Free USMLE Step 1 Hematology and Immunology practice questions

Pancytopenia with a very low reticulocyte count and a fatty, hypocellular marrow without blasts or fibrosis is aplastic anemia. Chloramphenicol, a 50S peptidyltransferase inhibitor, is still used for typhoid fever and rickettsial disease in resource-limited settings because it is cheap and penetrates tissues well. It causes two marrow toxicities. The first is a dose-related, reversible suppression of erythropoiesis during therapy, reflecting inhibition of mitochondrial protein synthesis in marrow precursors. The second, seen here, is a rare, idiosyncratic, dose-independent aplastic anemia that can appear weeks to months after the drug is stopped, even after a normal count at the end of treatment, and is often fatal.

A. Azithromycin can treat typhoid fever, but its main toxicities are QT prolongation, GI upset and, in neonates, pyloric stenosis; it does not cause marrow aplasia. C. Ciprofloxacin treats typhoid fever too; its classic toxicities are tendinopathy, QT prolongation and CNS effects. D. Linezolid causes thrombocytopenia and myelosuppression mainly during courses longer than about 2 weeks, and the counts recover after it is stopped; it is not a typhoid drug. E. Trimethoprim-sulfamethoxazole can cause megaloblastic anemia from folate antagonism (high MCV, hypersegmented neutrophils) and occasional cytopenias, but not delayed aplasia with a fatty marrow.

A platelet fall of more than 50% that begins about 5 to 10 days into heparin therapy, together with a new thrombosis, is heparin-induced thrombocytopenia (HIT). Heparin binds the positively charged chemokine platelet factor 4 (PF4), exposing neoepitopes. The patient forms IgG antibodies against the heparin-PF4 complex; the immune complexes bind platelet FcgammaRIIa receptors, activating platelets, releasing procoagulant microparticles, and generating thrombin. Platelets are consumed, but the dominant clinical problem is arterial and venous thrombosis, not bleeding. The 5 to 10 day delay reflects the time needed to mount an IgG response. Management is to stop all heparin and start a non-heparin anticoagulant such as argatroban, bivalirudin, or fondaparinux, delaying warfarin until platelets recover.

B. Anti-GPIIb/IIIa autoantibodies cause immune thrombocytopenia, which presents with bleeding and is not tied to heparin exposure or thrombosis.

C. ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura, with microangiopathic hemolysis and schistocytes on the smear.

D. Nonimmune heparin-associated platelet clumping (formerly HIT type I) produces a mild fall in the first 1 to 2 days that resolves despite continued heparin and does not cause thrombosis.

E. Disseminated intravascular coagulation would prolong the prothrombin time and lower fibrinogen, which are normal here.

Lipopolysaccharide binds CD14 and TLR4 on macrophages and induces the acute-inflammation cytokines IL-1, IL-6, IL-8, IL-12, and TNF-α. Of these, IL-8 (CXCL8) is the major chemokine that attracts neutrophils to sites of bacterial infection ("clean up on aisle 8"). It binds the G protein-coupled receptors CXCR1 and CXCR2 on neutrophils, triggering integrin activation, firm adhesion to endothelium, and directional migration along the chemokine gradient. Because the medium is serum-free, C5a cannot be generated, and blocking IL-8 therefore removes most of the chemotactic activity. Other neutrophil chemoattractants in vivo include C5a, leukotriene B4, and bacterial N-formylmethionyl peptides.

A. IL-5 promotes eosinophil growth and recruitment and IgA class switching; it is made mainly by Th2 cells, not by LPS-stimulated macrophages, and does not attract neutrophils. C. IL-10 is an anti-inflammatory cytokine that suppresses macrophage activation and would, if anything, reduce inflammation rather than recruit cells. D. IL-4, a Th2 cytokine, drives Th2 differentiation and IgE class switching. E. Interferon-β, released mainly by virus-infected cells, induces an antiviral state in neighboring cells and increases MHC class I; it is not a neutrophil chemoattractant.

Fever after travel to sub-Saharan Africa without prophylaxis, impaired consciousness with a seizure, hypoglycemia, thrombocytopenia, and a smear with high parasitemia (above 5%), multiple rings per cell, and banana-shaped gametocytes indicate severe Plasmodium falciparum malaria with cerebral involvement.

As falciparum trophozoites mature, the parasite exports PfEMP1 to knobs on the red cell membrane. PfEMP1 binds endothelial receptors such as ICAM-1 and CD36, so red cells carrying mature trophozoites and schizonts stick in capillaries and postcapillary venules. This sequestration keeps the mature stages out of the peripheral blood (only young rings and gametocytes circulate), lets the parasite escape splenic clearance, and obstructs microvascular flow. In the brain it causes cerebral malaria; in the placenta it causes low birth weight and fetal loss. Hypoglycemia comes from parasite glucose consumption, failing gluconeogenesis, and, if quinine is used, insulin release. IV artesunate is first line.

A. Hepatic dormancy (hypnozoites) belongs to P. vivax and P. ovale and explains relapse, not the stage pattern of the blood smear; falciparum forms no hypnozoites.

C. Intravascular lysis contributes to anemia and to blackwater fever, but it would not selectively remove only mature stages.

D. Avoiding the spleen is the point of sequestration; splenic clearance acts on circulating, deformed red cells and would remove rings as well.

E. Antibodies do not halt maturation; a nonimmune traveler has little antiparasite immunity, which is why parasitemia is so high.

Rifampin is the prototypical CYP450 inducer. It activates the nuclear pregnane X receptor, which increases transcription of CYP2C9 (the main enzyme clearing the potent S-enantiomer of warfarin) and CYP3A4. More enzyme protein means faster warfarin clearance, which is why this patient needed almost twice his usual dose to stay in range.

Induction depends on new enzyme synthesis, and its reversal depends on degradation of the extra enzyme, so both build and fade over days to weeks rather than hours. Once rifampin is stopped, the surplus CYP2C9 is gradually lost over 1 to 2 weeks, clearance falls back to baseline, and the now oversized warfarin dose accumulates. Because warfarin has a narrow therapeutic index, the INR climbs to 6.4 and he bleeds. Stopping an inducer is therefore as dangerous as starting an inhibitor, and the INR must be checked whenever any interacting drug is started or stopped, with the warfarin dose tapered back down as induction wears off.

A. P-glycoprotein inhibition matters for digoxin and dabigatran, not warfarin, and no inhibitor was added. B. Displacement from albumin raises the free fraction only transiently and requires a new displacing drug. C. Direct CYP2C9 inhibition by drugs such as fluconazole or amiodarone acts within hours to days, but no inhibitor was started; the change here is loss of induction. E. Vitamin K epoxide reductase sensitivity is set by VKORC1 genotype and does not change after rifampin is stopped.

A white cell count above about 50,000/mm3 made of neutrophils and their immediate precursors raises two possibilities: a malignant chronic myeloid leukemia or a reactive leukemoid reaction. This patient has a clear trigger, severe Clostridioides difficile colitis, which is a classic cause of extreme neutrophilia. The smear shows toxic granulation (coarse, dark primary granules) and Döhle bodies (pale blue patches of rough endoplasmic reticulum), the signature of activated, mature neutrophils responding to infection. The left shift is limited to bands and a few metamyelocytes, there is no basophilia, no splenomegaly, and the hemoglobin and platelet counts are normal. If tested, the leukocyte alkaline phosphatase score would be high and the Philadelphia chromosome absent, and the count falls once the infection is treated.

A. Chronic myeloid leukemia shows the full spectrum of maturing myeloid cells, including myelocytes and promyelocytes, with basophilia, splenomegaly and a low LAP score from the BCR-ABL fusion kinase; it has no infectious trigger. C. Acute myeloid leukemia requires 20% or more blasts and causes marrow failure with anemia and thrombocytopenia; this smear has no blasts. D. Chronic lymphocytic leukemia is a lymphocytosis of mature CD5+ CD23+ B cells with smudge cells in an older adult, not a neutrophilia. E. Primary myelofibrosis gives a leukoerythroblastic smear with teardrop cells and massive splenomegaly from extramedullary hematopoiesis.

Recurrent, nonpruritic angioedema without urticaria, abdominal attacks from bowel wall edema, autosomal dominant family history, unresponsiveness to antihistamines and steroids, and a low C4 with low C1 esterase inhibitor (C1-INH) indicate hereditary angioedema. Normal C1q favors the hereditary form over acquired C1-INH deficiency, in which C1q is often low.

C1-INH is a serine protease inhibitor that regulates not only activated C1r and C1s but also kallikrein and factor XIIa of the contact (kinin) system. With too little C1-INH, kallikrein cleaves high-molecular-weight kininogen unchecked, releasing bradykinin. Bradykinin acts on endothelial B2 receptors to increase vascular permeability, producing deep, nonpitting edema of skin, airway, and gut. C4 is low because uninhibited C1 continually cleaves it. Estrogen raises kinin system activity and worsens attacks, and ACE inhibitors are contraindicated because ACE degrades bradykinin. Attacks are treated with C1-INH concentrate, icatibant (a B2 receptor antagonist), or ecallantide (a kallikrein inhibitor).

A and E. Histamine and tryptase are released by mast cell degranulation, as in IgE-mediated angioedema, which is accompanied by urticaria and pruritus and responds to antihistamines and epinephrine.

B. Leukotriene C4 contributes to bronchoconstriction and vascular leak in allergic and aspirin-exacerbated reactions, not to C1-INH deficiency.

C. C5a is an anaphylatoxin and neutrophil chemoattractant; it is not the mediator of hereditary angioedema.

Red cells stored for transfusion lose 2,3-bisphosphoglycerate (2,3-BPG): in the cold, acidic storage solution glycolysis slows, and the Rapoport-Luebering shunt that makes 2,3-BPG shuts down, so levels fall to near zero within about 2 weeks. 2,3-BPG normally binds the central cavity of deoxyhemoglobin (T state), stabilizing it and lowering O2 affinity so that O2 is released in the tissues. Without it, transfused hemoglobin stays in the high-affinity state, shifting the dissociation curve to the left and lowering the P50, as measured here. Arterial blood is fully saturated and the hemoglobin is adequate, so O2 content is normal, but hemoglobin gives up less O2 at tissue PO2. The result is persistent tissue hypoxia (high lactate) with an unusually high venous O2 saturation, because O2 returns to the heart still bound. After transfusion, the cells regenerate 2,3-BPG over roughly 1 to 3 days, and the curve normalizes.

A. Oxidized (ferric) heme is methemoglobin, which would raise the measured methemoglobin fraction; his is 1%. B. Carboxyhemoglobin also left-shifts the curve, but his level is normal. D. A hemoglobin of 11.8 g/dL with full saturation gives a near-normal O2 content, so hemodilution does not explain tissue hypoxia with high venous saturation. E. Acidosis right-shifts the curve (Bohr effect) and raises the P50, which would improve unloading; his pH is normal and his P50 is low.

This infant has severe combined immunodeficiency (SCID): thrush, chronic diarrhea, failure to thrive, Pneumocystis pneumonia, an absent thymic shadow and low TRECs on newborn screening. Two clues identify the autosomal recessive adenosine deaminase (ADA) deficiency form: she is a girl, and her parents are consanguineous. ADA normally deaminates adenosine and deoxyadenosine in the purine salvage pathway. Without it, deoxyadenosine accumulates and is phosphorylated to dATP, which inhibits ribonucleotide reductase and blocks DNA synthesis. Lymphocytes are especially vulnerable because they have high kinase activity and divide rapidly, so T, B and NK cells are all lost. Treatment is hematopoietic stem cell transplant (enzyme replacement and gene therapy are options), and live vaccines must be avoided.

A. Common γ chain (IL2RG) mutation is the most common cause of SCID overall, but it is X-linked and typically spares B cells (T-B+NK- pattern), so it fits a boy rather than a girl with consanguineous parents. B. BTK deficiency causes X-linked agammaglobulinemia with absent B cells but normal T cells, so thrush and Pneumocystis would not occur. C. Defective double-strand break repair causes ataxia-telangiectasia (ATM), which presents later with ataxia, telangiectasias, high AFP and IgA deficiency; when it blocks V(D)J recombination (Artemis, DNA ligase IV), it causes a T-B- SCID that spares NK cells, unlike this infant's loss of NK cells. D. Third pharyngeal pouch failure in DiGeorge syndrome causes thymic aplasia with hypocalcemia and conotruncal heart defects, and B and NK cells are preserved.

The drug is romiplostim, a peptibody that activates the thrombopoietin (TPO) receptor, c-Mpl, on megakaryocytes and their progenitors; the oral small molecule eltrombopag acts on the same receptor. TPO is the main regulator of megakaryocyte growth, endomitosis and platelet shedding. It is produced mainly by hepatocytes, at a fairly constant rate. Plasma levels are set largely by clearance: platelets and megakaryocytes bind TPO through c-Mpl and remove it, so free TPO rises when the platelet mass falls and drops when it rises. This also explains why cirrhosis causes thrombocytopenia through low TPO output in addition to splenic sequestration. In ITP, platelet destruction outpaces production, and the agonist pushes megakaryocyte output higher. Adverse effects include thrombosis, marrow reticulin fibrosis and rebound thrombocytopenia when stopped.

B. Peritubular interstitial fibroblasts of the renal cortex produce erythropoietin, which drives red cell production and is mimicked by epoetin alfa and darbepoetin. C. Marrow stromal cells make small amounts of TPO and other niche factors, but the liver is the main source. D. Activated T cells secrete IL-3, IL-5 and GM-CSF, which act on other myeloid lineages. E. Splenic macrophages destroy antibody-coated platelets in ITP; they do not supply TPO.