All questions
Question 1
A 22-year-old African American man with a history of sickle cell disease presents to the emergency department with severe pain in his back and legs. He reports the pain began suddenly this morning. His temperature is 37.5°C (99.5°F), pulse is 110/min, and blood pressure is 130/80 mm Hg. Physical examination reveals tenderness to palpation over the lumbar spine and bilateral tibias. Laboratory studies show a hemoglobin of 8.2 g/dL. This patient's underlying disease is caused by a point mutation in the β-globin gene.
This mutation results in the substitution of which of the following amino acids?
- Glutamic acid with valine (correct answer)
- Valine with glutamic acid
- Lysine with arginine
- Alanine with glycine
Explanation: 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.
Question 2
A 72-year-old man with a history of pernicious anemia presents with a 6-month history of progressive numbness and tingling in his feet, along with difficulty with balance. He has been non-adherent with his intramuscular vitamin B12 injections. Laboratory studies show a hemoglobin of 10.5 g/dL and an MCV of 115 fL. Neurologic examination reveals decreased vibratory and position sense in the lower extremities.
The neurologic deficits in this patient are primarily due to impaired synthesis of which of the following substances?
- Myelin (correct answer)
- Acetylcholine
- Dopamine
- Heme
Explanation: 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.
Question 3
A 16-year-old girl presents for evaluation of heavy menstrual bleeding since menarche and frequent nosebleeds. Last month, she had prolonged bleeding for 2 hours after a tooth extraction. Her father has a similar history of easy bruising. Laboratory results show a normal platelet count, normal PT, and a slightly prolonged aPTT. A ristocetin cofactor assay shows reduced activity.
The protein deficient in this patient's disorder is essential for which of the following two functions?
- Platelet aggregation and stabilization of Factor V
- Platelet adhesion and stabilization of Factor VIII (correct answer)
- Activation of the intrinsic pathway and fibrin cross-linking
- Activation of the extrinsic pathway and platelet degranulation
Explanation: 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.
Question 4
A 28-year-old woman presents to her primary care physician with a 1-week history of a new petechial rash on her lower legs and several episodes of gum bleeding while brushing her teeth. She reports having a cold two weeks ago but is otherwise healthy. Physical examination is unremarkable except for the rash. A complete blood count reveals a platelet count of 12,000/μL, with normal hemoglobin and white blood cell count. A peripheral smear confirms isolated thrombocytopenia with some large platelets.
The pathogenetic mechanism of this patient's condition most likely involves which of the following?
- Formation of antibodies against platelet factor 4 complexed with heparin
- Decreased production of thrombopoietin by the liver
- Formation of IgG autoantibodies against platelet membrane glycoproteins (correct answer)
- Deposition of platelet-rich thrombi in small vessels
Explanation: 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.
Question 5
A 25-year-old man of Mediterranean descent is being treated for a urinary tract infection with trimethoprim-sulfamethoxazole. Three days into his treatment, he develops fatigue, shortness of breath, and dark-colored urine. His sclera are icteric. A complete blood count shows a hemoglobin of 9.5 g/dL (previously 14.5 g/dL). A peripheral blood smear reveals red blood cells with dark inclusions that are more visible with a crystal violet stain.
The hemolysis in this patient is due to an inability of his red blood cells to regenerate which of the following?
- Adenosine triphosphate (ATP)
- Reduced glutathione (GSH) (correct answer)
- 2,3-bisphosphoglycerate (2,3-BPG)
- Carbonic anhydrase
Explanation: 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).
Question 6
A 58-year-old woman with a 15-year history of poorly controlled rheumatoid arthritis presents with fatigue. Her laboratory results show: Hemoglobin 10.2 g/dL, Hematocrit 31%, MCV 88 fL. Iron studies are performed, showing serum iron 30 μg/dL (low), TIBC 200 μg/dL (low), and serum ferritin 350 ng/mL (high).
The abnormal iron metabolism in this patient is primarily mediated by increased production of which of the following proteins?
- Erythropoietin
- Transferrin
- Haptoglobin
- Hepcidin (correct answer)
Explanation: 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).
Question 7
A 62-year-old man presents with a 6-month history of generalized pruritus that is particularly severe after a hot shower. He also complains of headaches and a feeling of fullness in his abdomen. His face appears plethoric. Physical examination reveals splenomegaly. His hemoglobin is 20 g/dL and hematocrit is 60%. Serum erythropoietin levels are suppressed.
This patient's condition is most likely associated with a gain-of-function mutation in a gene that codes for which of the following?
- A cytoplasmic tyrosine kinase (correct answer)
- A receptor tyrosine kinase
- A G-protein coupled receptor
- A nuclear hormone receptor
Explanation: 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.
Question 8
An 8-month-old boy of Greek descent is brought to the pediatrician for failure to thrive and pallor. Physical examination reveals marked hepatosplenomegaly and frontal bossing. Laboratory studies show severe anemia with a hemoglobin of 6.0 g/dL and an MCV of 60 fL. Hemoglobin electrophoresis is performed.
The results of hemoglobin electrophoresis in this patient would most likely show a near-complete absence of which of the following?
- Hemoglobin A (correct answer)
- Hemoglobin F
- Hemoglobin A2
- Hemoglobin S
Explanation: 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.
Question 9
A 28-year-old woman develops a deep vein thrombosis in her left leg during the third trimester of her first pregnancy. She has no other medical problems and no history of trauma or prolonged immobilization. She mentions that her mother also had a blood clot after surgery several years ago. A workup for thrombophilia is initiated.
The most common inherited cause for this patient's condition leads to resistance of Factor Va to inactivation by which of the following?
- Antithrombin III
- Protein C (correct answer)
- Tissue factor pathway inhibitor
- Plasmin
Explanation: 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.
Question 10
A 4-year-old boy is brought to the clinic due to irritability and poor appetite. His parents recently moved into a house built in the 1950s, which they are renovating. The child has had intermittent abdominal pain and constipation. Physical examination is unremarkable. Laboratory studies reveal a hemoglobin of 9.5 g/dL and an MCV of 70 fL. The peripheral blood smear shows microcytic, hypochromic anemia with coarse, dark blue granules within the cytoplasm of the red blood cells.
The toxic substance responsible for this child's anemia directly inhibits which of the following pairs of enzymes?
- Uroporphyrinogen decarboxylase and coproporphyrinogen oxidase
- Aminolevulinate synthase and uroporphyrinogen I synthase
- Ferrochelatase and aminolevulinate dehydratase (correct answer)
- Heme oxygenase and biliverdin reductase
Explanation: 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.
Question 11
A 4-day-old infant, born at home without prenatal care, is brought to the emergency department with bleeding from the umbilical stump and widespread bruising. The mother declined all routine medications for the infant after birth. Laboratory studies show a markedly prolonged prothrombin time (PT) and a normal to slightly prolonged activated partial thromboplastin time (aPTT). Platelet count and fibrinogen levels are normal.
The coagulopathy in this infant is due to impaired function of which of the following post-translational modification processes?
- Phosphorylation
- Glycosylation
- Gamma-carboxylation (correct answer)
- Hydroxylation
Explanation: 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.
Question 12
A 25-year-old woman presents with a lifelong history of severe mucocutaneous bleeding, including recurrent epistaxis and prolonged bleeding after minor cuts. Her platelet count is normal. Platelet aggregation studies are performed. The addition of ADP, collagen, and epinephrine to her platelet-rich plasma fails to induce aggregation. However, the addition of ristocetin causes normal platelet agglutination.
The defective protein in this patient's platelets is most likely which of the following?
- Glycoprotein Ib
- Glycoprotein IIb/IIIa (correct answer)
- Von Willebrand factor
- Factor VIII
Explanation: 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.
Question 13
A 40-year-old woman is brought to the emergency department with confusion and fever. Her husband reports she has been feeling unwell for two days. Laboratory evaluation reveals a platelet count of 22,000/μL, hemoglobin of 8.9 g/dL with schistocytes on peripheral smear, and an elevated creatinine of 2.5 mg/dL. Her LDH is markedly elevated.
A deficiency of which of the following enzymes is most likely responsible for this patient's presentation?
- ADAMTS13 (correct answer)
- Glucose-6-phosphate dehydrogenase
- Pyruvate kinase
- Factor VIII
Explanation: 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.
Question 14
A 19-year-old man of Northern European descent presents with lifelong mild anemia and intermittent jaundice, which is exacerbated by viral infections. His father and paternal grandmother have a similar history. Physical examination reveals splenomegaly. Laboratory studies show a normocytic anemia, an elevated reticulocyte count, and a mean corpuscular hemoglobin concentration (MCHC) of 37 g/dL (normal 32-36 g/dL). An osmotic fragility test is positive.
This patient's condition is most likely caused by a defect in which of the following?
- Red blood cell membrane cytoskeletal proteins (correct answer)
- The β-globin chain of hemoglobin
- An enzyme in the glycolytic pathway
- The PIGA gene leading to complement susceptibility
Explanation: 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.
Question 15
An 8-year-old boy is brought to the clinic for evaluation of a swollen and painful right knee that developed after he fell while playing. His mother reports he has had several similar episodes of prolonged bleeding and joint swelling after minor injuries. His older maternal uncle has a similar condition. Laboratory studies show a normal platelet count, normal prothrombin time (PT), and a prolonged activated partial thromboplastin time (aPTT).
This patient's condition is most likely caused by a deficiency in which of the following coagulation factors?
- Factor VII
- Factor VIII (correct answer)
- Factor X
- Factor XIII
Explanation: 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.
Question 16
A 65-year-old woman is in the intensive care unit with septic shock secondary to pneumonia. Over the past 12 hours, she has developed widespread purpura and is noted to be oozing blood from her catheter insertion sites. Laboratory studies are ordered and show the following: Platelet count 45,000/μL, PT 22 seconds (normal 11-13.5s), aPTT 55 seconds (normal 30-40s), Fibrinogen 80 mg/dL (normal 200-400 mg/dL).
Which of the following pathophysiologic processes best explains this patient's clinical and laboratory findings?
- Autoantibody-mediated destruction of platelets
- Systemic activation of coagulation leading to factor consumption (correct answer)
- Deficiency of a metalloprotease that cleaves vWF multimers
- Inherited deficiency of a single coagulation factor
Explanation: 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.
Question 17
A 67-year-old man with a 10-year history of type 2 diabetes and hypertension presents with progressive fatigue. His blood pressure is well-controlled on lisinopril. Laboratory studies reveal a hemoglobin of 9.8 g/dL and a hematocrit of 29%. The MCV is 89 fL and the reticulocyte count is low. Peripheral smear shows normochromic, normocytic red blood cells.
The anemia in this patient is most likely due to a deficiency of a hormone produced by which of the following cells?
- Juxtaglomerular cells of the kidney
- Hepatocytes of the liver
- Peritubular interstitial cells of the kidney (correct answer)
- Chief cells of the stomach
Explanation: 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.
Question 18
A 34-year-old woman presents with a 3-month history of fatigue and shortness of breath on exertion. She also reports cravings for ice chips. Her menstrual periods have been heavy for the past year. Physical examination is notable for pale conjunctiva and koilonychia. Laboratory studies show: Hemoglobin 9.1 g/dL, Hematocrit 28%, MCV 72 fL, RDW 18%.
Which of the following sets of laboratory findings is most likely to be found in this patient?
- Decreased ferritin, increased TIBC, decreased transferrin saturation (correct answer)
- Increased ferritin, decreased TIBC, normal transferrin saturation
- Normal ferritin, normal TIBC, decreased transferrin saturation
- Decreased ferritin, decreased TIBC, increased transferrin saturation
Explanation: 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.
Question 19
A 45-year-old man who works as a painter presents with a 2-month history of progressive fatigue, weakness, and multiple episodes of epistaxis and gum bleeding. He has also had two episodes of bacterial pneumonia in the last month. A complete blood count reveals: Hemoglobin 7.8 g/dL, WBC 1,500/μL, and Platelet count 25,000/μL. A bone marrow biopsy is performed and shows marked hypocellularity with replacement by fat.
The primary defect responsible for this patient's condition is most likely which of the following?
- Infiltration of the bone marrow by malignant plasma cells
- Damage to or failure of pluripotent hematopoietic stem cells (correct answer)
- Ineffective hematopoiesis due to vitamin B12 deficiency
- Sequestration and destruction of blood cells in an enlarged spleen
Explanation: 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.
Question 20
A patient is evaluated for a lifelong bleeding disorder characterized by easy bruising and gingival bleeding. Laboratory tests show a moderately decreased platelet count and the peripheral smear reveals unusually large platelets. Platelet aggregation studies show no agglutination with ristocetin. This abnormality is corrected by the addition of normal plasma. Aggregation is normal with ADP and collagen.
This patient most likely has a genetic defect affecting which of the following platelet surface receptors?
- Glycoprotein IIb/IIIa
- Thromboxane A2 receptor
- ADP receptor (P2Y12)
- Glycoprotein Ib (correct answer)
Explanation: 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.