USMLE Step 2 CK hematology & oncology questions

In a premenopausal woman with microcytic anemia and a clear source of chronic blood loss (menorrhagia), serum ferritin is the most useful single test because it directly reflects total body iron stores and is highly specific for iron deficiency when low. Ferritin can be falsely normal or elevated in inflammation, but in an otherwise healthy patient a low ferritin confirms the diagnosis without further workup. TIBC and serum iron are supportive but less specific than ferritin. Bone marrow iron stain remains the gold standard but is invasive and unnecessary when ferritin is diagnostic.

• A. Bone marrow biopsy is invasive and reserved for cases where the diagnosis remains unclear after noninvasive testing.
• B. Smear findings (microcytosis, hypochromia) support but do not confirm the diagnosis as specifically as ferritin.
• D. Hemoglobin electrophoresis is used to diagnose hemoglobinopathies such as thalassemia, not iron deficiency.
• E. Vitamin B12 deficiency causes macrocytic, not microcytic, anemia.

New iron deficiency anemia in a man over 50 years old must be presumed to be from occult gastrointestinal blood loss, most importantly colorectal cancer, until proven otherwise. Colonoscopy is the recommended initial study because colorectal malignancy is the lesion of greatest concern and the one most likely to be missed by other modalities. If colonoscopy is negative, upper endoscopy is then performed to evaluate for an upper GI source. Empiric treatment without investigation risks missing a curable cancer at an early stage.

• A. Upper endoscopy alone would miss a colonic source, which is the higher-priority concern in this age group.
• B. Treating the anemia without identifying the source risks missing an underlying malignancy.
• C. Reassurance without investigation is inappropriate given the risk of underlying colorectal cancer.
• E. Capsule endoscopy evaluates the small bowel and is used only after colonoscopy and upper endoscopy are unrevealing.

This patient has microcytosis with a disproportionately elevated red blood cell count (producing a low Mentzer index, MCV/RBC less than 13) and a normal RDW, a pattern typical of thalassemia trait rather than iron deficiency. In thalassemia, red cells are uniformly small because of a genetic defect in globin chain synthesis, so RDW stays normal, whereas iron deficiency produces a heterogeneous cell population with high RDW. Normal iron studies exclude iron deficiency. The next confirmatory step would be hemoglobin electrophoresis.

• A. B12 deficiency causes macrocytic, not microcytic, anemia.
• B. Normal serum iron, ferritin, and TIBC exclude iron deficiency, and RDW would typically be elevated in that condition.
• C. There is no history or examination finding suggesting occult blood loss, and iron studies are normal.
• E. Anemia of inflammation typically shows low serum iron with low or normal TIBC and elevated or normal ferritin, not seen here.

Lead poisoning should be suspected in a young child from an older home undergoing renovation, which disturbs lead-based paint used before its 1978 ban in the United States, creating lead-contaminated dust and chips that children ingest through normal hand-to-mouth behavior. Lead inhibits enzymes in heme synthesis, producing a microcytic anemia with basophilic stippling (aggregated ribosomal RNA) on smear. Confirmation requires a venous blood lead level. Chelation therapy is used for significantly elevated levels or symptomatic encephalopathy.

• A. Undercooked pork is associated with trichinellosis or taeniasis, not lead poisoning.
• B. Nitrate-contaminated well water causes methemoglobinemia, not microcytic anemia with stippling.
• C. Mercury toxicity presents with neurologic and renal findings rather than this hematologic picture.
• D. Excessive cow's milk intake causes iron deficiency anemia, which lacks basophilic stippling.

An appropriate response to oral iron therapy is an increase in the reticulocyte count, which typically begins within 5-10 days of starting treatment as the bone marrow ramps up erythropoiesis once adequate iron is available. Hemoglobin rises more slowly, typically increasing by about 1 g/dL every 2-3 weeks, with full normalization taking 1-2 months. Mean corpuscular volume and iron studies normalize even later, after red cell turnover and iron stores are replenished, generally over 3-6 months of continued therapy.

• A. Hemoglobin normalization takes several weeks to months, not 1 week, and is too slow to be the earliest marker of response.
• C. TIBC changes lag behind the reticulocyte response and take longer to normalize.
• D. Ferritin repletion occurs last, after hemoglobin has normalized and iron stores are rebuilt, often requiring several months of therapy.
• E. MCV normalizes gradually over months as iron-replete red cells replace microcytic ones.

Pernicious anemia results from autoimmune destruction of gastric parietal cells or anti-intrinsic factor antibodies, impairing intrinsic factor-mediated absorption of vitamin B12 in the terminal ileum. This causes megaloblastic anemia with hypersegmented neutrophils and, because B12 is also required for myelin synthesis, posterior column and peripheral nerve dysfunction producing impaired proprioception, vibratory loss, and a positive Romberg sign. Its association with other autoimmune conditions, such as autoimmune thyroiditis, is classic. Diagnosis is confirmed with a low serum B12 level and positive anti-intrinsic factor antibodies.

• A. Folate deficiency causes megaloblastic anemia and hypersegmented neutrophils but does not cause neurologic symptoms.
• C. Hypothyroidism can cause mild macrocytic anemia but does not cause hypersegmented neutrophils or myelopathy/neuropathy of this type.
• D. Myelodysplastic syndrome can cause macrocytosis but does not typically produce this combined neurologic and autoimmune picture.
• E. Liver disease causes macrocytosis through membrane lipid changes, not hypersegmented neutrophils or subacute combined degeneration.

Both folate and vitamin B12 deficiency impair DNA synthesis and cause megaloblastic anemia with elevated homocysteine, because both vitamins participate in homocysteine remethylation to methionine. However, methylmalonic acid is elevated only in B12 deficiency, since B12 is also a required cofactor for the methylmalonyl-CoA mutase reaction, a pathway that does not involve folate. A normal methylmalonic acid level in the setting of elevated homocysteine points to folate deficiency rather than B12 deficiency as the cause.

• B. Indirect bilirubin can be mildly elevated in both conditions due to ineffective erythropoiesis and intramedullary hemolysis.
• C. Reticulocyte count is typically low in both due to ineffective erythropoiesis and does not differentiate the two deficiencies.
• D. Haptoglobin can decrease in ineffective erythropoiesis from either deficiency and is not specific for either diagnosis.
• E. LDH is elevated in megaloblastic anemia from ineffective erythropoiesis in both B12 and folate deficiency, so it does not distinguish between them.

Chronic alcohol use causes macrocytosis through a direct toxic effect on erythroid precursors and altered lipid composition of the red cell membrane, producing round macrocytes without megaloblastic features (no hypersegmented neutrophils, normal B12/folate). This is a non-megaloblastic macrocytosis and does not require vitamin replacement or further hematologic workup when B12 and folate are normal and megaloblastic changes are absent. The appropriate management is counseling on alcohol cessation, since the macrocytosis typically resolves with abstinence, and routine monitoring of the blood count. Further testing is reserved for cases with anemia, neurologic symptoms, or persistent macrocytosis despite abstinence.

• A. Bone marrow biopsy is unnecessary in straightforward alcohol-related macrocytosis without cytopenias or suspicion of marrow pathology.
• B. These tests help distinguish true B12 deficiency from other causes but are unnecessary when B12 and folate levels are already normal and smear findings argue against megaloblastic anemia.
• D. There is no indication of pernicious anemia; endoscopy is not warranted based on these findings.
• E. Vitamin levels are normal and there are no megaloblastic features, so replacement therapy is not indicated.

The USPSTF recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 mcg) of folic acid, starting at least one month before conception and continuing through the first 2 to 3 months of pregnancy. This reduces the risk of neural tube defects, which occur due to failure of neural tube closure in the first 28 days after conception, often before pregnancy is recognized. Women with a prior pregnancy affected by a neural tube defect should receive a higher dose of 4 mg daily. Waiting until a positive pregnancy test or the second trimester is too late, since the neural tube closes very early in gestation.

• A. Dietary folate alone is often insufficient and unreliable; supplementation is recommended regardless of diet.
• B. Starting at the first prenatal visit, typically after 6-8 weeks gestation, is too late since neural tube closure has already occurred.
• C. The neural tube closes by the end of the first month of gestation, long before the second trimester, making this timing ineffective.
• D. The 4 mg dose is reserved for women with a prior neural tube defect-affected pregnancy, and starting only after a positive test is too late for primary prevention.

This patient has evidence of extravascular hemolysis (anemia, elevated indirect bilirubin, elevated LDH, low haptoglobin, reticulocytosis, spherocytes) in the setting of an autoimmune disease, raising strong suspicion for autoimmune hemolytic anemia. The direct antiglobulin (Coombs) test detects IgG or complement (C3) bound to the surface of red blood cells and is the diagnostic test of choice, distinguishing immune-mediated hemolysis from hereditary spherocytosis or other causes. A positive result confirms antibody-mediated destruction, often warm IgG-type in association with lupus. Osmotic fragility and EMA binding tests are used for hereditary spherocytosis, which lacks an autoimmune trigger and would have a negative Coombs test.

• A. This enzyme assay diagnoses G6PD deficiency, which is triggered by oxidative stressors, not autoimmune disease.
• B. This test is used to diagnose hereditary spherocytosis, not autoimmune hemolysis, and does not distinguish antibody-mediated destruction.
• C. Hemoglobin electrophoresis identifies hemoglobinopathies such as sickle cell disease, not autoimmune hemolysis.
• D. This flow cytometry pattern is used to diagnose paroxysmal nocturnal hemoglobinuria, not autoimmune hemolytic anemia.

G6PD deficiency impairs the hexose monophosphate shunt, reducing the regeneration of NADPH, which is required to maintain glutathione in its reduced (protective) form. Under oxidative stress from drugs such as dapsone, sulfonamides, or primaquine, or from fava bean ingestion, hemoglobin and membrane proteins become oxidized, forming denatured hemoglobin precipitates called Heinz bodies, seen as the dark inclusions on smear. Splenic macrophages then remove these Heinz bodies, creating the characteristic bite cells. This produces an acute episodic hemolytic anemia rather than a chronic hemolytic process.

• A. Cold agglutinin disease involves IgM-mediated complement activation, not oxidative drug-induced hemolysis.
• B. This describes warm autoimmune hemolytic anemia, which would show spherocytes and a positive Coombs test, not Heinz bodies.
• C. Mechanical shearing describes microangiopathic hemolytic anemia, which produces schistocytes, not bite cells or Heinz bodies.
• D. Defective spectrin describes hereditary spherocytosis, an inherited membrane disorder unrelated to oxidative drug exposure.

This child's history of chronic jaundice, splenomegaly, family history of splenectomy, elevated MCHC, spherocytes on smear, and a negative Coombs test (ruling out autoimmune hemolysis) strongly suggests hereditary spherocytosis, an autosomal dominant disorder of red cell membrane proteins such as ankyrin or spectrin. The eosin-5-maleimide (EMA) binding test measures binding of a fluorescent dye to band 3 protein on the red cell membrane and has largely replaced the osmotic fragility test as the preferred confirmatory test due to its higher sensitivity and specificity. Splenectomy is indicated in patients with moderate to severe hemolysis, significant anemia, growth impairment, or recurrent biliary complications, typically performed after age 5 to 6 years to reduce the risk of overwhelming post-splenectomy infection.

• A. G6PD assay is used for suspected oxidative hemolysis, not a chronic inherited membrane defect with a positive family history.
• C. Hemoglobin electrophoresis evaluates for hemoglobinopathies, which are not suggested by this clinical picture.
• D. Bone marrow examination is not required when peripheral smear findings and family history strongly suggest hereditary spherocytosis.
• E. Iron studies would help evaluate for iron deficiency anemia, not a hemolytic process with spherocytosis.

This presentation is consistent with an uncomplicated vaso-occlusive (painful) crisis in sickle cell disease, caused by sickled erythrocytes occluding small vessels and causing tissue ischemia, typically affecting the back, long bones, and chest. The mainstay of acute management is aggressive intravenous or oral hydration to reduce blood viscosity and prompt parenteral opioid analgesia to control pain, which should be given rapidly and does not require evidence of infection or other complications. Oxygen supplementation is reserved for hypoxemia, and there is no indication of acute chest syndrome, stroke, or infection to warrant antibiotics, transfusion, or imaging in this patient. Hydroxyurea is used for chronic prevention of crises, not acute pain management.

• A. Exchange transfusion is reserved for severe complications such as acute chest syndrome or stroke, not an uncomplicated pain crisis.
• C. Hydroxyurea reduces the frequency of future crises by increasing fetal hemoglobin but has no role in acute pain management.
• D. There is no focal neurologic or structural finding that would warrant spinal imaging at this time.
• E. There is no fever or other sign of infection to justify empiric antibiotics in this uncomplicated pain crisis.

This patient has developed acute chest syndrome, defined as a new pulmonary infiltrate on imaging accompanied by fever, respiratory symptoms, or hypoxemia in a patient with sickle cell disease, a leading cause of death in this population. Management includes supplemental oxygen to maintain adequate saturation, empiric intravenous antibiotics covering typical and atypical pathogens (since infection can trigger or coexist with the syndrome and the two cannot always be distinguished clinically), incentive spirometry to prevent atelectasis, and pain control that avoids oversedation and hypoventilation. Simple or exchange transfusion is added for patients with significant hypoxemia, rapid clinical deterioration, or multilobar involvement, but antibiotics and supportive care should not be withheld. Prompt recognition and treatment are essential because acute chest syndrome can progress quickly to respiratory failure.

• A. Acute chest syndrome is not a thromboembolic event, and anticoagulation is not standard treatment.
• B. Transfusion may be used for severe or progressive disease but should be combined with, not substituted for, antibiotics and supportive care.
• C. Corticosteroids are not standard therapy for acute chest syndrome and do not replace antibiotics and oxygen support.
• D. Delaying treatment risks rapid progression to respiratory failure; acute chest syndrome requires immediate intervention, not observation.

Children with sickle cell disease develop functional asplenia early in life due to repeated splenic infarction, markedly increasing the risk of overwhelming infection with encapsulated organisms such as Streptococcus pneumoniae. Daily oral penicillin V (or amoxicillin in young infants) prophylaxis, started by 2-3 months of age and continued until at least age 5, has been shown to significantly reduce the incidence of invasive pneumococcal disease. This is used in conjunction with, not instead of, the routine pneumococcal conjugate and polysaccharide vaccination series. Prophylaxis may be discontinued after age 5 in patients without a history of severe pneumococcal infection or splenectomy.

• A. Trimethoprim-sulfamethoxazole is not the standard prophylactic agent for pneumococcal infection in asplenic children.
• B. Azithromycin is not the recommended first-line prophylactic antibiotic in functional asplenia from sickle cell disease.
• D. Benzathine penicillin is used for conditions like rheumatic fever prophylaxis, not for asplenia-related infection prevention.
• E. The patient already has functional (autosplenectomy) asplenia; surgical splenectomy is not indicated and would not be protective against infection.

Hydroxyurea increases the production of fetal hemoglobin (HbF) in erythroid precursors. HbF does not copolymerize with deoxygenated hemoglobin S, so raising its proportion within red cells interferes with the polymerization process that drives red cell sickling. This decreases the frequency of vaso-occlusive pain crises, acute chest syndrome, and the need for transfusions. Hydroxyurea is a ribonucleotide reductase inhibitor, and while this contributes to its cytoreductive and myelosuppressive effects, the clinically relevant benefit in sickle cell disease is mediated through HbF induction.

• A. Gardos channel inhibition describes the mechanism of senicapoc, an investigational agent, not hydroxyurea.
• B. Hydroxyurea does not act through erythropoietin receptor signaling; its benefit comes from fetal hemoglobin induction.
• C. Hydroxyurea inhibits ribonucleotide reductase, not thymidylate synthase; this is not the mechanism responsible for its clinical benefit in sickle cell disease.
• E. Iron chelation is the mechanism of agents like deferasirox, not hydroxyurea.

This patient's intravascular hemolysis (elevated LDH, indirect hyperbilirubinemia, undetectable haptoglobin, hemoglobinuria without hematuria) without schistocytes or a clear autoimmune trigger raises suspicion for paroxysmal nocturnal hemoglobinuria (PNH). PNH results from an acquired somatic mutation in the PIGA gene, leading to deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins, including the complement-regulatory proteins CD55 and CD59, on blood cell surfaces. Flow cytometry demonstrating absence or deficiency of CD55/CD59 on red cells and granulocytes is the current gold-standard diagnostic test, replacing the older, less sensitive and specific sucrose hemolysis and acidified serum (Ham) tests.

• A. Osmotic fragility testing is used to evaluate for hereditary spherocytosis, not PNH.
• B. Hemoglobin electrophoresis is used to diagnose hemoglobinopathies such as thalassemia or sickle cell disease, not PNH.
• C. A direct/indirect Coombs test evaluates for autoimmune hemolytic anemia, which this patient's presentation does not primarily suggest and it would not explain the hemoglobinuria pattern seen here.
• E. Bone marrow biopsy may show hypocellularity in PNH associated with aplastic anemia but is not the confirmatory diagnostic test for PNH itself.

This patient has a microangiopathic hemolytic anemia (schistocytes, elevated LDH, undetectable haptoglobin) with severe thrombocytopenia and neurologic symptoms, but normal coagulation studies and fibrinogen, which argues against consumptive coagulopathy. This combination is classic for thrombotic thrombocytopenic purpura (TTP), caused by severe deficiency of ADAMTS13, which normally cleaves large von Willebrand factor multimers; their accumulation causes widespread platelet microthrombi, mechanically shearing red cells into schistocytes. Normal renal function and normal coagulation parameters help distinguish TTP from hemolytic uremic syndrome (which typically causes greater renal impairment) and DIC (which classically prolongs PT/PTT and lowers fibrinogen).

• A. Autoimmune hemolytic anemia does not produce the severe thrombocytopenia or schistocytosis seen here and is a Coombs-positive, non-microangiopathic process.
• B. DIC typically shows prolonged PT and PTT with low fibrinogen due to consumption of clotting factors, which is not seen in this patient.
• C. Hemolytic uremic syndrome typically presents with prominent acute kidney injury, which this patient does not have.
• E. Immune thrombocytopenic purpura causes isolated thrombocytopenia without hemolysis or schistocytes.

This patient has pancytopenia (anemia, neutropenia, thrombocytopenia) with a low reticulocyte count, indicating decreased marrow production rather than peripheral destruction or sequestration. Aplastic anemia is confirmed by bone marrow biopsy showing marked hypocellularity, with the hematopoietic marrow replaced by fat, and no evidence of an abnormal infiltrate, fibrosis, or dysplasia. This distinguishes it from leukemia (blast infiltration), myelodysplastic syndrome (dysplastic hypercellular marrow), multiple myeloma (plasma cell infiltration), and myelofibrosis (marrow fibrosis).

• B. Increased myeloblasts exceeding 20% cellularity is diagnostic of acute leukemia, not aplastic anemia.
• C. Monoclonal plasma cell infiltration is characteristic of multiple myeloma.
• D. Ringed sideroblasts and megakaryocyte dysplasia in a hypercellular marrow are characteristic of myelodysplastic syndrome.
• E. Marrow fibrosis with teardrop cells describes primary myelofibrosis, not aplastic anemia.

This elderly patient has unexplained macrocytic anemia with additional cytopenias (leukopenia, mild thrombocytopenia) and peripheral smear findings of dysplasia (anisopoikilocytosis, hypogranular neutrophils, nucleated red cells) despite normal B12, folate, and thyroid function, which excludes common reversible causes of macrocytic anemia. This clinical picture is characteristic of myelodysplastic syndrome (MDS), a clonal bone marrow disorder of hematopoietic stem cells common in older adults, leading to ineffective hematopoiesis and peripheral cytopenias. Diagnosis is confirmed by bone marrow biopsy showing dysplastic changes in one or more cell lines with less than 20% blasts, distinguishing it from acute leukemia.

• A. Acute myeloid leukemia requires 20% or more blasts in the marrow or peripheral blood, which is not described here.
• B. Normal serum vitamin B12 excludes B12 deficiency as the cause of this patient's macrocytic anemia.
• C. Primary myelofibrosis typically presents with splenomegaly, leukoerythroblastic smear with teardrop cells, which are not described here.
• D. Chronic lymphocytic leukemia presents with marked lymphocytosis and smudge cells, not the dysplastic morphologic changes described in this patient.

Immune thrombocytopenic purpura is diagnosed clinically after excluding other causes of isolated thrombocytopenia in a patient with an otherwise normal history, examination, and blood counts. The normal white cell differential, absence of schistocytes, normal coagulation studies, and lack of systemic findings argue against leukemia, lupus, DIC, and myelodysplasia. ITP results from autoantibody-mediated platelet destruction and typically presents with mucocutaneous bleeding and isolated thrombocytopenia without other cytopenias or organomegaly. No single confirmatory test exists; bone marrow biopsy is reserved for atypical presentations or poor treatment response.

• A. Is associated with an acute precipitating illness and would show prolonged PT/aPTT and low fibrinogen, which are normal here.
• B. Typically occurs in older adults and shows dysplastic changes or other cytopenias on smear, not an isolated normal-morphology thrombocytopenia.
• C. Would be expected to show blasts, anemia, or other cytopenias on smear and CBC, which are absent here.
• D. Would typically present with additional systemic features such as arthritis, rash, or other cytopenias, and serologic markers would often be positive.

In ITP with severe, active bleeding, intravenous immune globulin (IVIG) is used because it raises the platelet count more rapidly than corticosteroids, typically within 24-48 hours, by blocking Fc receptor-mediated platelet destruction in the reticuloendothelial system. Corticosteroids are first-line for ITP overall but act more slowly, over several days to a week, so IVIG (often combined with steroids) is preferred when urgent platelet elevation is needed. Platelet transfusions alone are rapidly consumed by ongoing autoantibody-mediated destruction and provide only transient benefit. Rituximab and splenectomy are second-line options for chronic or refractory ITP and have a delayed onset of action, making them unsuitable for acute severe bleeding.

• A. Has a delayed onset of action over weeks and is reserved for chronic or refractory ITP, not acute severe bleeding.
• B. Is a second-line option for chronic refractory ITP and does not provide an immediate increase in platelet count.
• C. Transfused platelets are rapidly destroyed by circulating autoantibodies and provide only brief, often inadequate benefit if used alone.
• E. Raises the platelet count more slowly than IVIG, over days, making it less suitable for urgent severe bleeding.

This patient has the classic pentad of thrombotic thrombocytopenic purpura: fever, neurologic changes, acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia (schistocytes, elevated LDH, indirect hyperbilirubinemia, low haptoglobin) with normal coagulation studies distinguishing it from DIC. TTP is a hematologic emergency, and urgent plasma exchange (plasmapheresis) is the most appropriate next step because it removes the causative ultra-large von Willebrand factor multimers and autoantibodies against ADAMTS13 while replenishing functional ADAMTS13. Delaying plasma exchange significantly increases mortality, so treatment should begin on clinical suspicion without waiting for ADAMTS13 assay results.

• A. Is not indicated because TTP is not primarily a coagulation disorder and there is no evidence of excessive clotting factor activation requiring anticoagulation.
• B. Does not remove the pathogenic antibodies or ultra-large vWF multimers as effectively as plasma exchange and is not the standard urgent therapy.
• D. Is contraindicated in TTP because it can worsen microthrombus formation and precipitate further ischemic organ damage.
• E. May be used as an adjunct but is not sufficient alone and does not replace the need for urgent plasma exchange.

ADAMTS13 is a plasma metalloprotease that normally cleaves ultra-large von Willebrand factor (vWF) multimers released from endothelial cells into smaller, less adhesive forms. Severe deficiency of ADAMTS13, most often due to an acquired autoantibody inhibitor, allows ultra-large vWF multimers to persist in the circulation, promoting spontaneous platelet adhesion and aggregation that forms disseminated microthrombi in small vessels. This microthrombus formation causes mechanical fragmentation of red blood cells (schistocytes) and consumes platelets, producing the microangiopathic hemolytic anemia and thrombocytopenia characteristic of TTP, along with ischemic organ damage. Congenital ADAMTS13 deficiency causes the rarer hereditary form, Upshaw-Schulman syndrome.

• A. Is a fibrinolysis inhibitor whose excess is associated with thrombosis risk but does not explain ultra-large vWF multimer accumulation.
• B. Is a natural anticoagulant whose deficiency causes a hypercoagulable state with venous thromboembolism, not the microangiopathic picture of TTP.
• D. Is a coagulation factor whose deficiency causes bleeding disorders such as hemophilia A, not microthrombus formation.
• E. Is a natural anticoagulant whose deficiency predisposes to venous thrombosis, unrelated to vWF multimer processing.

Once HIT is diagnosed or strongly suspected, all forms of heparin must be stopped immediately and replaced with a non-heparin anticoagulant because of the ongoing high risk of thrombosis from platelet-activating PF4-heparin antibodies. Argatroban, a direct thrombin inhibitor that does not cross-react with HIT antibodies, is a preferred first-line agent, particularly in patients with renal impairment, and is renally cleared or hepatically cleared depending on the agent chosen (argatroban is hepatically metabolized, useful in renal failure). Low-molecular-weight heparin cross-reacts with HIT antibodies and is contraindicated. Warfarin should be avoided in the acute phase because it can precipitate venous limb gangrene from unopposed procoagulant activity before adequate anticoagulation is established, and it is only started after platelet count recovery. Platelet transfusion is avoided because it can fuel further thrombosis and does not address the underlying immune mechanism.

• A. Can precipitate venous limb gangrene if started during the acute thrombocytopenic phase before an alternative anticoagulant has stabilized the patient.
• C. Cross-reacts with HIT antibodies due to shared heparin-based structure and is contraindicated.
• D. Platelet transfusion risks worsening thrombosis, and resuming heparin would perpetuate antibody-mediated platelet activation.
• E. Does not provide adequate anticoagulation to prevent thrombosis in this prothrombotic disorder and is not indicated as monotherapy.

Von Willebrand disease is the most common inherited bleeding disorder and classically presents with mucocutaneous bleeding, such as menorrhagia and epistaxis, a positive family history, a normal platelet count, and a prolonged bleeding time or platelet function analyzer closure time due to defective platelet adhesion from deficient or dysfunctional von Willebrand factor. The mildly prolonged aPTT reflects reduced factor VIII activity, since vWF stabilizes circulating factor VIII. Diagnosis is confirmed with von Willebrand factor antigen level, von Willebrand factor activity (ristocetin cofactor assay), and factor VIII activity. The normal platelet count distinguishes it from ITP, and the mucosal bleeding pattern without hemarthrosis distinguishes it from hemophilia.

• A. Typically presents with hemarthrosis and deep muscle bleeding rather than predominantly mucosal bleeding, and shows a markedly prolonged aPTT with normal platelet count and closure time.
• B. Causes an isolated prolonged PT with normal aPTT and is a rare cause of bleeding, inconsistent with this presentation.
• C. Is characterized by isolated thrombocytopenia with a low platelet count, which is normal in this patient.
• E. Is a rare inherited platelet glycoprotein IIb/IIIa defect causing severe mucocutaneous bleeding from birth, less common than vWD and not suggested by this milder, family-linked pattern.

Desmopressin (DDAVP) is a synthetic vasopressin analog that stimulates V2 receptors on endothelial cells, causing release of stored von Willebrand factor and factor VIII from Weibel-Palade bodies into the circulation. This transiently raises plasma levels of both proteins, improving platelet adhesion and clot formation, making it effective for minor bleeding or procedures in patients with type 1 von Willebrand disease who have adequate factor stores to mobilize. It is given intranasally or intravenously roughly 30-60 minutes before a procedure, and a trial dose is typically given beforehand to confirm response. It is less effective in type 3 disease and should be used cautiously in type 2B due to risk of worsening thrombocytopenia.

• A. Vitamin K promotes synthesis of factors II, VII, IX, and X in the liver and has no role in von Willebrand disease management.
• B. Tranexamic acid works by blocking fibrinolysis rather than releasing stored von Willebrand factor, and is often used adjunctively but does not match the described mechanism.
• C. Factor VIII concentrate replaces clotting factor directly rather than stimulating endogenous release and is reserved for more severe or refractory cases.
• D. Recombinant factor VIIa acts on the extrinsic pathway directly and is not the mechanism described, nor first-line for von Willebrand disease.

An isolated prolonged aPTT with a normal PT in a boy with hemarthroses and an X-linked family history points to hemophilia A (factor VIII deficiency) or hemophilia B. A mixing study first confirms a factor deficiency (correction of the aPTT) rather than an inhibitor, and a specific factor VIII activity assay then confirms the diagnosis and determines severity. Factor VIII deficiency does not affect platelet number or primary hemostasis, so platelet count and bleeding time are normal. Correction of a prolonged aPTT with normal plasma on mixing study points away from an acquired factor inhibitor.

• A. Platelet aggregation studies evaluate platelet function disorders, which do not prolong the aPTT isolated from PT.
• C. von Willebrand factor level is tested when there is mucocutaneous bleeding or when hemophilia A workup also shows low factor VIII and normal mixing correction needs further clarification, but it is not the next step here with this presentation.
• D. Fibrinogen level evaluates the common pathway and is relevant in DIC or dysfibrinogenemia, not isolated aPTT prolongation with hemarthrosis.
• E. Bleeding time assesses primary hemostasis (platelet-vessel wall interaction), which is normal in hemophilia A.

This patient has disseminated intravascular coagulation (DIC) triggered by sepsis: systemic activation of the coagulation cascade generates widespread microthrombi, consuming platelets and fibrinogen while simultaneously activating fibrinolysis, producing an elevated D-dimer. The combination of thrombocytopenia, prolonged PT, low fibrinogen, elevated D-dimer, and schistocytes (from microangiopathic hemolysis as red cells shear through fibrin strands) is classic for DIC. Immune thrombocytopenia would not explain the coagulopathy or schistocytes. Vitamin K deficiency affects factors II, VII, IX, and X but spares platelets and fibrinogen. ADAMTS13 deficiency (TTP) causes thrombocytopenia and schistocytes but typically normal coagulation studies and fibrinogen.

• A. Dilutional coagulopathy would prolong PT/aPTT and lower platelets proportionally but would not cause a markedly elevated D-dimer or selectively low fibrinogen.
• B. Vitamin K deficiency prolongs PT/INR but does not cause thrombocytopenia, hypofibrinogenemia, or schistocytes.
• D. Immune thrombocytopenia causes isolated low platelets without coagulation factor consumption or schistocytes.
• E. TTP from ADAMTS13 deficiency causes microangiopathic hemolysis and thrombocytopenia but coagulation studies and fibrinogen are usually normal, unlike this consumptive pattern.

This patient has life-threatening gastrointestinal hemorrhage with hemorrhagic shock in the setting of supratherapeutic INR from warfarin, requiring immediate and complete reversal. Four-factor prothrombin complex concentrate (containing factors II, VII, IX, and X) rapidly restores clotting factor levels within minutes, and it is combined with intravenous vitamin K to sustain reversal since PCC's effect is transient. Vitamin K alone, whether oral or intravenous, takes hours to days to normalize the INR and is insufficient for active major bleeding. Fresh frozen plasma acts more slowly, requires large volumes, and carries transfusion-related risks, making it inferior to PCC for emergent reversal. Simply holding warfarin does not address the active hemorrhage.

• A. Fresh frozen plasma reverses more slowly and requires larger volumes than PCC, making it a weaker choice for emergent major bleeding.
• C. Observation without reversal is dangerous in a patient with hemorrhagic shock and a markedly elevated INR.
• D. IV vitamin K alone still takes several hours to lower the INR and does not provide the immediate factor replacement needed in hemorrhagic shock.
• E. Oral vitamin K has a delayed onset of action and does not address active life-threatening bleeding.

Andexanet alfa is a recombinant modified factor Xa decoy protein approved for reversal of life-threatening bleeding associated with the factor Xa inhibitors apixaban and rivaroxaban; it binds the drug directly, restoring endogenous factor Xa activity. Idarucizumab is a monoclonal antibody fragment specific for dabigatran, a direct thrombin (factor IIa) inhibitor, and has no effect on factor Xa inhibitors. Protamine reverses heparin and partially reverses low molecular weight heparin, not DOACs. Vitamin K and FFP target vitamin K-dependent factor synthesis and are used for warfarin reversal, not for direct factor Xa inhibitors.

• A. Vitamin K restores synthesis of vitamin K-dependent factors and is used for warfarin, not for direct factor Xa inhibitors.
• B. Protamine sulfate reverses unfractionated heparin and has no significant effect on apixaban.
• C. Idarucizumab specifically reverses dabigatran, a direct thrombin inhibitor, not factor Xa inhibitors like apixaban.
• E. Fresh frozen plasma does not reliably reverse direct factor Xa inhibitors and is not first-line for this purpose.

Factor V Leiden is the most common inherited thrombophilia in individuals of European ancestry, resulting from a point mutation that renders factor Va resistant to inactivation by activated protein C, leading to prolonged factor Va activity and increased thrombin generation. Testing for inherited thrombophilia, including factor V Leiden, is generally reserved for patients with unprovoked VTE at a young age with a strong family history, as in this patient, since the result can inform decisions about anticoagulation duration and family counseling. Antithrombin III deficiency and protein S deficiency are much less common causes of inherited thrombophilia and typically cause more severe, earlier-onset thrombosis. The prothrombin G20210A mutation is the second most common inherited thrombophilia, less frequent than factor V Leiden. Hyperhomocysteinemia is a risk factor for thrombosis but is usually acquired or due to vitamin deficiencies rather than being the most common inherited cause.

• A. Prothrombin G20210A mutation is the second most common inherited thrombophilia after factor V Leiden.
• B. Protein S deficiency is an uncommon inherited thrombophilia, less prevalent than factor V Leiden.
• D. Antithrombin III deficiency is rare and typically causes more severe, often recurrent thrombosis at a young age, but it is less common than factor V Leiden.
• E. Hyperhomocysteinemia is often an acquired or nutritional condition and is not the most common inherited thrombophilia.

In a patient with a high pretest probability for DVT by Wells criteria, the appropriate next step is direct imaging with compression ultrasonography rather than D-dimer testing, because a negative D-dimer cannot reliably exclude DVT in high-probability patients and a positive result would not add diagnostic value. Compression ultrasound is highly sensitive and specific for proximal DVT and is the standard initial imaging test, assessing for loss of vein compressibility. D-dimer is most useful in low-probability patients to rule out VTE and avoid unnecessary imaging. Venography is invasive, is reserved for cases where ultrasound is inconclusive, and is rarely used today. Starting anticoagulation without any imaging confirmation is not appropriate given the availability of a timely, accurate, noninvasive test, and CT pulmonary angiography is used to diagnose pulmonary embolism, not DVT, and this patient has no respiratory symptoms suggesting PE.

• A. D-dimer is not useful for ruling in or ruling out DVT in a high pretest probability patient and should not replace imaging here.
• B. CT pulmonary angiography diagnoses pulmonary embolism, not DVT, and this patient has no symptoms suggesting PE.
• C. Starting anticoagulation without confirmatory imaging exposes the patient to unnecessary bleeding risk if the diagnosis is incorrect, when ultrasound is readily available.
• D. Venography is invasive and reserved for cases where ultrasound results are equivocal, not a first-line test.

The BCR-ABL1 fusion gene produced by the t(9;22) translocation encodes a constitutively active tyrosine kinase that drives uncontrolled myeloid proliferation in CML. Imatinib and other tyrosine kinase inhibitors (dasatinib, nilotinib) competitively bind the ATP-binding site of this kinase, blocking its activity and inducing hematologic and cytogenetic remission. This targeted mechanism contrasts with older cytotoxic chemotherapy that nonspecifically damages dividing cells. TKIs have transformed CML from a fatal disease into a chronic, manageable condition with near-normal life expectancy in most patients.

• A. This describes methotrexate, an antimetabolite.
• B. This describes rituximab, used in B-cell lymphomas, not CML.
• D. This describes alkylating agents such as cyclophosphamide.
• E. This describes agents like etoposide, not imatinib.

Chronic lymphocytic leukemia typically presents in older adults as an incidental finding of marked lymphocytosis with small, mature-appearing lymphocytes on smear. The ruptured, fragile lymphocytes seen on smear preparation are called smudge cells and are a classic feature of CLL due to the inherent fragility of the malignant cells. Diagnosis is confirmed by flow cytometry showing a monoclonal B-cell population co-expressing CD5, CD19, CD20, and CD23. Many patients are asymptomatic at diagnosis and may not require treatment immediately if they lack cytopenias, bulky lymphadenopathy, or systemic symptoms.

• A. ALL presents with blasts on smear and typically affects children or causes acute symptoms with cytopenias.
• C. Mantle cell lymphoma is less common, often presents with more aggressive lymphadenopathy, and lacks the classic smudge cell appearance.
• D. Hairy cell leukemia shows lymphocytes with cytoplasmic projections and usually causes pancytopenia with splenomegaly.
• E. Mononucleosis causes atypical reactive lymphocytes in younger patients, often with fever and pharyngitis.

This patient has tumor lysis syndrome, characterized by hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia from the massive release of intracellular contents after chemotherapy-induced lysis of rapidly dividing tumor cells, classically seen in high-grade lymphomas such as Burkitt lymphoma and in acute leukemias with high tumor burden. Rasburicase is a recombinant urate oxidase that rapidly converts uric acid to allantoin, which is far more water-soluble and easily excreted, and is the preferred prophylactic agent in high-risk patients because it acts faster and more effectively than allopurinol. Aggressive intravenous hydration is also used for prevention, but among the listed options rasburicase most directly prevents the uric acid-driven renal injury that perpetuates this syndrome.

• A. Sodium bicarbonate was previously used to alkalinize urine but is no longer recommended because it promotes calcium phosphate precipitation.
• B. Furosemide can worsen urate nephropathy and electrolyte derangements and is not used for TLS prophylaxis.
• D. Calcium gluconate treats symptomatic hypocalcemia or hyperkalemia-induced arrhythmia but does not prevent the underlying metabolic cascade.
• E. Allopurinol blocks new uric acid formation but acts more slowly and does not reduce existing uric acid levels, making it less effective than rasburicase in high-risk patients.

Hodgkin lymphoma classically presents in young adults with painless cervical or mediastinal lymphadenopathy accompanied by B symptoms (fever, night sweats, weight loss). The diagnostic hallmark is the Reed-Sternberg cell, a large binucleated cell with prominent "owl-eye" nucleoli, found within a mixed inflammatory background of lymphocytes, eosinophils, and plasma cells. These malignant cells are typically CD15 and CD30 positive on immunohistochemistry. Diagnosis requires excisional lymph node biopsy to preserve architecture and identify the characteristic cells within their reactive milieu.

• A. Reactive lymphadenitis shows benign follicular hyperplasia without atypical binucleated cells.
• B. Metastatic carcinoma shows epithelial cells arranged in glandular or papillary patterns, not Reed-Sternberg cells.
• C. Tuberculous lymphadenitis shows caseating granulomas with multinucleated giant cells, not Reed-Sternberg cells.
• D. DLBCL shows sheets of large atypical lymphocytes without Reed-Sternberg cells or the characteristic mixed inflammatory background.

When lymphoma is suspected, excisional lymph node biopsy is the preferred diagnostic procedure because it preserves the overall lymph node architecture, which is essential for accurate histologic subtyping and grading of lymphomas such as diffuse large B-cell lymphoma. Fine-needle aspiration provides only cytologic information and cannot assess architectural patterns, often yielding inconclusive or inadequate results, as in this patient. Excisional biopsy also allows for immunohistochemical staining and flow cytometry to confirm the specific lymphoma subtype, which guides treatment and prognosis. Core needle biopsy may be used when excisional biopsy is not feasible, but it provides less tissue and architectural information than a full excisional specimen.

• A. Empiric corticosteroids can lyse lymphoma cells and obscure the histologic diagnosis, and should be avoided before biopsy.
• B. Core needle biopsy alone yields less tissue and architecture than excisional biopsy and is a second-line option.
• C. PET-CT is useful for staging after a tissue diagnosis is established, not for establishing the diagnosis itself.
• E. Repeating FNA is unlikely to provide the architectural detail needed and would delay diagnosis further.

Burkitt lymphoma is a highly aggressive B-cell non-Hodgkin lymphoma strongly associated with Epstein-Barr virus infection, particularly in the endemic form seen in equatorial Africa, where it classically presents as a rapidly growing jaw or facial mass in children. The characteristic histologic finding is the "starry sky" appearance, created by numerous benign tingible-body macrophages (the "stars") scattered among a dense, diffuse population of darkly staining malignant lymphocytes with extremely high proliferative activity. The disease is driven by a t(8;14) translocation (or variants involving chromosomes 2 or 22) that places the MYC oncogene under control of an immunoglobulin gene promoter, leading to constitutive MYC overexpression. Because of its rapid growth, treatment requires intensive chemotherapy and aggressive management of tumor lysis syndrome.

• A. DLBCL occurs more commonly in older adults and lacks the characteristic starry sky pattern and jaw predilection in children.
• C. Follicular lymphoma shows a nodular growth pattern of small, cleaved lymphocytes and occurs in older adults, not children.
• D. Lymphoblastic lymphoma typically presents with a mediastinal mass in adolescents and shows blast-like cells without the starry sky pattern.
• E. Osteosarcoma would show malignant bone-forming cells on biopsy, not a lymphoid infiltrate with tingible-body macrophages.

Multiple myeloma is diagnosed by the combination of clonal bone marrow plasma cells (typically greater than 10%, here 35%) and evidence of end-organ damage attributable to the plasma cell disorder, summarized by the CRAB criteria: hyperCalcemia, Renal insufficiency, Anemia, and Bone lesions. This patient has all four: calcium 11.4 mg/dL, creatinine 2.3 mg/dL, hemoglobin 9.2 g/dL, and lytic lesions on skeletal survey. The monoclonal spike on serum protein electrophoresis reflects the paraprotein produced by the malignant plasma cell clone. Management typically includes proteasome inhibitors, immunomodulatory agents, and corticosteroids, often followed by autologous stem cell transplantation in eligible patients.

• B. Metastatic prostate carcinoma typically causes osteoblastic (sclerotic), not lytic, bone lesions and would not explain the monoclonal spike.
• C. MGUS requires a plasma cell count below 10% and the absence of any CRAB end-organ damage, which this patient does not meet.
• D. Primary amyloidosis can accompany plasma cell disorders but is characterized by organ infiltration with amyloid fibrils rather than lytic bone lesions as the defining feature.
• E. Waldenström macroglobulinemia produces an IgM spike and is associated with hyperviscosity symptoms, not lytic bone lesions.

This patient has monoclonal gammopathy of undetermined significance (MGUS), defined by a serum M protein below 3 g/dL, clonal bone marrow plasma cells below 10%, and absence of CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions) or other myeloma-defining events. Unlike multiple myeloma, MGUS does not cause end-organ damage and does not require chemotherapy; management consists of periodic clinical and laboratory monitoring because of a small annual risk (about 1%) of progression to multiple myeloma or related plasma cell disorders. Distinguishing MGUS from smoldering or active myeloma hinges on the absence of end-organ damage and a lower plasma cell burden, both of which are present in this patient's normal hemoglobin, calcium, creatinine, and skeletal survey. Treatment is reserved for patients who progress to symptomatic myeloma.

• A. Stem cell transplantation is a treatment for active multiple myeloma, not for MGUS.
• B. High-dose dexamethasone is used to treat myeloma, not an asymptomatic finding without end-organ damage.
• C. Bortezomib-based chemotherapy is reserved for symptomatic multiple myeloma with evidence of end-organ damage, which this patient lacks.
• D. Radiation therapy is used for localized myeloma-related bone lesions, which are absent here.

Cast nephropathy (myeloma kidney) results from excess monoclonal free light chains filtered by the glomerulus that bind Tamm-Horsfall protein (uromodulin) in the distal tubule and thick ascending limb, forming obstructing casts that trigger tubular injury and inflammation. This explains why standard urine dipstick, which detects albumin, is often negative or only mildly positive despite massive light chain excretion (the dipstick misses non-albumin proteins). Hypercalcemia can contribute to renal injury but is not the primary mechanism here given the markedly elevated creatinine with lytic disease and a monoclonal spike. Diagnosis is confirmed by urine protein electrophoresis/immunofixation showing free light chains (Bence Jones proteinuria).

• A. Hypercalcemia contributes to renal dysfunction via nephrogenic diabetes insipidus and vasoconstriction but is not the dominant mechanism in this classic cast nephropathy picture.
• B. Immune complex-mediated glomerulonephritis is not characteristic of myeloma-associated renal injury.
• C. There is no infectious process described; fever and signs of pyelonephritis are absent.
• D. Amyloidosis causes nephrotic-range proteinuria with glomerular deposits, not the typical tubular cast obstruction of acute myeloma kidney, and this patient lacks significant proteinuria.

This patient has an acute hemolytic transfusion reaction, most commonly due to ABO incompatibility, in which preformed recipient antibodies bind donor antigens and trigger complement-mediated intravascular hemolysis, causing fever, hypotension, flank pain, hemoglobinuria, and a positive direct antiglobulin test. The transfusion must be stopped immediately to limit further hemolysis, while IV access is maintained with normal saline to support blood pressure and renal perfusion. The blood bank should be notified and the unit, along with post-reaction patient samples, sent for crossmatch confirmation and workup. Continuing or merely slowing the transfusion risks worsening hemolysis, hypotension, and acute kidney injury.

• A. Diphenhydramine and slowing the rate are appropriate for a mild allergic reaction, not for suspected intravascular hemolysis with hypotension.
• B. The transfusion itself must be stopped first, not merely slowed, before other supportive measures are considered.
• C. Continuing the transfusion in suspected acute hemolytic reaction risks further hemolysis and hemodynamic collapse.
• D. Observing while the transfusion is paused is reasonable only after the transfusion has already been stopped, not as an alternative to stopping it.

The USPSTF recommends that average-risk adults begin colorectal cancer screening at age 45 years, using options including colonoscopy every 10 years, annual fecal immunochemical testing, or other validated stool-based or direct visualization tests. This recommendation was lowered from age 50 due to rising incidence of colorectal cancer in younger adults. Since this patient is 46 years old with no family history or symptoms, screening should begin now rather than being delayed. Average-risk screening recommendations apply regardless of symptoms, since colorectal cancer is often asymptomatic in early, detectable stages.

• A. Screening should begin at age 45 in average-risk individuals regardless of future family history changes.
• B. Age 50 was the prior threshold; current USPSTF guidance lowers the average-risk starting age to 45 years.
• C. Screening is recommended for asymptomatic average-risk adults; waiting for symptoms contradicts the purpose of screening.
• E. Age 55 is not a recognized starting point for average-risk colorectal cancer screening.

The USPSTF currently recommends biennial screening mammography for average-risk women starting at age 40 years and continuing through age 74 years, a change from the prior recommendation of starting at age 50. This update reflects evidence that earlier initiation reduces breast cancer mortality, including in women without additional risk factors. Mammography remains a screening test performed on asymptomatic women and should not be reserved only for those with a palpable abnormality, which would instead warrant diagnostic imaging. Average-risk women without mutations such as BRCA1/2 do not require earlier initiation or annual intervals, which are reserved for higher-risk individuals.

• A. Age 50 was the previous threshold; current guidelines recommend starting earlier, at age 40.
• B. Age 45 is not the current recommended starting age under USPSTF guidelines; screening should begin at 40.
• C. Screening mammography is intended for asymptomatic women; a palpable mass warrants diagnostic imaging, not screening.
• D. Annual screening starting at age 35 is not recommended for average-risk women and does not reflect current USPSTF guidance.

The USPSTF recommends annual low-dose CT screening for lung cancer in adults aged 50 to 80 years who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. This patient has a 25 pack-year history (1 pack/day for 25 years) and is a current smoker within the eligible age range, meeting all criteria. Screening is performed annually rather than at longer intervals, since annual low-dose CT has been shown in trials to reduce lung cancer mortality in this high-risk population. Chest radiography and sputum cytology have not been shown to reduce lung cancer mortality and are not recommended screening modalities.

• A. Low-dose CT screening should be performed annually, not every 3 years, according to current guidelines.
• C. Sputum cytology has not demonstrated a mortality benefit and is not a recommended screening test.
• D. Screening is recommended based on age and smoking history regardless of symptoms, since lung cancer screening targets asymptomatic high-risk individuals.
• E. Chest radiography has not been shown to reduce lung cancer mortality and is not a recommended screening modality.

Febrile neutropenia (temperature ≥38.3°C with ANC <500/mm³) is a medical emergency because the usual inflammatory response to infection is blunted, allowing rapid progression to sepsis. Current guidelines recommend empiric broad-spectrum antipseudomonal antibiotics, such as cefepime, piperacillin-tazobactam, or a carbapenem, within one hour of presentation, after blood cultures are obtained but without waiting for results. Delaying therapy increases mortality. Source control imaging and growth factor support may follow but do not replace immediate antibiotics.

• A. Imaging can be obtained after antibiotics are started but should not delay empiric therapy.
• B. Oral outpatient therapy is reserved for carefully selected low-risk patients, not for this patient with tachycardia and significant neutropenia.
• C. Waiting for culture results delays therapy and increases the risk of sepsis and death.
• D. Growth factors do not treat an active infection and are not a substitute for antibiotics.

This patient's facial plethora, periorbital edema, and non-pulsatile distended neck and chest wall veins are classic for superior vena cava (SVC) syndrome, most often caused by extrinsic compression or invasion of the SVC by a mediastinal mass, commonly lung cancer. Contrast-enhanced CT of the chest is the best initial imaging study because it rapidly identifies the level and cause of obstruction, defines mediastinal anatomy, and guides further tissue diagnosis and treatment planning. Echocardiography and Doppler studies do not adequately characterize mediastinal masses or central venous obstruction. Prompt recognition is important because SVC syndrome can progress to airway compromise or cerebral edema.

• B. A V/Q scan evaluates for pulmonary embolism, not mediastinal masses or venous obstruction.
• C. Echocardiography assesses cardiac structures and pericardial effusion but does not delineate the mediastinal mass causing SVC obstruction.
• D. Doppler ultrasound of the neck veins does not visualize intrathoracic structures or the SVC itself.
• E. Pulmonary function testing assesses lung mechanics and is not useful for diagnosing SVC syndrome.

This patient has humoral hypercalcemia of malignancy, in which tumor cells (frequently squamous cell carcinomas) secrete parathyroid hormone-related peptide (PTHrP), which binds PTH receptors in bone and kidney, increasing bone resorption and renal calcium reabsorption while suppressing endogenous PTH, as seen here. Initial management is isotonic saline to correct volume depletion and improve renal calcium clearance, followed by an intravenous bisphosphonate such as zoledronic acid, which inhibits osteoclast-mediated bone resorption and produces a more durable reduction in calcium. Calcitonin may be added for rapid effect in severe symptomatic cases but bisphosphonates provide the sustained correction.

• A. Loop diuretics without adequate volume repletion first can worsen volume depletion and are not first-line; hydration must precede or accompany diuretic use.
• B. Calcitriol increases intestinal calcium absorption and would worsen hypercalcemia; it is used for hypocalcemia, not malignancy-related hypercalcemia.
• C. Calcium gluconate would further raise serum calcium and is contraindicated in hypercalcemia.
• D. Cinacalcet lowers PTH secretion in primary or secondary hyperparathyroidism and is not effective in PTHrP-mediated hypercalcemia of malignancy.