I85PREP
⌘ K
Egyptian Board Hematology - independent subject foundations study materials
Egyptian Board Hematology - independent subject foundations study resources

Egyptian Board Hematology - independent subject foundations practice questions

One question at a time. Build your Egyptian Board Hematology - independent subject foundations understanding.

First 50 of 190 questions. Each one lists the choices, the correct answer, and an explanation. The checker at the top of this page saves progress in this browser when it is available.

Continue in the practice tool above to load more questions, 50 at a time.

Question 1Hematopoiesis, molecular regulation and diagnostic evidence

Which listed flow-cytometric profile can enrich a human marrow population for primitive long-term-repopulating hematopoietic stem-cell investigation, without independently proving functional repopulating capacity?

  1. CD34+ CD38- Lin- CD90+ CD45RA- Correct answer.
  2. CD34+ CD38+ Lin- CD90- CD45RA+
  3. CD34- CD38+ Lin+ CD90+ CD45RA-
  4. CD34+ CD38- Lin- CD90- CD45RA+

Explanation

Human long-term hematopoietic stem cells (LT-HSCs) reside within the CD34-positive, lineage-negative (Lin-) fraction and are specifically characterized by CD38 negativity, CD90 (Thy-1) positivity, and lack of CD45RA. Acquisition of CD38 or CD45RA reflects commitment toward multipotent progenitor or downstream lineage-restricted progenitor stages.

Question 2Hematopoiesis, molecular regulation and diagnostic evidence

A 48-year-old male with chronic kidney disease exhibits severe normocytic normochromic anemia. His hematologist considers the molecular cascade induced when recombinant erythropoietin binds its receptor (EpoR). Which of the following events is the critical proximal intracellular step following ligand-induced EpoR homodimer conformational change?

  1. Recruitment of SMAD4 and direct transcription of globin gene enhancers
  2. Transphosphorylation and activation of pre-associated JAK2 tyrosine kinase Correct answer.
  3. Cleavage of membrane-bound Notch1 to release its nuclear intracellular domain
  4. Direct GTP-binding and autophosphorylation of the c-Kit catalytic domain

Explanation

The erythropoietin receptor (EpoR) lacks intrinsic kinase activity and exists as a preformed homodimer. Binding of erythropoietin induces a conformational change that brings constitutive receptor-associated JAK2 tyrosine kinases into proximity, triggering JAK2 transphosphorylation and subsequent phosphorylation of specific tyrosine residues on the cytoplasmic tail of EpoR.

Question 3Hematopoiesis, molecular regulation and diagnostic evidence

Which listed maturation mechanism is promoted in megakaryopoiesis through thrombopoietin and MPL signaling, without claiming that no other biological influence contributes?

  1. Symmetric meiotic divisions producing haploid platelet precursor nuclei
  2. Clonal chromosomal translocations generating polycistronic heavy chain transcripts
  3. Endomitosis resulting in progressive cellular polyploidization up to 64N or 128N Correct answer.
  4. Selective phagocytosis of basophilic erythroblasts within marrow erythroblastic islands

Explanation

Thrombopoietin signaling through c-MPL promotes megakaryocyte differentiation, survival, and endomitosis. Endomitosis is a specialized cell cycle variant where DNA replication occurs repeatedly without intervening mitosis or cytokinesis, generating polyploid megakaryocytes (typically 8N to 64N or higher) necessary for abundant platelet generation.

Question 4Hematopoiesis, molecular regulation and diagnostic evidence

Hepcidin is the master systemic peptide hormone regulating human iron balance. Which of the following hepatic signaling mechanisms represents the principal physiological pathway inducing hepcidin transcription in response to systemic iron excess?

  1. The BMP6-SMAD1/5/8 pathway coordinated by hemojuvelin, HFE, and transferrin receptor 2 Correct answer.
  2. The canonical Wnt-beta-catenin pathway mediated by low-density lipoprotein receptor-related protein 6
  3. Direct nuclear translocation of NF-kappa-B upon cleavage of erythroferrone polymers
  4. Constitutive activation of Notch-HES1 signaling driven by transferrin receptor 1 endocytosis

Explanation

Elevated circulating iron (diferric transferrin) and hepatic iron stores stimulate the bone morphogenetic protein 6 (BMP6) pathway. BMP6 binds its receptor complex in concert with the co-receptor hemojuvelin (HJV), HFE, and transferrin receptor 2 (TfR2), triggering phosphorylation of SMAD1/5/8, which associates with SMAD4 to activate hepcidin (HAMP) gene transcription.

Question 5Hematopoiesis, molecular regulation and diagnostic evidence

At the post-transcriptional level, cellular iron homeostasis is precisely regulated by iron regulatory proteins (IRP1 and IRP2) binding to iron-responsive elements (IREs) on target mRNAs. When intracellular iron levels are critically depleted, what coordinate molecular events occur regarding ferritin and transferrin receptor 1 (TfR1) expression?

  1. IRPs detach from 5' IRE of ferritin to boost translation, and detach from 3' IRE of TfR1 to trigger mRNA degradation
  2. IRPs degrade ferritin mRNA via endonuclease cleavage and bind 5' IRE of TfR1 to accelerate ribosomal initiation
  3. IRPs bind the 5' IRE of ferritin to repress translation, and bind 3' IREs of TfR1 to protect its mRNA from endonucleolytic degradation Correct answer.
  4. IRPs translocate into the nucleus to hypermethylate the ferritin promoter and recruit RNA polymerase II to TfR1

Explanation

In iron-deficient cells, IRP1 and IRP2 assume high-affinity RNA-binding conformations. Binding of IRP to the single IRE in the 5' untranslated region (UTR) of ferritin mRNA sterically blocks ribosomal translation initiation, preventing futile iron storage. Concurrently, IRP binding to multiple IREs in the 3' UTR of TfR1 mRNA protects the transcript from endonuclease degradation, increasing TfR1 synthesis and cellular iron uptake.

Question 6Hematopoiesis, molecular regulation and diagnostic evidence

A 22-year-old medical student reviews erythroblast cellular iron acquisition. After circulating diferric transferrin binds to transferrin receptor 1 (TfR1 / CD71) on the erythroid membrane, which process is essential for releasing ferric iron from transferrin within the endosome?

  1. Direct cleavage of transferrin peptide bonds by intra-endosomal granzyme B
  2. Oxidation of ferrous iron to ferric iron by ceruloplasmin inside the endosome
  3. Neutralization of endosomal pH via passive bicarbonate-chloride anion exchange
  4. Proton pumping by vacuolar H+-ATPase to acidify the endosomal lumen to pH 5.5 Correct answer.

Explanation

Upon clathrin-mediated endocytosis of the diferric transferrin-TfR1 complex, endosomal acidification to approximately pH 5.5 driven by an ATP-dependent vacuolar proton pump (V-ATPase) triggers a conformational change that releases ferric iron (Fe3+) from transferrin. The metalloreductase STEAP3 then reduces Fe3+ to Fe2+, which is transported into the cytosol via divalent metal transporter 1 (DMT1).

Question 7Hematopoiesis, molecular regulation and diagnostic evidence

A 55-year-old female undergoes total gastrectomy for gastric adenocarcinoma. Four years later, she develops severe megaloblastic anemia. Which sequential physiologic process is responsible for the dietary absorption of vitamin B12 (cobalamin) along the gastrointestinal tract?

  1. Salivary haptocorrin binding in the stomach, degradation by pancreatic proteases in the duodenum, intrinsic factor binding, and cubam receptor-mediated endocytosis in the terminal ileum Correct answer.
  2. Direct gastric intrinsic factor binding at pH 1.5, mucosal pinocytosis in the proximal jejunum, and portal transport bound to transcobalamin I
  3. Gastric pepsin-mediated destruction of haptocorrin, bile salt conjugation in the jejunum, and passive paracellular absorption throughout the ascending colon
  4. Gastric mucin complexation, brush-border cleavage by enteropeptidase in the duodenum, and active cotransport via sodium-dependent SGLT1 in the ileum

Explanation

Dietary cobalamin is released from animal proteins in the stomach and initially binds salivary haptocorrin (R-binder), protecting it from gastric acid. In the duodenum, pancreatic proteases degrade haptocorrin, allowing cobalamin to bind gastric parietal cell-derived intrinsic factor (IF). The IF-cobalamin complex travels intact to the terminal ileum, where it binds the cubam receptor complex (cubilin and amnionless) for receptor-mediated endocytosis.

Question 8Hematopoiesis, molecular regulation and diagnostic evidence

A 6-month-old infant with failure to thrive and severe macrocytic anemia is evaluated. Laboratory testing reveals normal serum total vitamin B12 levels, but genetic sequencing demonstrates a homozygous null mutation in the TCN2 gene. Which statement explains why normal total serum B12 levels co-exist with severe cellular B12 deficiency in transcobalamin II deficiency?

  1. Transcobalamin II exclusively transports dietary folate, leaving cobalamin trapped in enterocytes
  2. Transcobalamin I carries approximately 80% of circulating B12 but cannot deliver it to tissues, whereas transcobalamin II delivers the metabolically critical 20% to cells via CD320 Correct answer.
  3. Transcobalamin II is a nuclear chaperone that converts inactive methylcobalamin into active cyanocobalamin within mitochondria
  4. Transcobalamin II functions as a serum scavenger that excretes toxic homocysteine conjugates into bile

Explanation

Approximately 70-80% of circulating cobalamin is bound to transcobalamin I (haptocorrin), which turns over slowly and lacks receptors for cellular tissue delivery. Transcobalamin II (TCN2) carries only 10-30% of total plasma B12, but this fraction constitutes the bioactive pool that undergoes rapid receptor-mediated endocytosis via the CD320 receptor in all proliferating tissues, including hematopoietic precursors.

Question 9Hematopoiesis, molecular regulation and diagnostic evidence

In human cellular biochemistry, cobalamin serves as an obligate coenzyme for only two enzymatic reactions. Which pair of biochemical conversions directly depends upon vitamin B12?

  1. Serine to glycine conversion and xanthine to uric acid oxidation
  2. Phenylalanine to tyrosine hydroxylation and pyruvate to acetyl-CoA decarboxylation
  3. Homocysteine to methionine methylation and methylmalonyl-CoA to succinyl-CoA isomerization Correct answer.
  4. Glutamate to GABA decarboxylation and ribonucleotide to deoxyribonucleotide reduction

Explanation

In humans, vitamin B12 acts as an essential cofactor for: (1) cytoplasmic methionine synthase (which uses methylcobalamin to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, generating methionine and tetrahydrofolate), and (2) mitochondrial methylmalonyl-CoA mutase (which uses 5'-deoxyadenosylcobalamin to isomerize methylmalonyl-CoA to succinyl-CoA).

Question 10Hematopoiesis, molecular regulation and diagnostic evidence

A 62-year-old strict vegan is diagnosed with macrocytic anemia and peripheral neuropathy. Bone marrow biopsy reveals prominent megaloblastic erythroid hyperplasia. Which biochemical mechanism explains the 'folate trap' hypothesis linking cobalamin deficiency to defective DNA synthesis?

  1. Folate is permanently cross-linked to hemoglobin polymers within circulating reticulocytes
  2. Intracellular folates are converted into non-metabolizable dihydrofolate polymers that inhibit RNA polymerase II
  3. Cobalamin deficiency directly represses the hepatic synthesis of the reduced folate carrier protein
  4. Failure of methionine synthase traps folate as 5-methyltetrahydrofolate, preventing regeneration of tetrahydrofolate for thymidylate synthesis Correct answer.

Explanation

Because the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-methyl-THF) by MTHFR is physiologically irreversible, the sole metabolic pathway to convert 5-methyl-THF back into active tetrahydrofolate (THF) is the cobalamin-dependent methionine synthase reaction. Cobalamin deficiency arrests this reaction, trapping cellular folate as 5-methyl-THF, which leads to cellular depletion of THF and 5,10-methylene-THF required for dUMP to dTMP conversion by thymidylate synthase.

Question 11Hematopoiesis, molecular regulation and diagnostic evidence

A patient with primary central nervous system lymphoma receives high-dose methotrexate chemotherapy. Three days later, her ANC drops to 0.1 x 10^9/L and platelet count to 18 x 10^9/L. At the enzymatic level, methotrexate halts cell cycle progression in hematopoietic progenitors by competitive inhibition of which target?

  1. Dihydrofolate reductase (DHFR), preventing the NADPH-dependent reduction of DHF back to THF Correct answer.
  2. Ribonucleotide reductase (RNR), preventing the conversion of ribonucleoside diphosphates to dNDPs
  3. Thymidylate synthase (TYMS), by irreversible covalent modification of the catalytic cysteine residue
  4. Serine hydroxymethyltransferase-1 (SHMT1), blocking mitochondrial glycine synthesis

Explanation

Methotrexate is a structural analogue of folic acid that competitively inhibits dihydrofolate reductase (DHFR) with an affinity approximately 1,000-fold higher than that of dihydrofolate (DHF). Inhibition of DHFR blocks the regeneration of tetrahydrofolate (THF) from DHF produced during thymidylate synthesis, rapidly depleting active intracellular folate pools and aborting de novo purine and pyrimidine biosynthesis.

Question 12Hematopoiesis, molecular regulation and diagnostic evidence

A 10-year-old child presents with congenital macrocytic anemia and severe thrombocytopenia. Genetic analysis reveals a missense mutation in GATA1 that abrogates its physical interaction with its obligate multi-type zinc finger cofactor, Friend of GATA-1 (FOG-1). What explains the combined erythroid and megakaryocytic defects resulting from disrupted GATA-1:FOG-1 cooperation?

  1. FOG-1 functions as a ubiquitin ligase that degrades the oncogenic transcription factor PU.1 in monocytes
  2. Disruption of GATA-1:FOG-1 binding accelerates globin switching from adult HbA back to embryonic Hb Gower-1
  3. GATA-1 requires FOG-1 recruitment to chromatin to activate lineage-specific erythroid and megakaryocytic gene expression while repressing alternative myeloid programs Correct answer.
  4. FOG-1 acts as an extracellular ligand that directly homodimerizes c-Kit and c-MPL receptors simultaneously

Explanation

GATA-1 is the master transcription factor for both erythroid and megakaryocytic lineages. Physical interaction between the N-terminal zinc finger of GATA-1 and the multi-zinc-finger coregulator FOG-1 (encoded by ZFPM1) is essential for recruiting chromatin remodeling complexes (such as NuRD) to activate erythroid/megakaryocytic genes and silence alternative mast cell/granulocytic programs. Mutations that disrupt GATA-1:FOG-1 binding produce dyserythropoietic anemia and macrothrombocytopenia.

Question 13Blood groups, components and transfusion reactions

A 25-year-old trauma patient is typed as blood group O in routine forward typing, but her serum demonstrates strong agglutination with all reagent screening red cells, including all group O donor units. Molecular testing reveals a homozygous null mutation in the FUT1 gene. What is the diagnosis and what is the specific biochemical nature of her red cell antigen defect?

  1. Acquired B phenomenon resulting from bacterial deacetylase action on red cell N-acetylgalactosamine
  2. Rh-null phenotype due to complete lack of the RHAG membrane transport complex
  3. Bombay phenotype (Oh) characterized by failure to add L-fucose to precursor oligosaccharides, resulting in absence of the H antigen and formation of potent anti-H Correct answer.
  4. Paroxysmal nocturnal hemoglobinuria with loss of glycosylphosphatidylinositol-anchored red cell antigens

Explanation

The Bombay phenotype (Oh, genotype hh) is caused by homozygous mutations in the FUT1 (and typically FUT2) fucosyltransferase gene. Without alpha-1,2-fucosyltransferase, individuals cannot synthesize the H antigen precursor. Consequently, they cannot express A or B antigens regardless of ABO genotype, and their serum contains potent, wide-thermal-range IgM/IgG anti-H that hemolyzes all normal red cells (groups O, A, B, AB); they can receive blood only from other Bombay individuals.

Question 14Blood groups, components and transfusion reactions

A 29-year-old female is evaluated for mild chronic macrocytic hemolytic anemia with circulating stomatocytes on blood smear. Immunohematology testing reveals complete absence of all Rh blood group antigens (D, C, c, E, e). Which statement correctly describes the genetic basis and clinical significance of the Rh-null syndrome?

  1. It results from homozygous deletion of the glycophorin A gene and causes severe red cell membrane rigidity with spherocytosis
  2. It arises from mutations in either the RHAG gene (regulator type) or RHD/RHCE genes (amorph type), causing membrane instability and stomatocytosis Correct answer.
  3. It is an X-linked dominant condition caused by mutations in the XK gene that encodes an erythrocyte urea transporter
  4. It is caused by acquired anti-LW autoantibodies that competitively displace Rh polypeptides from the spectrin-actin cytoskeleton

Explanation

Rh-null syndrome is a rare autosomal recessive condition arising from either mutations in the RHAG gene (regulator type, chromosome 6p) or deletion/inactivating mutations in both RHD and RHCE genes (amorph type, chromosome 1p). Because Rh proteins and RHAG are integral components of the red cell core membrane skeletal complex, their absence impairs membrane stability and cation transport, causing stomatocytic hemolytic anemia and spherocytosis.

Question 15Blood groups, components and transfusion reactions

A pregnant woman tests RhD-positive on automated typing, but subsequent evaluation indicates she carries a 'Partial D' (D variant) rather than a 'Weak D' phenotype. What is the critical distinction between Partial D and Weak D regarding transfusion management and alloimmunization risk?

  1. Weak D patients lack external protein epitopes and must always receive RhD-negative blood and Rh immune globulin
  2. Partial D patients possess normal quantities of intact D protein and are immune to anti-D alloantibody formation
  3. Weak D patients produce IgM anti-D that crosses the placenta, whereas Partial D patients produce non-pathogenic IgA
  4. Partial D patients lack one or more extracellular D epitopes and can form alloanti-D if exposed to normal RhD-positive red cells, so they must receive RhD-negative blood Correct answer.

Explanation

Partial D variants can lack epitopes and permit alloanti-D formation, so the relevant variant and transfusion context guide use of D-negative components. Weak D is not a single uniform genotype: some types have different alloimmunization risk and management. Do not infer that every weak-D result is automatically equivalent to every partial-D variant.

Question 16Blood groups, components and transfusion reactions

A 45-year-old male with progressive choreiform movements, peripheral neuropathy, elevated serum creatine kinase, and acanthocytes on peripheral blood smear is diagnosed with McLeod syndrome. What is the fundamental immunohematologic and molecular feature linking the Kell blood group to McLeod syndrome?

  1. The Kell glycoprotein is disulfide-linked to the XK protein, and mutations in the X-linked XK gene cause absent XK protein and marked down-regulation of Kell antigens Correct answer.
  2. A homozygous deletion of the KEL gene on chromosome 7 leads to complete absence of XK protein and neuroacanthocytosis
  3. Constitutive over-expression of KEL1 (K antigen) displaces ankyrin-1 from the membrane, triggering motor neuron apoptosis
  4. Anti-Kell autoantibodies cross-react with striatal dopamine D2 receptors, inducing secondary acanthocytosis

Explanation

The Kell blood group glycoprotein (encoded by KEL on chromosome 7) is covalently linked via a single disulfide bond to the multi-pass membrane protein XK (encoded by the XK gene on the X chromosome). Mutations in the XK gene cause McLeod syndrome, an X-linked neuroacanthocytosis disorder characterized by absent XK expression, markedly depressed expression of all Kell antigens (McLeod red cell phenotype), acanthocytosis, elevated CK, and progressive chorea.

Question 17Blood groups, components and transfusion reactions

A high prevalence of the Duffy-negative phenotype, Fy(a-b-), is observed among individuals of West African descent. What evolutionary selective pressure maintains this high allele frequency in endemic regions?

  1. Resistance to intra-erythrocytic replication of Babesia microti
  2. Resistance to cytoadherence of Plasmodium falciparum via PfEMP-1 binding
  3. Resistance of red cells to invasion by Plasmodium vivax due to absence of the DARC/ACKR1 chemokine receptor Correct answer.
  4. Selective protection against Dengue virus entry via erythrocyte mannose receptors

Explanation

Absence of erythrocyte Duffy/ACKR1 expression can substantially reduce susceptibility to the classical Plasmodium vivax invasion pathway and helps explain historical selection. This is not an absolute guarantee of protection: vivax infections in Duffy-negative individuals have been documented. Interpret resistance as reduced susceptibility rather than universal sterilizing immunity.

Question 18Blood groups, components and transfusion reactions

A 58-year-old female undergoes hip replacement and receives two units of packed red blood cells. Ten days later, she presents with low-grade fever, dark urine, and a falling hemoglobin. Repeat antibody screen demonstrates an antibody that was undetectable pre-transfusion. Which blood group antibody is notorious for rapid titer decline in circulation and causing severe delayed hemolytic transfusion reactions?

  1. Anti-M (MNS system)
  2. Anti-Jka or Anti-Jkb (Kidd system) Correct answer.
  3. Anti-Lea (Lewis system)
  4. Anti-N (MNS system)

Explanation

Antibodies of the Kidd blood group system (anti-Jka and anti-Jkb) are the most notorious cause of delayed hemolytic transfusion reactions (DHTRs). Kidd antibody titers characteristically drop rapidly below the limits of detection during antibody screening, only to undergo an aggressive anamnestic boost upon re-exposure to antigen-positive red cells, triggering complement-mediated intravascular and extravascular hemolysis.

Question 19Blood groups, components and transfusion reactions

A 42-year-old female presents with fatigue, jaundice, and dark urine. The laboratory performs a Direct Antiglobulin Test (DAT). What does a positive polyspecific DAT directly detect in a patient's whole blood sample?

  1. Circulating free unattached IgG antibodies against donor red cells present in the patient's serum
  2. Preformed anti-A and anti-B isohemagglutinins bound to vascular endothelial cells
  3. In vivo coating (sensitization) of the patient's erythrocytes with immunoglobulins (IgG) and/or complement components (such as C3d) Correct answer.
  4. The presence of bacterial endotoxins cross-linked to leukocyte membrane CD14

Explanation

The Direct Antiglobulin Test (DAT / direct Coombs test) detects red blood cells that have been sensitized in vivo by antibodies (principally IgG) and/or complement fragments (primarily C3d). Reagent anti-human globulin (AHG) binds to the cell-bound IgG or C3d, bridging adjacent erythrocytes to produce visible agglutination.

Question 20Blood groups, components and transfusion reactions

A 30-year-old polytrauma patient undergoes emergency massive transfusion following hemorrhagic shock. After transfusion of 12 units of PRBCs, 12 units of FFP, and 2 apheresis platelet units, he develops widening of the QTc interval on ECG, perioral paresthesias, and hypotension. What metabolic derangement is the primary cause of this presentation?

  1. Hypercalcemia resulting from bone resorption induced by parathyroid hormone-related peptide
  2. Hypocalcemia caused by systemic chelation of ionized calcium by citrate preservative in transfused blood components Correct answer.
  3. Severe hypernatremia resulting from high sodium chloride content in red cell additive solutions
  4. Hypokalemia caused by massive cellular potassium uptake driven by donor erythrocyte ATP

Explanation

Blood products are preserved with sodium citrate, which acts as an anticoagulant by chelating ionized calcium. During massive transfusion, the rate of citrate infusion exceeds hepatic metabolic clearance (conversion to bicarbonate), resulting in acute citrate toxicity, profound hypocalcemia (low ionized calcium), QTc prolongation, tetany, perioral paresthesias, and impaired cardiac contractility. Intravenous calcium gluconate or chloride is required.

Question 21Blood groups, components and transfusion reactions

During the refrigerated storage (1-6°C) of packed red blood cells (PRBCs) in preservative solutions (such as CPDA-1 or SAGM), progressive biochemical changes occur, termed the 'storage lesion.' Which metabolic alteration directly impairs the capacity of stored red blood cells to deliver oxygen to recipient tissues immediately upon transfusion?

  1. Depletion of 2,3-bisphosphoglycerate (2,3-DPG), causing a leftward shift of the oxygen-hemoglobin dissociation curve Correct answer.
  2. Accumulation of intra-erythrocytic sorbitol, causing immediate osmotic hemolysis in the pulmonary capillaries
  3. Excessive generation of cyclic AMP, causing irreversible opening of membrane aquaporin channels
  4. Shedding of band 3 protein, preventing carbon dioxide binding to the terminal valine of beta globin

Explanation

During ex vivo storage, red cell glycolytic intermediates decline, leading to progressive depletion of 2,3-bisphosphoglycerate (2,3-DPG) and ATP. Depletion of 2,3-DPG increases the affinity of hemoglobin for oxygen (shifting the oxygen-hemoglobin dissociation curve to the left, decreasing P50), which impairs oxygen offloading in hypoxic tissues until the recipient's cells regenerate 2,3-DPG over 12-24 hours.

Question 22Blood groups, components and transfusion reactions

A 52-year-old male with acute myeloid leukemia receives an apheresis platelet transfusion. One hour post-transfusion, his platelet count rises by only 2 x 10^9/L. Calculations yield a Corrected Count Increment (CCI) of 2,800. If an immune etiology is responsible for this platelet refractoriness, what is the most common target of recipient alloantibodies?

  1. Human platelet-specific antigen HPA-1a
  2. ABO blood group antigens expressed on platelet membranes
  3. Complement regulatory protein CD59
  4. Class I Human Leukocyte Antigens (HLA-A and HLA-B) Correct answer.

Explanation

Platelet refractoriness is defined as a 1-hour post-transfusion Corrected Count Increment (CCI) < 5,000 to 7,500 on two consecutive occasions. When caused by an immune mechanism (alloimmunization from prior transfusions or pregnancies), greater than 80-90% of cases are due to alloantibodies directed against polymorphic Class I Human Leukocyte Antigens (HLA-A and HLA-B) present on the platelet surface.

Question 23Blood groups, components and transfusion reactions

A 36-year-old postpartum patient experiences severe hemorrhage from uterine atony. Her fibrinogen concentration is 0.7 g/L (70 mg/dL). Cryoprecipitate is ordered for rapid replenishment. Which concentrated clotting factors are characteristically provided in a unit of cryoprecipitate?

  1. Prothrombin, Factor VII, Factor IX, and Protein C
  2. Albumin, Antithrombin, Factor X, and Protein S
  3. Fibrinogen (Factor I), Factor VIII, von Willebrand Factor, Factor XIII, and Fibronectin Correct answer.
  4. Platelet-derived growth factor, Plasminogen, Tissue Factor, and Factor XI

Explanation

Cryoprecipitate is prepared by slowly thawing Fresh Frozen Plasma (FFP) at 1-6°C and collecting the cold-insoluble precipitate by centrifugation. It contains concentrated Fibrinogen (typically 150-250 mg per unit), Factor VIII (80-150 IU), von Willebrand Factor (vWF), Factor XIII, and Fibronectin in a small volume of 15-20 mL.

Question 24Blood groups, components and transfusion reactions

Ten minutes into a packed red blood cell transfusion, an anesthetized surgical patient abruptly develops hypotension, generalized oozing from surgical incisions, and hemoglobinuria. What is the initiating immunologic mechanism of this Acute Hemolytic Transfusion Reaction (AHTR)?

  1. Recipient IgE antibodies cross-linking Fc-epsilon-RI on basophils triggering histamine release
  2. Preformed recipient IgM isohemagglutinins binding donor ABO antigens, triggering full classical complement pathway activation and intravascular hemolysis Correct answer.
  3. Donor cytotoxic T lymphocytes recognizing recipient HLA antigens on host renal tubules
  4. Recipient anti-IgA antibodies forming immune complexes in the pulmonary capillaries

Explanation

Acute hemolytic transfusion reactions are almost invariably the result of clerical error leading to ABO-incompatible red cell transfusion. Preformed recipient IgM isohemagglutinins bind donor A or B carbohydrate antigens, fixing C1q and activating the classical complement cascade through to the membrane attack complex (C5b-9). This causes rapid intravascular hemolysis, release of free hemoglobin, acute tubular necrosis, and DIC.

Question 25Blood groups, components and transfusion reactions

A 48-year-old male receives two units of red cells. Seven days later, his hemoglobin unexpectedly drops from 10.5 g/dL to 7.8 g/dL, with mild scleral icterus and elevated unconjugated bilirubin. Repeat antibody screen is positive for anti-Jka, and DAT is positive (IgG). What mechanism accounts for red cell clearance in this Delayed Hemolytic Transfusion Reaction (DHTR)?

  1. Lysis of circulating neutrophils by donor cytokine-mediated degranulation
  2. Direct bacterial endotoxin destruction of erythrocyte spectrin tetramers
  3. Perforin-granzyme mediated cytotoxicity executed by circulating CD8+ T cells
  4. Extravascular clearance by splenic and hepatic macrophages recognizing IgG-coated donor red cells via Fc-gamma receptors Correct answer.

Explanation

Delayed hemolytic transfusion reactions occur when anamnestic IgG alloantibodies (often Kidd, Duffy, or Rh system) coat transfused donor red cells. Rather than undergoing immediate complement-mediated intravascular lysis, these IgG-sensitized erythrocytes are recognized by Fc-gamma receptors (and C3b receptors) on macrophages within the reticuloendothelial system (spleen and liver), resulting in progressive extravascular phagocytosis and destruction.

Question 26Blood groups, components and transfusion reactions

Three hours following transfusion of one unit of FFP, a 65-year-old female develops acute hypoxemia (SpO2 84% on room air), bilateral fluffy pulmonary infiltrates on chest radiograph, fever, and mild hypotension. Cardiac evaluation reveals a normal pulmonary capillary wedge pressure (12 mmHg) and normal NT-proBNP. What pathophysiology explains Transfusion-Related Acute Lung Injury (TRALI)?

  1. Passive transfer of donor anti-HLA or anti-human neutrophil antigen (HNA) antibodies that bind primed recipient pulmonary neutrophils, triggering microvascular endothelial damage and non-cardiogenic pulmonary edema Correct answer.
  2. Rapid left ventricular volume overload causing high hydrostatic pressure and transudative fluid extravasation into alveoli
  3. Accumulation of circulating immune complexes in coronary arteries triggering acute transmural myocardial infarction
  4. Bacterial endotoxin seeding of the pleural space causing bilateral exudative pleural effusions

Explanation

The supplied acute noncardiogenic pulmonary injury pattern is compatible with TRALI after the appropriate competing-cause assessment. Donor anti-HLA or anti-HNA antibodies are one established mechanism that can activate primed pulmonary neutrophils and injure endothelium. Not every case requires detectable donor antibodies, and one normal biomarker alone does not establish the diagnosis.

Question 27Blood groups, components and transfusion reactions

An 82-year-old male with chronic kidney disease and coronary artery disease receives two units of PRBCs rapidly for anemia. Near the end of the second unit, he develops severe tachypnea, orthopnea, hypertension (180/100 mmHg), jugular venous distension, and diffuse crackles. Which finding is most helpful in distinguishing Transfusion-Associated Circulatory Overload (TACO) from TRALI?

  1. Presence of severe hypoxemia requiring supplemental oxygen
  2. Development of bilateral pulmonary infiltrates on chest X-ray
  3. Elevated post-transfusion NT-proBNP (>1.5 times pre-transfusion) and prompt clinical improvement following intravenous furosemide Correct answer.
  4. Neutropenia with transient leukopenia observed on automated CBC

Explanation

The volume-overload presentation supports TACO, and a rise in natriuretic peptide with improvement after diuresis can contribute to the assessment. These findings are not perfectly specific, particularly with preexisting kidney or heart disease. Timing, examination, imaging and competing causes are interpreted together rather than diagnose from one ratio alone.

Question 28Blood groups, components and transfusion reactions

A 50-year-old female with relapsed Hodgkin lymphoma receiving fludarabine and cyclophosphamide receives un-irradiated packed red blood cells from her brother. Two weeks later, she develops high fevers, an erythematous maculopapular rash, watery diarrhea, jaundice, and severe pancytopenia. What is the underlying pathogenesis of this condition?

  1. Transfusion-transmitted cytomegalovirus (CMV) pneumonitis causing secondary hemophagocytic lymphohistiocytosis
  2. Engraftment of viable donor T lymphocytes that attack host tissues because the immunocompromised host cannot reject them (TA-GvHD) Correct answer.
  3. Antibody-dependent cellular cytotoxicity mediated by host natural killer cells against donor platelets
  4. Delayed hemolytic transfusion reaction with extensive bone marrow necrosis

Explanation

Transfusion-Associated Graft-versus-Host Disease (TA-GvHD) occurs when viable donor T lymphocytes in cellular blood components engraft in an immunocompromised host or in an immunocompetent host who shares an HLA haplotype with a donor (e.g., first-degree relative). Donor T cells recognize recipient tissues as foreign and mount an immune attack against the skin, liver, GI tract, and crucially the bone marrow, causing fatal marrow aplasia and pancytopenia with >90% mortality.

Question 29Blood groups, components and transfusion reactions

Which listed clinical context is an established indication to assess and provide appropriate irradiation of cellular blood components to prevent transfusion-associated graft-versus-host disease?

  1. Directed blood donation from a first-degree biological relative, or patients receiving purine analogues (e.g., fludarabine, cladribine) Correct answer.
  2. Elective coronary artery bypass grafting in an immunocompetent non-diabetic patient
  3. Iron deficiency anemia during the third trimester of an uncomplicated pregnancy
  4. Acute upper gastrointestinal hemorrhage in a patient with alcoholic cirrhosis

Explanation

Irradiation prevents donor lymphocyte replication. Definite indications include: (1) cellular donations from first- or second-degree biological relatives (risk of shared HLA haplotypes where donor is homozygous and host is heterozygous), (2) HLA-matched or cross-matched platelets, (3) patients treated with purine analogues (fludarabine, cladribine, pentostatin) or bendamustine, (4) allogeneic and autologous stem cell transplant recipients, and (5) patients with Hodgkin lymphoma.

Question 30Blood groups, components and transfusion reactions

Which listed transfusion risks are reduced by appropriate prestorage leukoreduction, recognizing that reduction is not complete elimination and does not replace other indicated component modifications?

  1. Transfusion-Associated Circulatory Overload (TACO)
  2. Hemolytic disease of the fetus and newborn due to anti-D
  3. Bacterial septicemia from room-temperature stored platelets
  4. Febrile non-hemolytic transfusion reactions (FNHTR) and transfusion-transmitted cytomegalovirus (CMV) infection Correct answer.

Explanation

Leukoreduction reduces donor leukocytes and lowers risks including febrile nonhemolytic reactions and leukocyte-associated CMV transmission. Residual risks remain, and particular patients can require additional measures. It does not substitute for irradiation when prevention of viable donor-lymphocyte complications is indicated.

Question 31Anemia, hemolysis and hemoglobinopathies

A 9-month-old infant of Egyptian descent presents with profound pallor, poor feeding, hepatosplenomegaly, and frontal bossing. Hemoglobin is 4.5 g/dL with extreme microcytosis and hypochromia. Hemoglobin electrophoresis shows 96% HbF and absence of HbA. What is the fundamental cellular pathophysiology driving severe anemia and bone marrow expansion in beta-thalassemia major?

  1. Direct mechanical entrapment of rigid sickle polymers within the hepatic sinusoids
  2. Immune-mediated destruction of reticulocytes by maternal IgG anti-beta-globin antibodies
  3. Relative excess of unpaired alpha-globin chains that precipitate as toxic inclusions in erythroid precursors, causing oxidative damage, ineffective erythropoiesis, and apoptosis Correct answer.
  4. Failure of erythropoietin gene transcription in the fetal peritubular capillary endothelium

Explanation

In beta-thalassemia major (beta-0/beta-0), beta-globin chains are completely absent. The fundamental pathology is not merely the deficiency of HbA, but the massive excess of unpaired alpha-globin chains. Free alpha chains cannot form soluble tetramers and instead precipitate as toxic hemichromes within developing erythroblasts in the bone marrow, generating reactive oxygen species, membrane damage, and apoptosis (ineffective erythropoiesis).

Question 32Anemia, hemolysis and hemoglobinopathies

A 16-year-old female with transfusion-dependent beta-thalassemia major has a serum ferritin of 4,200 ng/mL despite irregular chelation therapy. Which endocrine peptide hormone, secreted by erythroblasts during massive ineffective erythropoiesis, directly suppresses hepatic hepcidin production and drives pathological hyperabsorption of dietary iron?

  1. Thrombopoietin (TPO)
  2. Erythroferrone (ERFE) Correct answer.
  3. Fibroblast growth factor-23 (FGF-23)
  4. Adiponectin

Explanation

During expanded, stress, or ineffective erythropoiesis (such as in beta-thalassemia), erythroblasts secrete high levels of erythroferrone (ERFE) in response to erythropoietin. ERFE acts directly on hepatocytes to suppress hepcidin transcription via inhibition of BMP/SMAD signaling, leading to unchecked ferroportin activity, hyperabsorption of dietary iron in the duodenum, and accelerated systemic iron overload even in non-transfused individuals.

Question 33Anemia, hemolysis and hemoglobinopathies

A 24-year-old male with beta-thalassemia major is treated with iron chelation therapy. His hematologist considers switching his regimen from subcutaneous deferoxamine to the oral chelator deferiprone. What specific, potentially life-threatening adverse drug reaction requires mandatory, regular absolute neutrophil count (ANC) monitoring in patients receiving deferiprone?

  1. Severe agranulocytosis / severe neutropenia (ANC < 0.5 x 10^9/L) Correct answer.
  2. Irreversible sensory sensorineural deafness and macular pigmentary retinopathy
  3. Acute tubular necrosis with massive Fanconi syndrome and renal glucosuria
  4. Fulminant hepatic necrosis associated with secondary copper accumulation

Explanation

Deferiprone is an oral bidentate iron chelator that is particularly effective at removing cardiac iron. However, its use carries a 1-2% risk of severe neutropenia and a 0.5% risk of life-threatening agranulocytosis (ANC < 0.5 x 10^9/L), requiring regular monitoring of the absolute neutrophil count (weekly to biweekly) throughout treatment.

Question 34Anemia, hemolysis and hemoglobinopathies

A 32-year-old male with non-transfusion-dependent beta-thalassemia (beta-thalassemia intermedia) presents with lower thoracic back pain and progressive lower extremity weakness. MRI reveals a lobulated, non-calcified, paraspinal posterior mediastinal mass compressing the spinal cord. Biopsy demonstrates active erythroid, myeloid, and megakaryocytic precursors. What is the diagnosis and appropriate management?

  1. Malignant paraspinal neuroblastoma requiring radical en bloc surgical resection
  2. Erythroid leukemia (FAB M6) requiring high-dose induction cytarabine and daunorubicin
  3. Multiple myeloma plasmacytoma requiring high-dose melphalan and autologous stem cell transplantation
  4. Extramedullary hematopoiesis pseudotumor, managed primarily with hypertransfusion therapy and/or low-dose local radiotherapy Correct answer.

Explanation

Patients with beta-thalassemia intermedia maintain baseline Hb 7-10 g/dL without regular transfusions, but severe chronic ineffective erythropoiesis and high erythropoietin drive massive extramedullary hematopoiesis (EMH). Paraspinal EMH pseudotumors can expand into the spinal canal causing cord compression. Primary management involves hypertransfusion therapy (to suppress endogenous Epo) and/or low-dose radiation therapy (hematopoietic tissue is exquisitely radiosensitive), reserving surgical decompression for refractory or emergency cases.

Question 35Anemia, hemolysis and hemoglobinopathies

A routine fetal ultrasound at 26 weeks of gestation shows generalized fetal subcutaneous edema, massive ascites, pleural effusions, cardiomegaly, and marked placentomegaly (hydrops fetalis). Genetic amniocentesis demonstrates deletion of all four alpha-globin genes (--/--). What is the molecular composition and pathophysiologic characteristic of the predominant hemoglobin present in this fetus?

  1. HbA2 (alpha-2 delta-2), which polymerizes in acidic environments to cause capillary occlusion
  2. HbS (alpha-2 beta-S-2), which forms helical crystalline fibers upon deoxygenation
  3. Hemoglobin Bart's (gamma-4 tetramers), which possesses an extremely high oxygen affinity and cannot release oxygen to fetal tissues, causing severe tissue hypoxia and high-output heart failure Correct answer.
  4. Hemoglobin Portland-1 (zeta-2 gamma-2), which undergoes massive intravascular auto-oxidation into toxic methemoglobin

Explanation

Homozygous alpha-0 thalassemia (--/--) causes complete absence of alpha-globin production. In the fetus, unpartnered gamma-globin chains assemble into stable homotetramers called Hemoglobin Bart's (gamma-4). Hb Bart's has an exceptionally high oxygen affinity (P50 around 12 mmHg; no Bohr effect or cooperativity) and fails to release oxygen to peripheral tissues, causing fatal intrauterine anoxia, hydrops fetalis, high-output cardiac failure, and fetal death in utero or shortly after birth.

Question 36Anemia, hemolysis and hemoglobinopathies

A 7-year-old child presents with mild microcytic hypochromic anemia (Hb 9.2 g/dL, MCV 62 fL) and splenomegaly. Supravital staining with brilliant cresyl blue of peripheral blood shows numerous erythrocytes with fine granular 'golf-ball' inclusions. Genetic testing confirms loss of three alpha-globin genes (--/-alpha). What is the molecular composition of these inclusion bodies?

  1. alpha-4 homotetramers (Hb Bart's) formed in the fetus
  2. beta-4 homotetramers (Hemoglobin H) that are unstable and precipitate upon oxidative stress Correct answer.
  3. delta-4 homotetramers that bind erythrocyte ankyrin
  4. gamma-4 homotetramers that form paracrystalline needles

Explanation

Hemoglobin H disease results from deletion or inactivation of three of the four alpha-globin genes (--/-alpha). The extreme excess of beta-globin chains during childhood and adult life leads to the formation of unstable beta-4 homotetramers (Hemoglobin H). HbH precipitates as erythrocytes age or under oxidative stress, forming intra-erythrocytic inclusion bodies with a characteristic 'golf-ball' appearance on brilliant cresyl blue supravital staining.

Question 37Anemia, hemolysis and hemoglobinopathies

Using conventional mature beta-globin-chain numbering, which listed codon and amino-acid substitution characterizes sickle hemoglobin?

  1. A point mutation at codon 6 (GAG to GTG) substituting hydrophobic valine for hydrophilic glutamic acid (p.Glu6Val) on the beta-globin chain surface Correct answer.
  2. A nonsense mutation at codon 39 introducing a premature stop codon in the beta-globin chain
  3. A point mutation at codon 6 (GAG to AAG) substituting basic lysine for glutamic acid (p.Glu6Lys)
  4. A frameshift deletion of two nucleotides in codon 8 causing truncated beta-globin chain synthesis

Explanation

Sickle hemoglobin (HbS) is caused by a single nucleotide substitution (c.20A>T, codon GAG to GTG) in the sixth codon of the beta-globin gene (HBB). This mutation substitutes a nonpolar, hydrophobic valine for a negatively charged, hydrophilic glutamic acid at position 6 (p.Glu6Val). Under deoxygenated conditions, this hydrophobic valine inserts into a complementary hydrophobic pocket on an adjacent deoxygenated beta-globin chain, initiating polymerisation.

Question 38Anemia, hemolysis and hemoglobinopathies

An 18-year-old male with homozygous sickle cell anemia (HbSS) presents to the emergency department with severe, unremitting bone pain in his femora and lumbar spine. Laboratory evaluation shows Hb 8.0 g/dL (baseline 8.2 g/dL), reticulocytes 11%, and white blood cell count 14 x 10^9/L. In addition to rapid, multimodal opioid analgesia and hydration, what is the primary pathophysiology precipitating this acute vaso-occlusive crisis (VOC)?

  1. Massive platelet aggregation mediated by anti-heparin/PF4 antibodies
  2. Acute splenic pooling of half the circulating red cell mass
  3. Paroxysmal intravascular complement activation cleaving CD59
  4. Entrapment of rigid deoxygenated sickle erythrocytes driven by adhesive interactions with activated vascular endothelial ligands (VCAM-1, selectins) and leukocytes Correct answer.

Explanation

Sickle vaso-occlusive crisis (VOC) is a complex multicellular adhesive event triggered by hypoxia, acidosis, dehydration, or infection. Deoxygenation causes HbS polymerisation and erythrocyte sickling. Simultaneously, endothelial activation upregulates adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin). Adherent reticulocytes, sickled erythrocytes, activated neutrophils, and platelets aggregate within the microcirculation, causing vascular obstruction, tissue ischemia, and severe pain.

Question 39Anemia, hemolysis and hemoglobinopathies

A 22-year-old female with sickle cell disease admitted for a painful crisis develops fever (38.9°C), pleuritic chest pain, tachypnea, and an acute drop in oxygen saturation from 98% to 88% on ambient air. Chest radiography demonstrates a new dense consolidation in the right lower lobe. What is the diagnosis, and what emergent intervention is indicated for rapidly progressive hypoxemia?

  1. Pulmonary embolism; immediate systemic thrombolysis with recombinant tPA
  2. Hospital-acquired bacterial pneumonia; monotherapy with oral macrolides and fluid restriction
  3. Acute Chest Syndrome (ACS); immediate respiratory support, broad-spectrum antibiotics, and emergent red blood cell transfusion (simple or exchange) Correct answer.
  4. Transfusion-related acute lung injury; high-dose methylprednisolone and emergent plasma exchange

Explanation

Acute Chest Syndrome (ACS) is defined by a new pulmonary infiltrate on chest radiography combined with at least one new symptom/sign (fever, chest pain, tachypnea, hypoxemia, or cough). ACS is the leading cause of premature death in sickle cell disease. Initial management includes supplemental oxygen, empiric broad-spectrum antibiotics covering typical and atypical pathogens, multimodal analgesia, and prompt simple or automated exchange red blood cell transfusion for progressive hypoxemia (SpO2 < 90%) or multi-lobar disease.

Question 40Anemia, hemolysis and hemoglobinopathies

A 15-year-old male with HbSS experiences frequent vaso-occlusive crises and is initiated on oral hydroxyurea (hydroxycarbamide). What is the primary therapeutic mechanism through which hydroxyurea reduces the frequency of acute sickle crises and acute chest syndrome?

  1. Selective covalent alkylation of the beta-globin promoter to silence sickle hemoglobin
  2. Induction of fetal hemoglobin (HbF) synthesis via ribonucleotide reductase inhibition and soluble guanylyl cyclase activation, thereby diluting HbS and inhibiting polymerization Correct answer.
  3. Chelation of intra-erythrocytic calcium to block Gardos channel activation
  4. Neutralization of circulating P-selectin via monoclonal antibody binding

Explanation

Increasing fetal hemoglobin is a major beneficial effect of hydroxyurea in sickle cell disease because HbF reduces HbS polymerization. The drug also has other cellular effects, and its mechanism is not exhausted by one signaling pathway. Clinical use requires appropriate monitoring and does not eliminate every vaso-occlusive or infectious complication.

Question 41Anemia, hemolysis and hemoglobinopathies

A 12-year-old boy with HbSS presents with acute right-sided hemiparesis and expressive aphasia. Neuroimaging confirms an acute ischemic stroke in the middle cerebral artery territory. What is the immediate goal of emergency automated red blood cell exchange transfusion (erythrocytapheresis) in this acute setting?

  1. Rapidly reduce sickle hemoglobin (HbS) to less than 30% while maintaining total hemoglobin around 10 g/dL to avoid hyperviscosity Correct answer.
  2. Increase total hemoglobin to greater than 14 g/dL to maximize oxygen delivery regardless of HbS percentage
  3. Deplete circulating platelets to less than 50 x 10^9/L to inhibit ongoing arterial thrombosis
  4. Elevate serum ferritin above 1,000 ng/mL to promote endothelial cytoprotection

Explanation

In acute ischemic stroke or life-threatening acute chest syndrome in sickle cell anemia, emergency automated red blood cell exchange transfusion is the standard of care. The therapeutic goal is to rapidly reduce the HbS concentration to less than 30% without raising the total hemoglobin above 10.0 to 10.5 g/dL. Exceeding a total Hb of 10-11 g/dL markedly increases whole blood viscosity in the presence of circulating sickle cells, precipitating secondary vaso-occlusive and cerebrovascular complications.

Question 42Anemia, hemolysis and hemoglobinopathies

A 19-year-old male is evaluated for chronic microcytic hemolytic anemia and intermittent vaso-occlusive bone pain. High-performance liquid chromatography (HPLC) demonstrates: HbS 84%, HbF 12%, HbA2 4.0%, and complete absence of HbA (0%). Both parents are carriers: the mother has sickle cell trait (HbAS), while the father has beta-thalassemia trait (elevated HbA2 5.5%). What is the definitive diagnosis?

  1. Sickle cell trait (HbAS)
  2. Hemoglobin SC disease (HbSC)
  3. Sickle-beta-plus thalassemia (HbS/beta+ thalassemia)
  4. Sickle-beta-zero thalassemia (HbS/beta-0 thalassemia) Correct answer.

Explanation

Compound heterozygosity for the sickle mutation and a beta-0 thalassemia mutation (HbS/beta-0) results in complete failure to produce normal beta chains from the thalassemic allele. Consequently, HbA is 0% on HPLC, mimicking homozygous HbSS, but differentiated by marked microcytosis (low MCV/MCH), elevated HbA2 (>3.5-4.0%), and one parent having beta-thalassemia trait. In contrast, HbS/beta+ thalassemia retains some normal beta-chain synthesis, exhibiting 5% to 30% HbA.

Question 43Anemia, hemolysis and hemoglobinopathies

A 38-year-old female presents with severe fatigue, scleral jaundice, and exertional dyspnea. Hemoglobin is 6.2 g/dL, reticulocytes 14%, LDH 890 U/L, and indirect bilirubin 3.8 mg/dL. Peripheral blood smear shows abundant microspherocytes and polychromasia. Direct Antiglobulin Test (DAT) is strongly positive for IgG (3+) and negative for C3d. What is the most likely diagnosis?

  1. Cold agglutinin disease
  2. Paroxysmal nocturnal hemoglobinuria
  3. Warm autoimmune hemolytic anemia (wAIHA) Correct answer.
  4. Hereditary spherocytosis

Explanation

Warm autoimmune hemolytic anemia (wAIHA) accounts for 70-80% of autoimmune hemolytic anemias. It is mediated by warm-reactive polyclonal IgG autoantibodies (optimally reactive at 37°C, often directed against Rh core epitopes). Sensitized erythrocytes undergo partial phagocytosis of their lipid membrane by splenic macrophages expressing Fc-gamma receptors, converting biconcave red cells into rigid microspherocytes with a positive IgG DAT.

Question 44Anemia, hemolysis and hemoglobinopathies

A 44-year-old female is diagnosed with idiopathic warm autoimmune hemolytic anemia (wAIHA) with symptomatic anemia (Hb 6.8 g/dL). What is the established first-line medical therapy to induce remission in this condition?

  1. Intravenous eculizumab (anti-C5 monoclonal antibody)
  2. Oral corticosteroids (prednisone 1.0 to 1.5 mg/kg/day) Correct answer.
  3. Urgent emergent splenectomy within 48 hours of presentation
  4. Subcutaneous recombinant erythropoietin plus oral iron supplementation

Explanation

Systemic corticosteroids (oral prednisone at 1.0-1.5 mg/kg/day or IV methylprednisolone for severe acute presentations) represent the standard first-line therapy for warm AIHA, inducing responses in approximately 70-80% of patients. Corticosteroids act by downregulating splenic macrophage Fc-gamma receptors, decreasing autoantibody affinity, and reducing autoantibody production by B cells over several weeks.

Question 45Anemia, hemolysis and hemoglobinopathies

A 72-year-old male presents with painful acrocyanosis of his earlobes and fingers triggered by cold weather. Automated CBC cannot be processed at room temperature due to erythrocyte clumping, but warms up cleanly at 37°C showing Hb 8.4 g/dL. DAT is positive for C3d and negative for IgG. Monoclonal IgM-kappa is detected on serum protein electrophoresis. What is the mechanism of red cell destruction in Cold Agglutinin Disease (CAD)?

  1. Monoclonal IgM binds red cell I/i antigens in cooler peripheral circulation, fixing C1q and depositing C3b; upon warming, IgM dissociates, and C3b-opsonized red cells are cleared extravascularly by hepatic Kupffer cells via CR1/CR3 receptors Correct answer.
  2. Polyclonal IgG binds erythrocyte Rh antigens at 37°C, triggering splenic cord macrophage phagocytosis via Fc-gamma receptors
  3. Biphasic IgG autoantibodies bind the P antigen at cold temperatures and directly trigger perforin-mediated osmotic lysis in the pulmonary vein
  4. Monoclonal IgA antibodies form insoluble cryoglobulins that directly occlude large capacitance veins

Explanation

In Cold Agglutinin Disease (CAD), a clonal B-cell lymphoproliferative disorder secretes monoclonal IgM (usually with kappa light chains) that binds carbohydrate I/i antigens on red cells at lower temperatures (0-20°C in acral circulation). Pentameric IgM activates C1q, depositing C3b on the red cell membrane. When blood warms to 37°C in the core, IgM detaches, but C3b remains bound; the C3b-sensitized erythrocytes are recognized and cleared primarily by Kupffer cells in the liver via complement receptors (CR1, CR3).

Question 46Anemia, hemolysis and hemoglobinopathies

A 6-year-old boy develops sudden gross dark-brown hemoglobinuria, chills, and severe back pain 10 days after an uncomplicated upper respiratory tract infection. The Donath-Landsteiner test is positive. What are the immunologic characteristics of the autoantibody responsible for Paroxysmal Cold Hemoglobinuria (PCH)?

  1. Monoclonal IgM antibody directed against the I antigen that fixes complement at 37°C
  2. Polyclonal IgE autoantibody directed against glycophorin A causing mast cell degranulation
  3. Secretory IgA autoantibody directed against band 3 that activates the alternative complement pathway
  4. Biphasic polyclonal IgG autoantibody with anti-P specificity that binds erythrocytes in cold peripheral capillaries and fixes early complement components, then causes MAC-mediated intravascular lysis upon warming to 37°C Correct answer.

Explanation

Paroxysmal Cold Hemoglobinuria (PCH) is caused by the Donath-Landsteiner autoantibody: a biphasic polyclonal IgG antibody directed against the P antigen (globoside) on erythrocytes. In cool extremities (temperatures < 20°C), the IgG antibody binds to red cells and fixes C1, C4, and C2. As the sensitized cells circulate back to core body temperature (37°C), the antibody can elute off, but the complement cascade proceeds to full assembly of the membrane attack complex (C5b-9), causing acute intravascular hemolysis and massive hemoglobinuria.

Question 47Anemia, hemolysis and hemoglobinopathies

Which listed acquired molecular defect explains loss of relevant GPI-linked surface proteins in a classic PNH clone, without by itself explaining every selective process driving expansion?

  1. Germline loss-of-function mutation in the complement factor H (CFH) gene on chromosome 1
  2. Gain-of-function point mutation in the JAK2 gene (V617F) in hematopoietic stem cells
  3. Acquired somatic loss-of-function mutation in the X-linked PIGA gene in a hematopoietic stem cell, disrupting the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor Correct answer.
  4. Clonal translocation t(9;22)(q34;q11) generating a constitutively active BCR-ABL1 kinase

Explanation

Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by somatic loss-of-function mutations in the PIGA gene located on the X chromosome. Because PIGA encodes an essential catalytic subunit of the enzyme that synthesizes the glycosylphosphatidylinositol (GPI) anchor, mutated stem cells cannot attach GPI-anchored proteins to the cell surface, leading to complete or partial absence of complement regulators CD55 (decay-accelerating factor) and CD59 (membrane attack complex inhibitor).

Question 48Anemia, hemolysis and hemoglobinopathies

What is the gold-standard diagnostic assay for confirming Paroxysmal Nocturnal Hemoglobinuria (PNH) and quantifying clone size in peripheral blood?

  1. Acidified serum test (Ham test) measuring erythrocyte optical density after acid addition
  2. High-sensitivity multi-parameter flow cytometry using FLAER (fluorescently labeled aerolysin) and antibodies against GPI-linked markers (e.g., CD157, CD24, CD59) on granulocytes and monocytes Correct answer.
  3. Direct Antiglobulin Test (DAT) using monospecific anti-C3d and anti-IgG
  4. Sucrose hemolysis test (sugar water test) evaluating turbidity in low ionic strength media

Explanation

High-sensitivity multi-parameter flow cytometry is the gold standard for PNH diagnosis. It utilizes FLAER (fluorescent aerolysin, which binds specifically and directly to the core of the GPI anchor) in combination with monoclonal antibodies against GPI-linked markers (such as CD157, CD24, CD14, and CD59) on granulocytes and monocytes. Testing white cells is critical because red cells may be cleared by hemolysis or masked by recent blood transfusions.

Question 49Anemia, hemolysis and hemoglobinopathies

A 26-year-old Egyptian male presents with acute dark urine, scleral icterus, and fatigue 36 hours after ingesting fava beans. Hemoglobin is 7.5 g/dL (normal 14.5 g/dL), serum LDH is 1,450 U/L, and peripheral blood smear reveals bite cells ('degmacytes') and blister cells. What is the fundamental enzymatic vulnerability in Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency during oxidative stress?

  1. Inability to generate NADPH via the pentose phosphate pathway, leading to failure to regenerate reduced glutathione (GSH) to detoxify reactive oxygen species, causing hemoglobin oxidation into Heinz bodies Correct answer.
  2. Deficiency of pyruvate kinase resulting in catastrophic depletion of ATP and failure of the Na+/K+-ATPase pump
  3. Complete absence of methemoglobin reductase, causing irreversible conversion of ferric to ferrous iron
  4. Inactivation of catalase, leading to direct peroxidation of band 3 cytoskeletal attachments

Explanation

Erythrocytes lack mitochondria and rely solely on the hexose monophosphate (pentose phosphate) shunt and G6PD to reduce NADP+ to NADPH. NADPH is the essential cofactor for glutathione reductase to convert oxidized glutathione (GSSG) back into reduced glutathione (GSH). GSH detoxifies hydrogen peroxide and free radicals generated by oxidants (such as vicine and convicine in fava beans). Without G6PD, NADPH is depleted, GSH cannot be regenerated, and sulfhydryl groups on hemoglobin oxidize, precipitating as insoluble Heinz bodies.

Question 50Anemia, hemolysis and hemoglobinopathies

In an adult male presenting with acute hemolytic crisis secondary to G6PD deficiency, why is testing of erythrocyte G6PD enzymatic activity frequently falsely normal during the acute hemolytic episode?

  1. Circulating free hemoglobin enzymatically mimics G6PD in spectrophotometric assays
  2. Hepatic compensatory release of soluble G6PD into serum masks intra-erythrocytic deficiency
  3. High circulating reticulocyte count is suppressed by bone marrow exhaustion
  4. Older, enzyme-deficient erythrocytes have already hemolyzed, leaving predominantly young erythrocytes and reticulocytes with higher residual G6PD activity Correct answer.

Explanation

In G6PD-deficient erythrocytes, G6PD enzyme stability is diminished, and its activity decays exponentially as erythrocytes age. During an acute hemolytic crisis, the oldest erythrocytes (with the lowest G6PD activity) undergo oxidative lysis first and are cleared. The surviving red cell population is enriched with newly released, younger erythrocytes and reticulocytes that retain relatively higher G6PD enzyme levels, yielding a falsely normal enzymatic assay; definitive testing should be performed 2 to 3 months after the hemolytic episode resolves.