- Labs: CD55/59-⊝ RBCs on flow cytometry Treatment: Eculizumab (C5 complement inhibitor)
• Sickle cell anemia HbS point mutation causes a single amino acid replacement in β chain (substitution of glutamic acid with valine). Causes extravascular and intravascular hemolysis.- 8% of African Americans carry and HbS allele (resistance to malaria). Low O2, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes) → anemia and vaso-occlusive disease. - Newborns are initially asymptomatic because of ↑ HbF and ↓ HbS.- Heterozygotes (sickle cell trait) also have resistance to malaria. - "Crew cut" on skull x-ray due to marrow expansion from ↑ erythropoiesis (also seen in thalassemias). Complications:- Aplastic crisis (due to parvovirus B19)- Autosplenectomy (Howell-Jolly bodies) → ↑ risk of infection by encapsulated organisms- Splenic infarct/sequestration crisis- Salmonella osteomyelitis- Painful crises (vaso-occlusive): dactylitis (painful swelling of hands/feet), priapism, acute chest syndrome, avascular necrosis, stroke- Renal papillary necrosis (↓ PO2 in papilla) and microhematuria (medullary infarcts) Diagnosis: hemoglobin electrophoresis Treatment: hydroxyurea (↑ HbF), hydration
• Autoimmune hemolytic anemia Warm (IgG) – chronic anemia seen in SLE and CLL and with certain drugs (eg, α-methyldopa). Cold (IgM and complement) – acute anemia triggered by cold; seen in CLL, Mycoplasma pneumonia infections, and infectious mononucleosis. RBC agglutinates may cause painful, blue fingers and toes with cold exposure. Findings:- Autoimmune hemolytic anemias are usually Coombs ⊕- Direct Coombs test – anti-IgG antibody (Coombs reagent) added to patient's blood. RBCs agglutinate if RBCs are coated with Ig.- Indirect Coombs test – normal RBCs added to patient's serum. If serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added.
• Microangiopathic anemia RBCs are damaged when passing through obstructed or narrowed vessel lumina. Seen in DIC, TTP/HUS, SLE, HELLP, and hypertensive emergency. - Schistocytes (eg, "helmet cells") are seen on peripheral blood smear due to mechanical destruction of RBCs.
• Macroangiopathic anemia Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia 2° to mechanical destruction of RBCs. Findings: Schistocytes on peripheral blood smear
• Neutropenia Absolute neutrophil count <1500 cells/mm3Severe infections typical when <500 cells/mm3 Causes:- Sepsis/postinfection- drugs (including chemotherapy)- aplastic anemia- SLE- radiation
• Lymphopenia Absolute lymphocyte count <1500 cells/mm3(<3000 cells/mm3 in children) Causes:- HIV- DiGeorge syndrome- SCID (severe combined immune deficiency)- SLE- corticosteroids- radiation- sepsis, postoperative
• Eosinopenia Absolute eosinophil count <30 cells/mm3 Causes:- Cushing syndrome- corticosteroids
• Left shift ↑ neutrophil precursors, such as band cells and metamyelocytes, in peripheral blood. Usually seen with neutrophila in the acute response to infection or inflammation. Called leukoerythroblastic reaction when left shift is seen with immature RBCs; occurs with severe anemia (physiologic response) or marrow response (eg, fibrosis, tumor taking up space in marrow).
• Acute intermittent porphyria Deficient enzyme: Porphobilinogen deaminaseAccumulated substrate: Porphibilinogen, δ-ALA- Autosomal dominant  Symptoms:- Painful abdomen- Port wine-colored urine- Polyneuropathy- Psychological distrubances- Precipitated by drugs (eg, cytochrome P-450 inducers), alcohol, starvation Treatment: glucose and hemin, which inhibit ALA synthase
• Porphyria cutanea tarda Deficient enzyme: Uroporphyrinogen decarboxylaseAccumulated substrate: Uroporphyrin (tea-colored urine)- Autosomal dominant Symptoms:- Blistering cutaneous photosensitivity and hyperpigmentation - Most common porphyria- Exacerbated with alcohol consumption- Associated with hepatitis C
• Coagulation tests PT – tests function of common and extrinsic pathway (factors VII, X, V, II, I). INR (international normalized ratio) – calculated from PT. 1 = normal, >1 = prolonged. Most common test used to follow patients on warfarin. PTT – tests function of common and intrinsic pathway (all factors except VII and XIII). Coagulation disorders can be due to clotting factor deficiencies or acquired inhibitors. Diagnosed with a mixing study, in which normal plasma is added to patient's plasma. Clotting factor deficiencies should correct (the PT or PTT returns to within the appropriate normal range), whereas factor inhibitors will not correct.
• Hemophilia A, B, or C Intrinsic pathway coagulation defect (↑ PTT).A: deficiency of factor VIII → X-linked recessiveB: deficiency of factor IX → X-linked recessiveC: deficiency of factor XI →  autosomal recessive- Normal bleeding time (no inherent platelet disorder) Hemorrhage in hemophilia – hemarthroses (bleeding into joints, eg, knee), easy bruising, bleeding after trauma or surgery (eg, dental procedures). Treatment: desmopressin + factor VIII concentrate (A), factor IX concentrate (B), factor XI concentrate (C).
• Vitamin K deficiency General coagulation defect. Bleeding time normal. ↓ activity of factors II, VII, IX, X, protein C, protein S ↑ PT↑ PTT

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