Hematologic Physiology And Disorders - USMLE Step 1

1. This mutation results in the substitution of which of the following amino acids?
   Answer: Glutamic acid with valine Sickle cell disease is caused by an autosomal recessive point mutation in the β-globin gene, leading to the substitution of a glutamic acid (a hydrophilic amino acid) with a valine (a hydrophobic amino acid) at the sixth position. This change promotes the polymerization of deoxygenated hemoglobin (HbS), causing red blood cells to deform into a sickle shape, leading to vaso-occlusion and hemolysis.
2. The coagulopathy in this infant is due to impaired function of which of the following post-translational modification processes?
   Answer: Gamma-carboxylation This infant is presenting with hemorrhagic disease of the newborn, which is caused by vitamin K deficiency. Newborns have low vitamin K stores and sterile guts, preventing bacterial synthesis of vitamin K. Vitamin K is a necessary cofactor for the enzyme gamma-glutamyl carboxylase, which performs a crucial post-translational modification on several clotting factors. This process, gamma-carboxylation, adds a carboxyl group to glutamic acid residues on Factors II, VII, IX, and X, as well as proteins C and S. This modification allows the factors to bind calcium and interact with phospholipid surfaces during coagulation. Factor VII has the shortest half-life, so its deficiency is manifested first as a prolonged PT.
3. Which of the following sets of laboratory findings is most likely to be found in this patient?
   Answer: Decreased ferritin, increased TIBC, decreased transferrin saturation This patient's clinical presentation (fatigue, pica, koilonychia, heavy menses) and microcytic anemia (low MCV) are highly suggestive of iron deficiency anemia. In this condition, iron stores are depleted, leading to a low serum ferritin. The liver compensates by increasing the synthesis of transferrin, the iron transport protein, resulting in an increased total iron-binding capacity (TIBC). Because there is little iron to bind to the increased number of transferrin molecules, the transferrin saturation is low.
4. This patient most likely has a genetic defect affecting which of the following platelet surface receptors?
   Answer: Glycoprotein Ib This presentation is classic for Bernard-Soulier syndrome, an autosomal recessive disorder of platelet adhesion. Key features include mild to moderate thrombocytopenia, giant platelets on peripheral smear, and impaired ristocetin-induced agglutination. The underlying defect is a deficiency of the glycoprotein Ib (GpIb) receptor on the platelet surface. This receptor is necessary for the initial adhesion of platelets to the subendothelium via von Willebrand factor (vWF). The lack of response to ristocetin, which mimics this interaction, is the hallmark laboratory finding. Aggregation in response to agonists like ADP and collagen, which test GpIIb/IIIa function, is normal.
5. The neurologic deficits in this patient are primarily due to impaired synthesis of which of the following substances?
   Answer: Myelin Vitamin B12 is a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. In B12 deficiency, methylmalonyl-CoA accumulates, leading to the incorporation of abnormal fatty acids into neuronal lipids. This disrupts the structure and maintenance of myelin sheaths, particularly in the dorsal and lateral spinal columns, causing the subacute combined degeneration seen in these patients. This results in deficits in proprioception, vibration sense, and motor pathways.
6. The most common inherited cause for this patient's condition leads to resistance of Factor Va to inactivation by which of the following?
   Answer: Protein C This patient's presentation of a venous thromboembolism at a young age, especially in the setting of a prothrombotic state (pregnancy) and a positive family history, is highly suggestive of an inherited thrombophilia. The most common cause is Factor V Leiden, which is a point mutation in the Factor V gene. This mutation makes Factor Va resistant to cleavage and inactivation by activated Protein C. Protein C (along with its cofactor Protein S) is a natural anticoagulant that normally downregulates the coagulation cascade by inactivating Factors Va and VIIIa. Resistance to this process leads to a hypercoagulable state.
7. The defective protein in this patient's platelets is most likely which of the following?
   Answer: Glycoprotein IIb/IIIa This patient's clinical and laboratory findings are characteristic of Glanzmann thrombasthenia, an autosomal recessive disorder of platelet function. The key finding is the failure of platelets to aggregate in response to multiple agonists (ADP, collagen, epinephrine), while agglutination in response to ristocetin is normal. This pattern points to a defect in the final common pathway of platelet aggregation, which is the cross-linking of adjacent platelets by fibrinogen. This cross-linking is mediated by the glycoprotein IIb/IIIa receptor. Ristocetin-induced agglutination is normal because it depends on the interaction between vWF and the GpIb receptor, which is intact in this disorder.
8. The toxic substance responsible for this child's anemia directly inhibits which of the following pairs of enzymes?
   Answer: Ferrochelatase and aminolevulinate dehydratase This child's presentation, including living in an old house, neurobehavioral symptoms (irritability), and microcytic anemia with basophilic stippling (the coarse blue granules), is classic for lead poisoning. Lead interferes with heme synthesis by inhibiting two key enzymes: aminolevulinate (ALA) dehydratase and ferrochelatase. Ferrochelatase is the final enzyme in the pathway, incorporating iron into protoporphyrin IX to form heme. Inhibition of these enzymes leads to a microcytic anemia (due to impaired hemoglobin production) and an accumulation of precursors like ALA and protoporphyrin.
9. This patient's condition is most likely associated with a gain-of-function mutation in a gene that codes for which of the following?
   Answer: A cytoplasmic tyrosine kinase This patient's symptoms (aquagenic pruritus, plethora, splenomegaly) and labs (erythrocytosis with suppressed EPO) are classic for polycythemia vera (PV). PV is a myeloproliferative neoplasm characterized by the overproduction of all three hematopoietic cell lines, most prominently red blood cells. Over 95% of cases are associated with a gain-of-function mutation in the JAK2 gene (V617F). JAK2 is a cytoplasmic (non-receptor) tyrosine kinase that transduces signals from the erythropoietin receptor. The mutation leads to constitutive activation of the kinase, resulting in cytokine-independent proliferation of hematopoietic precursors.
10. The results of hemoglobin electrophoresis in this patient would most likely show a near-complete absence of which of the following?
    Answer: Hemoglobin A This patient's presentation is classic for β-thalassemia major (Cooley anemia). This is an autosomal recessive disorder caused by mutations that lead to absent or severely reduced synthesis of the β-globin chains of hemoglobin. Hemoglobin A (α2β2) is the major adult hemoglobin and requires β-globin chains for its synthesis. Therefore, in β-thalassemia major, there is a severe deficiency or absence of HbA. The body compensates by producing increased amounts of fetal hemoglobin (HbF, α2γ2) and HbA2 (α2δ2), which become the predominant forms of hemoglobin after birth.
11. The anemia in this patient is most likely due to a deficiency of a hormone produced by which of the following cells?
    Answer: Peritubular interstitial cells of the kidney This patient has normocytic, normochromic anemia with a low reticulocyte count in the setting of chronic kidney disease (suggested by his history of diabetes and hypertension). The kidneys are the primary source of erythropoietin (EPO), a hormone that stimulates the bone marrow to produce red blood cells. Specifically, EPO is produced by the peritubular interstitial cells of the renal cortex in response to tissue hypoxia. In chronic kidney disease, damage to these cells leads to decreased EPO production, resulting in anemia.
12. A deficiency of which of the following enzymes is most likely responsible for this patient's presentation?
    Answer: ADAMTS13 This patient's classic pentad of neurologic symptoms (confusion), fever, thrombocytopenia, microangiopathic hemolytic anemia (schistocytes), and renal dysfunction is characteristic of Thrombotic Thrombocytopenic Purpura (TTP). TTP is caused by a deficiency of the enzyme ADAMTS13, a von Willebrand factor-cleaving protease. Without this enzyme, ultra-large vWF multimers accumulate and spontaneously bind to platelets, causing the formation of platelet-rich microthrombi in the circulation. These thrombi consume platelets and shear red blood cells, leading to the clinical manifestations.
13. This patient's condition is most likely caused by a deficiency in which of the following coagulation factors?
    Answer: Factor VIII The clinical presentation of hemarthrosis after minor trauma in a male patient with a family history suggestive of X-linked recessive inheritance points towards hemophilia. The laboratory findings of a prolonged aPTT with a normal PT and platelet count are classic for a defect in the intrinsic pathway. Hemophilia A, a deficiency of Factor VIII, is the most common type and fits this presentation perfectly. Factor VII deficiency would prolong PT. Factor X deficiency would prolong both PT and aPTT. Factor XIII deficiency presents with delayed bleeding and normal PT/aPTT.
14. The primary defect responsible for this patient's condition is most likely which of the following?
    Answer: Damage to or failure of pluripotent hematopoietic stem cells The patient's presentation with pancytopenia (anemia, leukopenia, and thrombocytopenia) and a hypocellular, fatty bone marrow is the hallmark of aplastic anemia. This condition is caused by the failure or destruction of multipotent hematopoietic stem cells. This can be idiopathic or secondary to insults such as drugs, chemicals (like benzene, found in paints), radiation, or viral infections. The loss of stem cells leads to a failure to produce mature blood cells of all lineages.
15. This patient's condition is most likely caused by a defect in which of the following?
    Answer: Red blood cell membrane cytoskeletal proteins The combination of chronic hemolytic anemia, splenomegaly, a positive family history (autosomal dominant), and a high MCHC is characteristic of Hereditary Spherocytosis. This disorder is caused by defects in RBC membrane proteins that link the lipid bilayer to the cytoskeleton, such as spectrin, ankyrin, or band 3. These defects cause the RBC membrane to lose surface area, forcing the cell into a spherical shape. These less deformable spherocytes are trapped and destroyed in the spleen, leading to extravascular hemolysis.
16. Which of the following pathophysiologic processes best explains this patient's clinical and laboratory findings?
    Answer: Systemic activation of coagulation leading to factor consumption This patient's presentation in the setting of sepsis with simultaneous thrombosis (purpura) and bleeding (oozing), along with thrombocytopenia, prolonged PT and aPTT, and low fibrinogen, is classic for Disseminated Intravascular Coagulation (DIC). The underlying mechanism is a massive, systemic activation of the coagulation cascade by pro-inflammatory cytokines and bacterial endotoxins. This leads to widespread microthrombi formation, which consumes platelets and coagulation factors, resulting in a paradoxical state of bleeding.
17. The pathogenetic mechanism of this patient's condition most likely involves which of the following?
    Answer: Formation of IgG autoantibodies against platelet membrane glycoproteins The patient's presentation of acute onset, isolated severe thrombocytopenia following a recent viral illness is characteristic of Immune Thrombocytopenic Purpura (ITP). The underlying pathophysiology involves the production of IgG autoantibodies that target platelet membrane glycoproteins, most commonly GpIIb/IIIa. These antibody-coated platelets are then cleared from circulation by phagocytes in the spleen, leading to thrombocytopenia.
18. The hemolysis in this patient is due to an inability of his red blood cells to regenerate which of the following?
    Answer: Reduced glutathione (GSH) This patient is experiencing an acute hemolytic episode triggered by an oxidative stressor (sulfonamide drug), which is classic for Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. G6PD is the rate-limiting enzyme in the pentose phosphate pathway, which is the sole source of NADPH in red blood cells. NADPH is required by glutathione reductase to regenerate reduced glutathione (GSH). GSH is essential for detoxifying reactive oxygen species. Without adequate G6PD activity, RBCs cannot produce sufficient NADPH to maintain GSH levels, making them highly susceptible to oxidative damage, which leads to hemolysis and the formation of Heinz bodies (denatured hemoglobin).
19. The protein deficient in this patient's disorder is essential for which of the following two functions?
    Answer: Platelet adhesion and stabilization of Factor VIII This patient's presentation of mucocutaneous bleeding with an autosomal dominant inheritance pattern is classic for von Willebrand disease (vWD). Von Willebrand factor (vWF) has two main functions in hemostasis: it mediates the adhesion of platelets to injured endothelium by binding to glycoprotein Ib, and it serves as a carrier protein for Factor VIII, protecting it from degradation. The deficiency of vWF leads to impaired platelet plug formation and a secondary decrease in Factor VIII levels, which can mildly prolong the aPTT.
20. The abnormal iron metabolism in this patient is primarily mediated by increased production of which of the following proteins?
    Answer: Hepcidin This patient has anemia of chronic disease (also called anemia of inflammation), secondary to her rheumatoid arthritis. Chronic inflammatory states lead to increased production of pro-inflammatory cytokines, particularly IL-6. IL-6 stimulates the liver to produce hepcidin, an acute phase reactant that acts as the central regulator of iron homeostasis. Hepcidin downregulates ferroportin on intestinal enterocytes and macrophages, which traps iron within these cells. This leads to decreased iron absorption, reduced iron release from macrophage stores, and ultimately a functional iron deficiency for erythropoiesis, resulting in the characteristic lab pattern of low serum iron, low TIBC, and high ferritin (as iron is trapped in storage).

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