UWorld Anemia

A 37-year-old man comes to the emergency department due to blood-tinged vomiting and abdominal discomfort. Six months ago, he lost his job as an investment banker and began drinking large amounts of whiskey on a daily basis. He has since been hospitalized several times with alcohol intoxication. His temperature is 36.7 C (98 F), blood pressure is 110/70 mm Hg, pulse is 84/min, and respirations are 18/min. Physical examination shows a firm, enlarged liver. Peripheral blood smear results show neutrophils with 6-8 nuclear lobes. Which of the following is the most likely explanation for this patient's abnormal hematologic findings? Blood lipid abnormality Chronic blood loss Cobalamin deficiency Folate deficiency Myelodysplasia

Alcohol use disorder is one of the most common causes of folate deficiency anemia due to poor dietary intake and impaired folate absorption, utilization, and enterohepatic recycling. A normal individual with a folate-deficient diet can maintain normal red blood cell (RBC) production for months due to folate recycling, whereas a patient who consumes large amounts of alcohol will experience anemia within a few weeks. A reduced form of folic acid, tetrahydrofolic acid, is necessary for the synthesis of amino acids, thymidine, and purines. Impaired nucleotide synthesis leads to defective DNA production in blood cell precursors, resulting in abnormal cell division and megaloblastic hyperplasia of the bone marrow. The peripheral blood smear shows pancytopenia and hypersegmented neutrophils containing nuclei with >5 lobes. RBC abnormalities include ovalocytosis and macrocytosis, with a mean corpuscular volume (MCV) >100 µm3. (Choice A) Lipid abnormalities such as extreme hypertriglyceridemia can cause acute pancreatitis. (Choice B) Chronic blood loss causes iron deficiency anemia, which is not characterized by hypersegmented neutrophils. (Choice C) Chronic alcohol use can deplete vitamin B12 levels; however, depletion would take place over a period of years, not weeks (in contrast to folate deficiency). In addition, this patient does not have any of the classic neurologic symptoms that accompany B12 deficiency (eg, subacute combined degeneration). (Choice E) Myelodysplasia is a premalignant condition that manifests with pancytopenia, impaired blood cell differentiation, and clonal expansion of mutated hematopoietic cells in the bone marrow. Elevated MCV can be present, but hypersegmented neutrophils are not commonly seen. Educational objective: Folic acid deficiency anemia commonly occurs in alcoholism. It is a megaloblastic anemia that can develop within weeks. Peripheral blood smear shows macrocytosis, ovalocytosis, and neutrophils with hypersegmented nuclei.

A 60-year-old African-American female is evaluated for fatigue. Past surgical history includes mitral valve repair with a mechanical valve due to severe mitral insufficiency. She has 30-pack year history of smoking and occasionally drinks alcohol. Examination shows pallor. Laboratory studies show the following: Complete blood count Hemoglobin 9.0g/L Reticulocytes 6.8% Platelets 218,000/mm3 Leukocyte count 4,500/mm3 Serum chemistries are within normal limits. Her peripheral smear shows red blood cell fragments, "burr cells," and "helmet cells". Which of the following is the most likely cause of her condition? Microvascular thrombi Cytoskeleton abnormality Impaired DNA synthesis Gastrointestinal blood loss Mutation in beta globin chain Complement-mediated hemolysis Mechanical trauma

All of the choices represent mechanisms for anemia. The key to answering this question is this patient's history and peripheral smear. Red blood cell fragments, burr cells and helmet cells are consistent with traumatic hemolysis, which can result from either microangiopathic hemolytic anemia or mechanical damage (e.g. prosthetic valve). Prosthetic valves produce excessive shear and turbulence in the cardiac circulation, causing mechanical trauma to the RBCs. Burr cells are erythrocytes with short, evenly-spaced projections. They can occur as an artifact or in association with uremia, pyruvate kinase deficiency, microangiopathic hemolytic anemia, or mechanical damage. (Choice A) Microvascular thrombi are the pathophysiologic mechanism for microangiopathic hemolytic anemia, which causes thrombocytopenia. In this patient, platelet count is normal. (Choice B) Cytoskeleton abnormalities describe an intracorpuscular defect characteristic of a group of anemias that includes hereditary spherocytosis, hereditary elliptocytosis, and hereditary stomatocytosis. Respectively, spherocytes, elliptocytes, or stomatocytes are characteristically seen in the peripheral blood smear. (Choice C) Impaired DNA synthesis is the pathophysiologic mechanism for megaloblastic anemia. Ovalo-macrocytes are the associated morphologic RBC variant seen in this group of anemia. In addition, hypersegmented neutrophils are also characteristic. (Choice D) Gastrointestinal blood loss results in hypochromic, microcytic anemia due to iron deficiency. (Choice E) Mutation of the beta globin chain results in beta thalassemia; target cells are the RBC morphologic variant commonly seen. (Choice F) Paroxysmal nocturnal hemoglobinuria is an episodic hemolysis caused by a complement-mediated mechanism. Leukopenia and thrombocytopenia (pancytopenia) are commonly associated. Educational Objective: Red blood cell fragments, burr cells, and helmet cells are associated with either microangiopathic hemolytic anemia or mechanical red cell destruction. In patients with prosthetic valves, red blood cells are exposed to excessive shear and turbulence in the circulation, causing damage from mechanical trauma.

A 24-year-old man comes to the clinic due to 2 weeks of progressive generalized weakness. He has also had significant bruising on his trunk that developed spontaneously without trauma. The patient has no known medical conditions and takes no medications. Temperature is 37.1 C (98.8 F), pulse is 120/min, and respirations are 20/min. Conjunctival pallor is present. Cardiac examination reveals mild sinus tachycardia with no murmurs. Skin examination shows truncal ecchymoses but is otherwise normal. Laboratory results reveal a hemoglobin of 6.8 g/dL and a normal creatinine. Bone marrow aspiration is grossly pale and histologically appears diluted due to high lipid content. Which of the following laboratory patterns is most likely present in this patient? EPO Reticulocytes MCV Haptoglobin up up normal low up down normal normal up down down high down up down low down down normal normal

Answer is B This patient with a low hemoglobin level has several symptoms of anemia, including generalized weakness, tachycardia, and conjunctival pallor. The presence of spontaneous bruising in the absence of trauma likely indicates thrombocytopenia. Bone marrow aspirate reveals an abundance of lipids instead of cells, which is usually seen with bone marrow aplasia or hypoplasia. This constellation of findings is highly suggestive of aplastic anemia (AA). AA is a form of bone marrow failure primarily caused by cytotoxic T-cell destruction of multipotent hematologic stem cells. Because multipotent stem cells produce all mature blood cells, patients usually develop pancytopenia (not just anemia as the name suggests) and have manifestations of anemia, thrombocytopenia, and/or leukopenia (eg, infections). As with most forms of anemia, anemia-induced tissue hypoxia stimulates interstitial cells in the kidney to increase the release of erythropoietin. However, in AA, erythropoietin is unable to stimulate significant new red blood cell production due to the reduced population of functioning hematologic stem cells; therefore, reticulocytes are inappropriately low. Because the blood cells produced by the remaining undamaged hematopoietic stem cells are normal in morphology, erythrocytes are normal in size and appearance; therefore, mean corpuscular volume is normal. Because there is no intravascular hemolysis, haptoglobin (binds free hemoglobin in the blood) is also normal. Educational objective: Aplastic anemia (AA) is a form of bone marrow failure associated with pancytopenia and bone marrow aplasia/hypoplasia. Although erythropoietin levels are high, reticulocytes remain low because the production of new erythrocytes is impaired by a paucity of bone marrow stem cells. However, the blood cells produced by the remaining stem cells are normal in morphology and red cell indexes (eg, mean corpuscular volume) are usually normal.

A 70-year-old female presents to your office complaining of easy fatigability, exertional dyspnea and weight loss. She also complains of frequent falls. Physical examination reveals symmetrically decreased vibratory sensation to the lower extremities. Her hemoglobin is 7.8 g/dL and a peripheral blood smear shows hypersegmented neutrophils. Which of the following is the best treatment for this patient? Iron preparations Vitamin B12 Pyridoxine Vitamin C Folic acid Erythropoietin Filgrastim Interleukin-2 Antithymocyte globulin

Deficiencies of folic acid and vitamin B12 are the most important causes of megaloblastic anemia. Both of these vitamins are required for DNA synthesis in erythropoiesis. When there is a deficiency of either of these vitamins, cell division is delayed, though the cytoplasm develops normally. Thus, the cells enlarge (megaloblasts) but do not divide. The bone marrow is hypercellular in megaloblastic anemia, but the megaloblastic erythroid precursor cells are rapidly destroyed in the bone marrow and few differentiated large RBCs are released into the circulation. In severe megaloblastic anemia, 90% of erythroid precursors are destroyed without ever entering the circulation. Vitamin B12 and folic acid deficiencies cause similar hematological pictures. However, neurological dysfunction is only seen in patients with vitamin B12 deficiency. This is because B12 deficiency also causes axonal demyelination and degeneration. In late disease, the neurological dysfunction may be irreversible. The main sites of neurological involvement include the peripheral nerves, spinal cord (posterior and lateral columns), and the cerebrum. Decreased vibratory and position sense are early signs of vitamin B12 deficiency. Patients experience ataxia and recurrent falls because of compromised proprioception. Importantly, neurologic abnormalities can occur in vitamin B12 deficiency in the absence of frank anemia. Treating megaloblastic anemia due to vitamin B12 deficiency with folate alone could worsen the neurological dysfunction. An RBC mean corpuscular volume (MCV) of more than 100 fL is suggestive of megaloblastic anemia. However, RBC macrocytosis can also occur in liver disease, hypothyroidism, and alcohol-induced liver disease. MCVs greater than 110 fL are typically seen only with vitamin B12 and folic acid anemias. On peripheral blood smear, there is macrocytosis (large RBCs), hypersegmented neutrophils, and large bizarrely shaped platelets. The presence of even a single neutrophil with more than 6 lobes should raise the suspicion of megaloblastic anemia. The medications listed in the other answer choices are not used for the treatment of megaloblastic anemia. Educational Objective: Vitamin B12 and folic acid deficiencies cause similar hematological pictures. However, neurological dysfunction is only seen in patients with vitamin B12 deficiency. If megaloblastic anemia due to vitamin B12 deficiency is mistakenly treated with folate alone, the neurologic dysfunction can worsen.

A researcher is studying the role of glucose metabolites in normal cellular function. A specific human cell type is incubated in glucose-rich media. Intracellular levels of glucose metabolizing enzymes, intermediate products, and generated ATP are measured. In these cells, glycolysis of a single glucose molecule always yields pyruvate but sometimes generates no net ATP. Which of the following cells is most likely being studied in this experiment? Adipocytes Erythrocytes Hepatocytes Neurons Skeletal muscle cells

Erythrocytes use glycolysis as the major pathway to generate energy as they do not have mitochondria and therefore cannot use the citric acid cycle. During normal glycolysis, ATP is generated when 1,3-BPG is converted to 3-phosphoglycerate by the enzyme phosphoglycerate kinase. However, erythrocytes can bypass this part of the pathway using bisphosphoglycerate mutase, an enzyme that converts 1,3-BPG to 2,3-BPG in a step that produces no ATP. 2,3-BPG is subsequently catabolized to 3-phosphoglycerate by bisphosphoglycerate phosphatase in a step that also yields no ATP. By generating 2,3-BPG rather than proceeding with regular glycolysis, erythrocytes sacrifice the net ATP gain achieved in normal glycolysis. The major function of erythrocytes is to carry hemoglobin-bound oxygen from the lungs to the peripheral tissues, and 2,3-BPG is a very important regulator of oxygen-hemoglobin binding. The conversion of 1,3-BPG to 2,3-BPG is increased in hypoxia and chronic anemia. 2,3-BPG allosterically decreases hemoglobin's affinity for oxygen. As a result, in the presence of lower blood oxygen concentrations, higher 2,3-BPG levels within erythrocytes enable increased oxygen delivery in the peripheral tissues. (Choices A, C, D, and E) The enzyme bisphosphoglycerate mutase is present in large amounts in erythrocytes. However, it is present in insignificant quantities in adipocytes, hepatocytes, neurons, and myocytes; this causes virtually negligible 2,3-BPG production in these cell types. Educational objective: 2,3-BPG decreases hemoglobin's affinity for oxygen. Therefore, in the presence of lower blood oxygen concentrations, higher 2,3-BPG levels within erythrocytes enable increased oxygen delivery in the peripheral tissues. 2,3-BPG is produced from 1,3-BPG by the enzyme bisphosphoglycerate mutase. This reaction bypasses an ATP-generating step of glycolysis, causing no net gain in ATP.

A 59-year-old woman comes to the office due to progressive fatigue and occasional heart palpitations over the last 6 months. The patient has been under a lot of stress recently due to problems at work. She has no dietary restrictions, eats out at restaurants frequently, and drinks 2 or 3 cans of beer on the weekends. The patient is postmenopausal and has not noticed any uterine bleeding, dark stools, or bleeding with bowel movements. Her BMI is 25 kg/m2. Hemoglobin is 8.5 g/dL. Peripheral blood smear reveals pale, microcytic erythrocytes. Which of the following is the most likely underlying cause of this patient's abnormal laboratory findings? Substance use disorder Hematologic malignancy Hemolysis Liver disease Occult blood loss Poor nutrition

Fatigue and heart palpitations are common manifestations of all forms of anemia. This patient's peripheral smear findings indicate hypochromic, microcytic anemia, which most often arises in the setting of iron deficiency. The primary, and most dangerous if overlooked, mechanism of iron deficiency is blood loss, and it should be excluded first. Women of childbearing age are commonly iron deficient due to menstruation. Men (especially over the age of 60) or postmenopausal women have no physiologic reason to be iron deficient and therefore should be evaluated for blood loss in the gastrointestinal (GI) tract (eg, due to malignancy). GI blood loss is often occult, so the lack of dark or bright red stools in this patient should not rule out GI hemorrhage. Iron studies (including ferritin) should be obtained, and the patient will likely require endoscopic evaluation. (Choice A) Ingestion of the more commonly abused drugs is not associated with microcytic anemia. (Choice B) Hematologic malignancies (eg, leukemia, lymphoma, multiple myeloma) tend to be associated with normochromic, normocytic anemia. The decrease in erythropoiesis seen in these patients results from hypersplenism or tumor replacement of bone marrow mass. (Choice C) Hemolysis often presents with a normochromic, normocytic anemia. Spherocytes or schistocytes are often seen on peripheral blood smear. (Choice D) The anemia of chronic liver disease is usually normocytic or slightly macrocytic with target cells on the peripheral blood smear. Microcytic anemia occurs in <25% of cases, and most patients have only mild anemia with a hemoglobin level of 10-11 g/dL. (Choice F) This patient has a normal BMI and no factors predisposing her to malnutrition (eg, dietary restrictions, chronic alcohol use). A normal Western diet provides 6 mg of iron for every 1,000 calories, and the recommended intake for individuals age >50 is 8 mg per day. As a result, men and postmenopausal women (ie, not menstruating, pregnant, or lactating) usually have no dietary iron shortage. Educational objective: Hypochromic, microcytic anemia is most commonly due to iron deficiency. Blood loss, especially occult loss from the gastrointestinal tract, must be ruled out in a patient with iron deficiency anemia.

A 6-year-old African American boy is brought to the physician because of easy fatigability. Physical examination reveals splenomegaly, and his complete blood count shows mild anemia. Hemoglobin electrophoresis is performed at alkaline pH on a cellulose acetate strip. Findings for the patient are shown below compared to individuals with normal hemoglobin and known sickle cell disease. ID=1470 Cathode (-) Anode (+) Furthest to the anode I Normal Patient Near Anode, behind normal patient I Sickle Cell Disease Near patient, behind SCD I Patient Which of the following is the most likely cause of this patient's condition? Alpha globin gene deletion Missense mutation Nonsense mutation Silent mutation Trinucleotide expansion

Hemoglobin electrophoresis is used to assess for different forms of hemoglobin in patients with suspected hemoglobinopathy. Normal hemoglobin consists primarily of hemoglobin A (HbA), which migrates rapidly toward the positive electrode (anode) because of its negative charge. Hemoglobin S (HbS) is an abnormal type of hemoglobin in which a nonpolar amino acid (valine) replaces a negatively charged amino acid (glutamate) in the beta globin chain. This amino acid replacement decreases the negative charge on the HbS molecule, which causes HbS to move more slowly toward the anode. Similarly, hemoglobin C (HbC) has a glutamate residue replaced by lysine in the beta globin chain. Because lysine is a positively charged amino acid, HbC has even less total negative charge than HbS and moves even more slowly toward the anode. Both HbC and HbS result from missense mutations, a type of mutation in which a single base substitution results in a codon that codes for a different amino acid. Patients with sickle cell disease have HbS mutations in both beta chains; those with HbC disease have HbC mutations involving both beta chains. Patients with hemoglobin SC disease have 1 HbS allele and 1 HbC allele and will have 2 hemoglobin bands on electrophoresis. This patient's electrophoresis results show a single band that migrates less than the HbA and HbS bands, meaning that he has HbC disease. Patients with HbC disease are typically asymptomatic and often have mild hemolytic anemia and splenomegaly. (Choice A) Deletions involving the alpha globin genes cause alpha thalassemia, which results in imbalanced beta chain production and formation of beta tetramers (hemoglobin H) that migrate further than HbA during electrophoresis. (Choice C) Nonsense mutations introduce a stop codon within gene sequences, resulting in the formation of truncated proteins. As a result of their decreased size, these proteins tend to move further during electrophoresis. (Choice D) Silent mutations are point mutations that have no effect on the protein formed. A mutation from UCA to UCC does not result in any change in protein structure as both codons result in the placement of serine into the growing polypeptide chain. (Choice E) Trinucleotide expansions increase the number of trinucleotide repeats within a gene, resulting in large, unstable proteins or alterations in the epigenetic effects. These proteins would tend to move less during electrophoresis due to their increased size. However, the hemoglobinopathies are not caused by trinucleotide expansions, as the hemoglobin genes do not contain trinucleotide repeat regions. Educational objective: Hemoglobin C is caused by a missense mutation that results in a glutamate residue being substituted by lysine in the beta globin chain. This results in an overall decrease in negative charge for the hemoglobin molecule. The speed of hemoglobin movement during gel electrophoresis is hemoglobin A > hemoglobin S > hemoglobin C.

A 9-year-old boy with beta-thalassemia major is brought to the office for a routine red blood cell transfusion. He was diagnosed at age 6 months and has since received numerous blood transfusions. The patient has tolerated each transfusion well with no immediate reactions. Vital signs are normal. On physical examination, the patient has mild frontal bossing, hepatosplenomegaly, and jaundice. A recent liver biopsy showed Kupffer cells containing coarse, yellow-brown cytoplasmic granules. The granules are most likely composed of which of the following? Amyloid Bilirubin Copper Glycogen Glycolipid Hemosiderin Lipofuscin

Patients with chronic hemolytic anemia (eg, beta-thalassemia major) depend on recurrent red blood cell (RBC) transfusions to maintain an adequate hemoglobin level. Iron overload (hemosiderosis) from increased iron absorption is a common complication resulting from both the primary condition (due to ineffective erythropoiesis) and its treatment (frequent RBC transfusions). Circulating iron is carried by transferrin. Once deposited in cells, iron binds to apoferritin to form ferritin micelles. Because iron is used poorly in patients with thalassemia and cannot be excreted actively, the ferritin micelles accumulate in macrophages of the reticuloendothelial system. When ferritin accumulates intracellularly, it is degraded into an iron-storage complex is known as hemosiderin. Hemosiderin iron stores mobilize slowly, and microscopically appear as brown or yellow-brown pigments in either granular or crystalline form. Hemosiderin can be confirmed histologically with Prussian-blue staining. In the liver, hemosiderin is typically seen in Kupffer cells (hepatic macrophages that line the walls of the sinusoids and participate in RBC breakdown). Eventually, the iron burden will overwhelm the reticuloendothelial cells' capacity to sequester iron, resulting in parenchymal iron overload in the liver, myocardium, skin, and pancreas (eg, "bronze diabetes"). Patients receiving regular transfusions should undergo routine iron chelation therapy to reduce the overall iron load within the body and improve survival. (Choice A) Amyloid protein appears as an amorphous, pink, extracellular material that shows apple-green birefringence under polarized light after Congo red staining. Hepatic amyloid can be seen in primary (eg, multiple myeloma) or secondary (eg, chronic inflammation) amyloidosis. (Choice B) Bilirubin is the primary pigment found within bile, which has a brown, yellow, or green appearance microscopically. Accumulation in hepatocytes and canaliculi (ie, cholestasis) is associated with defects in bile production or flow (eg, duct obstruction). (Choice C) Copper accumulation is seen in Wilson disease, an autosomal recessive disease characterized by cirrhosis and neurologic complications. (Choice D) Glycogen appears as clear cytoplasmic vacuoles and stains pink-purple with the periodic acid-Schiff reaction. Glycogen is abundant in the liver shortly after a meal. (Choice E) Patients with Gaucher disease (glucocerebrosidase enzyme deficiency) have pancytopenia, hepatosplenomegaly, and pathologic fractures. Gaucher cells, macrophages laden with cerebrosides and other glycolipids, have a "wrinkled tissue paper" appearance microscopically. (Choice G) Lipofuscin is an insoluble yellow-brown pigment composed of lipids and phospholipids complexed with proteins. This pigment accumulates with age (ie, typically seen in adults) and is associated with cellular "wear and tear." Educational objective: Iron overload (hemosiderosis) is a common and serious complication of chronic hemolytic anemia and frequent blood transfusions. Accumulation of yellow-brown hemosiderin pigment is the cardinal histologic finding. Chelation therapy is indicated to reduce parenchymal iron deposition.

An 8-year-old boy is brought to the emergency department due to 24 hours of fever and chills. Temperature is 38.3 C (101 F). On examination, the patient is lethargic with dry mucous membranes. There are no oropharyngeal lesions, and tympanic membranes are normal. The lungs are clear on auscultation, and heart sounds are normal. The abdomen is soft and nontender. There is no skin rash. Laboratory testing shows a leukocyte count of 24,000/mm3 with 15% bands, 80% neutrophils, and 5% lymphocytes. Peripheral blood smear is shown in the exhibit. Blood cultures are obtained and intravenous fluids and empiric antibiotics are initiated. The patient's blood cultures are most likely to grow which of the following organisms? Escherichia coli Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Viridans streptococci

Patients with sickle cell anemia have mutations in the beta-globulin gene that cause hemoglobin to reversibly polymerize when deoxygenated, which leads to the formation of sickled-shaped erythrocytes that clog small capillaries and cause end-organ ischemia. The spleen is particularly vulnerable; repeated microinfarction of splenic vascular beds usually results in functional asplenia within the first 18-36 months of life. Because the spleen produces opsonizing antibodies that are important for clearing encapsulated bacteria from the blood, asplenia is associated with significant risk of fulminant bacterial infections. Streptococcus pneumoniae is the leading pathogen, but Neisseria meningitidis and Haemophilus influenzae are also frequently isolated. Therefore, patients with sickle cell anemia who present with signs/symptoms of infection (eg, fever, chills, leukocytosis) require urgent empiric antibiotic therapy that covers these pathogens. Vaccination (pneumococcal and Haemophilus influenzae type b) is recommended to reduce risk of future infection. (Choices A, B, C, E, and F) Patients with sickle cell anemia are at increased risk for overwhelming bacterial infections with a variety of pathogens. However, S pneumoniae infections are particularly common, accounting for 40%-60% of total bacterial infections in this population. Although Pseudomonas aeruginosa is encapsulated, it is not a common pathogen in patients with sickle cell disease (it occurs more often in those with cystic fibrosis, severe chronic obstructive pulmonary disease, and diabetes mellitus). Patients with sickle cell anemia are also particularly prone to salmonella osteomyelitis. Educational objective: Patients with sickle cell disease become functionally asplenic within the first few years of life due to repeated microinfarction of splenic vascular beds. This dramatically increases the risk for fulminant infections with encapsulated bacterial organisms, particularly Streptococcus pneumoniae. Patients with sickle cell disease are also at increased risk for other bacterial infections, most notably salmonella osteomyelitis.

A 53-year-old female treated with high-dose folic acid for anemia experiences a moderate increase in her hemoglobin level. She returns to clinic complaining of bilateral foot numbness and difficulty in walking. The latter symptoms are most likely related to which of the following? Folate overdose Iron deficiency Cobalamin deficiency Hemolysis Aplastic anemia

The clinical decision to treat this patient with folic acid suggests that her anemia was megaloblastic and therefore likely secondary to a deficiency in folate and/or vitamin B12 (cobalamin). Her subsequent development of neurological symptoms (a finding not associated with folate deficiency alone) indicates that she is deficient in vitamin B12. A moderate improvement in the hemoglobin level often occurs when a deficiency in vitamin B12 is treated with folate, or vice versa. However, the treatment of vitamin B12 deficiency with folate will not reverse any neurologic dysfunction caused by the vitamin B12 deficiency. In fact, the usage of folate alone can worsen demyelination and cause abnormal myelin synthesis by depleting the concentration of unmethylated cobalamin available for methylmalonyl-CoA processing. The walking difficulties and paresthesias seen in this patient were therefore likely precipitated by the administration of folate alone. (Choice A) High doses of folate may antagonize phenytoin, thereby precipitating seizures in a select group of patients. Walking difficulties and paresthesias are not typically associated with folate overdose, however. (Choice B) Iron deficiency is characterized by a hypochromic, microcytic anemia that is best treated with iron supplementation. Walking difficulties and paresthesias are not typically associated with iron deficiency anemia. (Choice D and E) Anemia of any cause can provoke nonspecific neurologic symptoms (eg, tinnitus, irritability, generalized weakness). Walking difficulties and paresthesias are not commonly associated with hemolysis or aplastic anemia, however. Educational Objective: Deficiency of vitamin B12 is associated with both megaloblastic anemia and neurologic dysfunction, while folate deficiency is associated with megaloblastic anemia alone. Moderate improvement in the hemoglobin level often occurs when a deficiency in vitamin B12 is treated with folate, or vice versa. Treatment of vitamin B12 deficiency with folate alone can actually worsen neurologic dysfunction.

A 4-year-old male dies in the hospital from overwhelming infection. Autopsy findings include bone deformities and hepatosplenomegaly. Clumps of erythroid precursor cells are found in the liver and the spleen. The presence of these precursor cells is most likely related to which of the following conditions? Frequent transfusions Immune deficiency Erythropoietin deficiency Chronic hemolysis Iron deficiency Cyanocobalamin deficiency Portal hypertension

The presence of erythroid precursor cells in the liver and spleen is indicative of extramedullary hematopoiesis, a condition characterized by erythropoietin-stimulated, hyperplastic marrow cell invasion of extramedullary organs. Extramedullary hematopoiesis is most frequently caused by severe chronic hemolytic anemias, such as β-thalassemia (which the child depicted here may well have had). Extramedullary hematopoiesis can cause a range of skeletal abnormalities. The expanding mass of progenitor cells in the bone marrow thins the bony cortex and impairs bone growth. Pathologic fractures are common in the most symptomatic of children. Maxillary overgrowth and frontal bossing are associated with the characteristic "chipmunk facies" observed in the pediatric population. (Choice A) Red blood cell transfusions limit extramedullary hematopoiesis by reducing hypoxia. (Choice B) Immune deficiencies are not frequently associated with red blood cell hemolysis. (Choice C) Erythropoietin deficiency is observed in patients with chronic renal disease and would be associated with anemia, not extramedullary hematopoiesis. (Choice E) Iron deficiency results in a relative depression of erythropoietic activity and is not associated with extramedullary hematopoiesis. (Choice F) Cyanocobalamin (vitamin B12) deficiency causes a megaloblastic anemia that is not associated with extramedullary hematopoiesis. (Choice G) Intrahepatic extramedullary hematopoiesis can cause portal hypertension, and portal hypertension can cause hepatosplenomegaly. The reverse is not true, however. Educational Objective: The presence of erythroid precursors in organs such as the liver and spleen is indicative of extramedullary hematopoiesis, a condition characterized by erythropoietin-stimulated, hyperplastic marrow cell invasion of extramedullary organs. Extramedullary hematopoiesis is most frequently caused by severe chronic hemolytic anemias, such as β-thalassemia.

An 18-month-old boy is brought to the office due to language regression. He said several words at his 1-year appointment but now no longer speaks any words at all. His moods have also become more unpredictable over the past 4 months with frequent tantrums. The parents tried to bring him in sooner for evaluation, but they live in an impoverished part of the city and experienced financial difficulties with transportation to the office. On physical examination, the boy is quiet and maintains appropriate eye contact throughout the visit. Hemoglobin is 9 g/dL. Which of the following enzymes is most likely inhibited in this patient? δ-Aminolevulinate dehydratase Bilirubin glucuronyl transferase Prophobilinogen deaminase Pyruvate kinase Uroporphyrinogen decarboxylase

This child's language regression and anemia are most likely due to lead poisoning. Lead toxicity is most prevalent among impoverished children residing in deteriorating urban housing built before 1978. Young children are particularly susceptible to lead poisoning via inhalation and ingestion of lead-based paint dust or chips due to normal crawling and mouthing behaviors. The incomplete blood-brain-barrier in children is vulnerable to the neurotoxic effects of lead, which include long-standing behavioral problems and developmental delay or regression. Anemia in lead poisoning results from inhibition of ferrochelatase and δ-aminolevulinic acid (ALA) dehydratase in the heme biosynthesis pathway. Because protoporphyrin IX cannot combine with iron (Fe2+) to form heme due to ferrochelatase inhibition, it instead incorporates a zinc ion, leading to elevated zinc protoporphyrin levels. In addition, ALA levels are increased. Lead poisoning also commonly coexists with iron deficiency anemia, and severe lead poisoning can also induce hemolytic anemia. (Choice B) Glucuronyl transferase (uridine 5'-diphospho-glucuronosyltransferase) is necessary for hepatic bilirubin conjugation. Gilbert syndrome, a condition marked by jaundice (elevated unconjugated bilirubin levels) during times of stress, results from mutations in the gene encoding glucuronyl transferase. (Choice C) Defects in porphobilinogen deaminase result in acute intermittent porphyria (AIP), a disorder characterized by acute attacks of abdominal pain, neuropsychiatric symptoms, and red or brown urine. The chronicity of symptoms, lack of abdominal pain, and anemia make AIP unlikely in this patient. (Choice D) Pyruvate kinase deficiency is typically inherited in an autosomal recessive pattern and leads to hemolytic anemia. Pyruvate kinase deficiency can present with pallor, scleral icterus, and splenomegaly, but it does not present with behavioral regression or language difficulties. (Choice E) Defects in uroporphyrinogen decarboxylase cause porphyria cutanea tarda (PCT), the most common form of porphyria. Patients with PCT exhibit chronic photosensitivity with blistering in areas of sun exposure and elevated levels of uroporphyrinogen in the urine. Educational objective: Young children who reside in homes built before 1978 are at significant risk for lead toxicity. Lead directly inhibits ferrochelatase and δ-aminolevulinic acid (ALA) dehydratase, resulting in anemia, ALA accumulation, and elevated zinc protoporphyrin levels. Neurotoxicity is also a significant long-term complication.

A 28-year-old man starts taking a prophylactic medication before leaving on a business trip to Costa Rica. Five days later, he comes to the emergency department due to jaundice and dark urine. Laboratory results are as follows: Hemoglobin 8.2 g/dL Reticulocytes 8% Total bilirubin 3.5 mg/dL Direct bilirubin 0.5 mg/dL Lactate dehydrogenase 342 U/L Haptoglobin 42 mg/dL (normal: 50-150) A peripheral smear shows red blood cells with dark inclusions when stained with crystal violet, a supravital stain. This patient's condition most likely demonstrates which of the following inheritance patterns? Autosomal dominant Autosomal recessive Mitochondrial X-linked dominant X-linked recessive

This patient developed acute hemolytic anemia (eg, jaundice, dark urine, low haptoglobin) after taking a new medication, suggesting glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD catalyzes production of NADPH in erythrocytes; loss of G6PD function limits regeneration of reduced glutathione, impairing the ability of erythrocytes to handle increased oxidative stress (eg, foods, medications). The trigger in this case was likely primaquine prescribed for malaria prophylaxis. Manifestations of G6PD deficiency typically begin within 2-5 days and often include pallor, dark urine, and jaundice. Laboratory evaluation reveals signs of erythrocyte lysis such as elevated bilirubin, elevated lactate dehydrogenase, and low haptoglobin (protein that binds free heme). The bone marrow responds by releasing young erythrocytes, leading to reticulocytosis. Peripheral smear will demonstrate signs of denatured hemoglobin precipitation such as intraerythrocytic dark inclusions (Heinz bodies). G6PD deficiency is an X-linked recessive disorder; males (46,XY) who carry the mutation are affected because all erythrocytes have the defective G6PD gene. Females (46,XX) who carry a copy of the defective gene (heterozygous) are usually unaffected because random inactivation of the X chromosome (lyonization) results in ~50% of erythrocytes with the normal gene. However, heterozygous females can develop acute hemolysis when lyonization is skewed toward expression of the mutated gene. (Choice A) Most structural erythrocyte abnormalities (eg, hereditary spherocytosis) are inherited in an autosomal dominant manner. Although jaundice from hemolysis can be seen, peripheral smear would not show Heinz bodies. (Choice B) In contrast to G6PD deficiency, most other erythrocyte enzyme deficiencies (eg, pyruvate kinase [PK] deficiency) are inherited in an autosomal recessive pattern. PK catalyzes the last step in glycolysis; because erythrocytes rely solely on glycolysis for ATP production (due to a lack of mitochondria), patients develop chronic (not episodic) hemolysis. (Choice C) Mitochondrial DNA is of maternal origin. Mitochondrial diseases generally limit cellular ATP generation due to impaired oxidative phosphorylation and often present with neuromuscular dysfunction. Heinz bodies would not be seen; in addition, hemolysis following medication exposure indicates likely G6PD deficiency. (Choice D) X-linked dominant disorders affect males and females equally. Nearly all cases of symptomatic G6PD deficiency occur in males, indicating an X-linked recessive inheritance pattern. Educational objective: Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder that causes acute hemolysis after exposure to oxidizing medications, foods, or acute infection. Nearly all affected persons are male, but heterozygous females can become symptomatic due to skewed lyonization.

The patient is admitted to the hospital and receives opioid analgesics and intravenous fluids. He has no evidence of active infection. His hemoglobin electrophoresis results are consistent with sickle cell disease (hemoglobin SS). Further laboratory evaluation shows a mean corpuscular volume of 113 µm3 and a reticulocyte index of 1.5, which is low given the patient's severe anemia. Which of the following is the most likely cause of this patient's macrocytosis? Extramedullary erythropoiesis Increased folic acid requirement Iron overload Liver disease Myelodysplastic syndrome

This patient has macrocytic anemia (mean corpuscular volume [MCV] >100 µm3). Severe macrocytosis (MCV >110 µm3) is usually due to megaloblastic anemia, a subtype of macrocytic anemia caused by impaired DNA synthesis. Cytoplasmic components then accumulate within the slowly dividing erythrocytes, producing cells that are larger than normal (macrocytes). Patients with sickle cell disease (SCD) or other hemolytic anemias have increased folic acid requirements due to increased erythrocyte turnover. As such, they are prone to developing relative folic acid deficiency and megaloblastic anemia. (Choice A) Extramedullary erythropoiesis can occur in SCD and lead to an elevated reticulocyte count and MCV, as the reticulocytes produced are larger than those released by the bone marrow. However, this patient's low reticulocyte index (representing the reticulocyte percentage corrected for the degree of anemia) suggests an inadequate response to anemia and a lack of erythropoiesis. (Choice C) Patients with SCD may receive multiple transfusions for treatment of severe or symptomatic anemia. Transfusion related iron overload can cause severe liver disease, but would be unlikely to produce an MCV >110 µm3. (Choice D) Macrocytosis can occur in liver failure due to an increase in circulating phospholipids and cholesterol that adsorb onto erythrocytes, resulting in membrane expansion. However, liver-associated macrocytosis is generally mild (<110 µm3) and this patient does not have any findings to suggest advanced liver disease (eg, ascities/edema, bleeding). (Choice E) A disease of the elderly, myelodysplastic syndrome can cause macrocytic anemia. In the setting of a young patient with SCD and hemolytic anemia, however, folic acid deficiency is much more likely. Educational objective: An MCV >110 µm3 is highly suggestive of megaloblastic anemia, such as that caused by folic acid or vitamin B12 deficiency. Patients with chronic hemolytic anemia have increased folic acid requirements due to increased erythrocyte turnover and are predisposed to developing macrocytosis.

A 45-year-old man comes to the office for evaluation of fatigue that has been gradually increasing over the past 4 months. The patient has had difficulty keeping up with the labor involved with his job as a construction worker. Over the past 2 weeks, he has been unable to climb past the second floor of the building his company is renovating. The patient also has increasing shortness of breath with minor activities, such as lifting his toolbox out of the car. Review of systems reveals constipation and decreased concentration. Physical examination shows an overweight male with conjunctival pallor who has difficulty getting onto the examination table due to shortness of breath. Laboratory test results are as follows: Complete blood count Hematocrit 26% Mean corpuscular volume 72 fL Ferritin 50 ng/mL (normal: 15-200 ng/mL) Iron studies Iron 120 µg/dL (normal: 60-160 µg/dL) Iron binding capacity 320 µg/dL (normal: 250-460 µg/dL) Which of the following findings would most likely be seen on this patient's peripheral blood smear? Basophilic stippling Heinz bodies Howell-Jolly bodies Ring siderbolasts Schistocytes

This patient has microcytic anemia, constipation, and mental status changes in the setting of construction work. The most likely diagnosis is lead poisoning. Lead is a soft, heavy metal used for manufacturing a wide range of items, including batteries, alloys, and ammunition. Individuals working in these industries and others (eg, construction, mining, smelting, chemical processing, recycling, spray painting, radiator repair) can be regularly exposed to lead. Lead inhibits the heme synthesis pathway (δ-aminolevulinate dehydratase and ferrochelatase), causing a microcytic, hypochromic anemia. Shortness of breath, particularly with exertion, occurs due to decreased oxygen delivery to peripheral tissues. Iron studies are normal unless co-existing iron deficiency is present as well. Basophilic stippling is frequently seen on peripheral blood smear. Inhibition of erythrocyte 5' nucleotidase by lead results in ribosome aggregation due to inability to degrade RNA, which is represented by coarse blue punctate dots in the cytoplasm of red blood cells (RBCs). Basophilic stippling is nonspecific and also seen in the thalassemias and myelodysplastic syndrome. Adult lead poisoning can also have the following manifestations: Bluish pigmentation ("lead line") at the gum-tooth line. Wrist drop or foot drop due to peripheral neuropathy. (Choice B) Heinz bodies are inclusions of denatured hemoglobin most commonly seen after oxidant stress in patients with glucose-6-phosphate dehydrogenase deficiency. (Choice C) Howell-Jolly bodies are nuclear DNA remnant inclusions in peripheral RBCs that are normally removed by the spleen during circulation. The presence of Howell-Jolly bodies indicates decreased or absent splenic function (eg, post-splenectomy). (Choice D) Ring sideroblasts are formed from precipitation of iron granules in developing erythrocytes due to defects in the heme synthesis pathway, including enzymatic inhibition induced by lead poisoning. Ring sideroblasts are seen in the bone marrow but not in the peripheral blood smear. (Choice E) Schistocytes are fragmented parts of RBCs formed from mechanical hemolysis via sheer force of blood flow. Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation all present with schistocytes. Educational objective: Lead poisoning in adults typically occurs through occupational exposure. Symptoms include colicky abdominal pain, constipation, lead lines on the gum, peripheral neuropathy, and anemia. Laboratory testing shows microcytic anemia with normal iron studies, and peripheral blood smear may reveal basophilic stippling.

A 6-year-old African American male is brought to your office for a routine check-up. His mother remarks that he often seems uninterested in playing with his peers and appears to "run out of breath quickly." His medical records reveal that he has missed several pediatric vaccinations and has been hospitalized twice, once with a "chest infection" and once with abdominal pain. The patient mentions to you that occasionally his "bones hurt." Which of the following protein changes most likely accounts for this patient's condition? Phenylalanine deletion Valine substitution for glutamic acid Phenylalanine substitution for proline Valine substitution for lysine Early termination of polypeptide synthesis

This patient is exhibiting signs and symptoms of sickle cell anemia. Sickle cell anemia is a hemoglobinopathy that typically affects patients of African ancestry. A point mutation in the 6th codon of the beta-globin gene, which causes the substitution of valine (hydrophobic) for glutamic acid (hydrophilic), is responsible. The incorporation of this abnormal beta-globin protein into hemoglobin results in the formation of hemoglobin S (HbS). HbS polymerizes at low oxygen tension, causing sickling and hemolysis of erythrocytes and resultant vascular occlusion. This patient's poor exercise tolerance and exertional dyspnea are due to anemia. His history of acute chest syndrome, abdominal pain, and bone pain are due to vaso-occlusive events in the lungs, spleen and bone, respectively. (Choice A) A phenylalanine deletion (ΔF508) is the most common cause of cystic fibrosis, the most common fatal genetic disease of Caucasians. (Choice E) Early termination of polypeptide synthesis (nonsense mutation) will produce a truncated protein. Educational Objective: Exertional dyspnea, pneumonia resulting in life-threatening acute chest syndrome, and recurrent abdominal and bone pain are clinical features of sickle cell anemia. Sickle cell anemia results from a point mutation that causes valine to substitute for glutamic acid in the sixth position of the b-globin chain of hemoglobin.

A 24-year-old man is evaluated for episodic anemia, jaundice, and dark urine. These episodes typically occur after the use of certain drugs or following infection. Additional history reveals that he has a brother who experiences similar episodes. Peripheral blood smear reveals red blood cells with the findings shown below. Bite Cells Deficiency of which of the following enzymes would most likely result in a condition similar to this patient's presentation? Bisphosphoglycerate mutase Glutathione reductase Hexokinase Pyruvate kinase Transketolase

This patient likely has glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder causing hemolytic anemia and jaundice in response to oxidant stressors (eg, sulfonamide & antimalarial drugs, infection). Heinz bodies (oxidized hemoglobin conglomerates) precipitate in red blood cells and are removed by splenic macrophages, leaving behind characteristic bite cells. G6PD is an enzyme of the pentose phosphate pathway. It generates the reducing agent NADPH, which is essential for detoxification of hydrogen peroxide produced by partial reduction of molecular oxygen in red blood cells. In the absence of NADPH, reduced glutathione (the molecule required for reduction of hydrogen peroxide to water) remains in an oxidized state, and red blood cells become susceptible to oxidative damage. Glutathione reductase catalyzes the reduction of oxidized glutathione. Its absence leads to an inability to use NADPH to reduce glutathione, resulting in a clinical scenario similar to G6PD deficiency. (Choice A) Bisphosphoglycerate mutase is an enzyme unique to red blood cells and placental cells. It catalyzes the production of 2,3-bisphosphoglycerate, a molecule that binds to hemoglobin and increases offloading of oxygen in the tissues. (Choices C and D) Deficiency of the glycolytic enzymes hexokinase and pyruvate kinase leads to hemolytic anemia due to lack of ATP generation. However, these conditions would not present with bite cells and the hemolysis is not associated with exposure to oxidant stressors. (Choice E) Transketolase, along with transaldolase, catalyzes the nonoxidative reactions of the pentose phosphate pathway, producing the ribose sugar necessary for nucleotide synthesis. The reducing equivalent NADPH is not generated in this portion of the pathway. Educational objective: Glucose 6-phosphate dehydrogenase deficiency causes hemolytic anemia and jaundice secondary to increased oxidative stress due to the lack of NADPH. Glutathione reductase deficiency has a similar clinical consequence as its absence results in an inability to utilize NADPH to reduce glutathione.

A 7-year-old boy is brought to the office due to easy bruising and frequent epistaxis for 2 weeks. Temperature is 36.7 C (98 F), blood pressure is 106/60 mm Hg, pulse is 94/min, and respirations are 18/min. Examination shows pale lips with mucositis in the oropharynx. The neck is supple. The abdomen is soft, and pulses are 2+. Laboratory results are as follows: Hemoglobin8.2 g/LPlatelets40,000/mm3Leukocytes2,100/mm3 Findings from a bone marrow biopsy are shown in the image below: Big white circles present Which of the following is the most likely diagnosis? Acute lymphoblastic leukemia Aplastic anemia Myelodysplastic syndrome Myelofibrosis Parvovirus B19 infection

This patient with pancytopenia has bone marrow biopsy findings consistent with aplastic anemia, a form of acquired bone marrow failure caused by direct toxic injury or cytotoxic T-cell destruction of multipotent hematopoietic stem cells. Because these stem cells generate all mature blood cells for the body, their destruction dramatically reduces mature and immature blood cell populations in the bone marrow. Therefore, bone marrow biopsy typically reveals a profoundly hypocellular marrow with abundant lipid cells and small clusters of morphologically normal hematopoietic cells. Although most cases of aplastic anemia are idiopathic, a minority are triggered by viruses (eg, Epstein-Barr, hepatitis), exposures (eg, toxic chemicals, radiation), or medications (eg, chemotherapy, antiseizure agents). Patients usually present with manifestations of pancytopenia such as pale lips (anemia), easy bruising/bleeding (thrombocytopenia), and infections (leukopenia) (eg, this patient's mucositis). In contrast to many other causes of pancytopenia, extramedullary hematopoiesis (eg, splenomegaly) is usually absent because stem cells are damaged and unable to generate cells in any organ. (Choice A) Acute lymphoblastic leukemia is the most common childhood malignancy. Although it can present with pancytopenia, most patients have lymphadenopathy and hepatosplenomegaly due to leukemic cell infiltration. In addition, bone marrow biopsy would show a hypercellular marrow with numerous lymphoblasts (immature lymphocytes). (Choice C) Myelodysplastic syndrome is a clonal hematopoietic neoplasm that crowds out the bone marrow, leading to pancytopenia. Bone marrow biopsy usually shows a hypercellular marrow with abnormally differentiated cells (eg, hypogranular neutrophils, erythroid precursors with misshapen nuclei). Most cases occur in patients age ≥65. (Choice D) Primary myelofibrosis is a myeloproliferative neoplasm that usually occurs in older adults. Patients may be cytopenic, but bone marrow biopsy would show marrow fibrosis; in addition, splenomegaly is usually prominent due to extramedullary hematopoiesis. (Choice E) Parvovirus B19 infects erythrocyte precursors and can cause an aplastic crisis in patients with preexisting hematologic disease (eg, sickle cell anemia, hereditary spherocytosis). Leukocytes and thrombocytes are not generally affected. Educational objective: Aplastic anemia is a form of bone marrow failure caused by direct toxic injury or cytotoxic T-cell destruction of multipotent hematologic stem cells, which leads to pancytopenia. Bone marrow examination will show profound hypocellularity, an abundance of fat cells, and small clusters of morphologically normal hematologic cells.

A 12-year-old boy is brought to the emergency room due to high fever, chest pains, and dyspnea. Medical history is significant for 2 prior hospitalizations for abdominal pain that resolved with analgesics and hydration. Evaluation today shows a hematocrit of 23% and reticulocyte count of 9%. Several hours after being admitted to the hospital, the patient dies. At autopsy, the spleen is small and firm. This patient's autopsy finding is most likely related to which of the following? Extramedullary hematopoiesis Follicular hyperplasia Lipid accumulation Pressure atrophy Vascular occlusion

This patient's hematologic findings (eg, anemia, reticulocytosis) and medical history (eg, recurrent episodes of abdominal pain that resolved with analgesics and hydration) are suggestive of sickle cell disease (SCD). SCD is a hemoglobinopathy characterized by sickle hemoglobin (HbS), an abnormal hemoglobin that can polymerize in deoxygenated conditions. HbS polymerization leads to sickle-shaped erythrocytes that can occlude small vessels. This patient's most recent presentation (eg, fever, chest pain, dyspnea) was most likely due to small-vessel occlusion localized to the pulmonary vasculature (ie, acute chest syndrome). Vascular occlusion can also cause splenic infarctions. Repeated infarctions produce a shrunken, fibrotic spleen. By adulthood, most patients with SCD have undergone autosplenectomy and have a small, scarred splenic remnant. As a result, these patients have functional asplenia and are susceptible to infection with encapsulated organisms (eg, Streptococcus pneumoniae). (Choice A) Extramedullary hematopoiesis (EMH) can develop in patients with hemolytic anemias (eg, beta-thalassemia, SCD) or myeloproliferative neoplasms (eg, primary myelofibrosis) and typically occurs in the liver and spleen. Splenic EMH would result in splenomegaly, not splenic atrophy. (Choice B) Splenic follicular hyperplasia can be seen with systemic infections and can result in an enlarged, not small and firm, spleen. (Choice C) Intrasplenic lipid accumulation may occur in lysosomal storage disorders such as Gaucher disease. Although such patients can have bone pain and anemia, they typically have splenomegaly. (Choice D) Pressure atrophy of the splenic parenchyma can be seen when a lesion (eg, a cyst) compresses the spleen, which would likely have been detected during autopsy. Educational objective: In patients with sickle cell disease, repetitive splenic infarctions caused by microvessel occlusion result in a small, firm splenic remnant (ie, autosplenectomy).

A 2-week-old girl is brought to her primary care provider for a routine visit. The patient was born by normal spontaneous vaginal delivery at 39 weeks gestation. The mother is breastfeeding exclusively, and the infant has regained her birth weight. Newborn screening results from hemoglobin electrophoresis are as follows: Hemoglobin F 70% Hemoglobin A 20% Hemoglobin S 10% The patient's mother has sickle cell trait, and a maternal cousin has sickle cell anemia. Examination shows a well-appearing infant with no pallor or splenomegaly. Which of the following is most likely true about this patient? Life expectancy will be shorter than average Mean corpuscular volume will be decreased Reticulocyte count will be elevated She has relative protection against Plasmodium falciparum She will likely develop pain crises

This patient's hemoglobin electrophoresis from her newborn screen is most consistent with sickle cell trait. At birth, infants who are heterozygous for sickle cell trait typically have the greatest amount of fetal hemoglobin (Hb F), followed by hemoglobin A (Hb A), and the smallest amount of hemoglobin S (Hb S). Hb A continues to be higher than Hb S throughout the lifetime of these patients as Hb F naturally declines, offering protection from sickle cell anemia, aplastic crises, and splenic sequestration. Patients with sickle cell trait are usually asymptomatic with normal hemoglobin level, reticulocyte count, and red blood cell (RBC) indices. However, they may develop hematuria, priapism, and increased incidence of urinary tract infections. Splenic infarction at high altitudes has also been reported. Patients with sickle cell trait have relative protection from Plasmodium falciparum (malaria), resulting in lower rates of severe malaria and hospitalization than seen in the general population. Possible mechanisms include increased sickling of parasitized sickle cell trait RBCs and accelerated removal of these cells by the splenic monocyte-macrophage system. These patients are not immune to malaria, however, and those visiting malaria-endemic areas should still receive prophylaxis. (Choice A) Life expectancy of patients with sickle cell trait is no different than that of the general population. Patients who are homozygous for the sickle cell mutation have a decreased life expectancy due to significant complications of disease (eg, acute chest syndrome, infection from encapsulated organisms). (Choices B and C) Patients with sickle cell trait typically have normal RBC indices and reticulocyte counts. Individuals with sickle cell anemia (eg, no normal Hb A) will have an elevated reticulocyte count but will maintain a normal mean corpuscular volume. (Choice E) It is unlikely that this patient will develop painful crises as she is protected by the predominance of Hb A (normal hemoglobin) over Hb S. Vaso-occlusive pain crises that develop in patients with sickle cell anemia are thought to occur when Hb S polymerizes and causes the RBCs to assume a sickle shape, typically in response to a trigger (eg, cold weather, dehydration). Educational objective: Patients with sickle cell trait are typically asymptomatic and have relative protection from malaria caused by Plasmodium falciparum. These patients usually have normal hemoglobin, reticulocyte, and red blood cell index values. Life expectancy is the same as that of the general population.

A 5-year-old boy is brought to the office by his parents who say that he "looks yellow" and has been uncharacteristically tired lately. He has had upper respiratory tract infection symptoms for the past 3 days, including cough, rhinorrhea, sneezing, and sore throat. The parents say that "a lot of kids at daycare have been sick lately." The patient has no prior medical problems. He is consistently at the 50th percentile for height and weight. He takes no medications, and his immunizations are up to date. Pallor, scleral icterus, and palpable splenomegaly are seen on examination. Laboratory results are as follows: Complete blood count Hemoglobin 9 g/dL Reticulocytes 10.8% Platelets 218,000/mm3 Leukocytes 7500/mm3 Liver studies Total bilirubin 3 mg/dL Direct bilirubin 0.8 mg/dL Alkaline phosphatase 95 U/L Aspartate aminotransferase (AST) 18 U/L Alanine aminotransferase (ALT) 15 U/L The patient recovers spontaneously after a few weeks. Peripheral smear of the boy's blood after recovery is shown in the exhibit (disco-shaped RBC with no central area of pallor). Which of the following is the most likely cause of this patient's condition?' Glucose-6 phosphate dehydrogenase enzyme deficiency Imbalance between alpha and beta globin chain production Nuclear maturation defect due to defective DNA synthesis Polymerization of hemoglobin within red blood cells Red blood cell membrane cytoskeleton abnormalities

This patient's peripheral smear shows spherocytes, which are approximately two-thirds of the diameter of normal RBCs, more densely hemoglobinized at the periphery, and often lack a zone of central pallor. This patient's presentation is consistent with hereditary spherocytosis (HS), an autosomal dominant hemolytic anemia due to a red blood cell (RBC) membrane defect. The mutation in HS most often affects the plasma-membrane scaffolding proteins spectrin and ankyrin. Without this scaffolding, spherocytes are less deformable than normal RBCs and are prone to sequestration and subsequent accelerated destruction in the spleen. Clinical manifestations include hemolytic anemia, jaundice (increased RBC destruction results in greater bilirubin production), and splenomegaly (spherocytes have difficulty passing through the cords of Billroth and accumulate in the spleen). Infections can trigger hemolysis and lead to an acute hemolytic crisis, as seen in this patient. Age of diagnosis varies considerably, but many patients have jaundice and fatigue in times of increased hemolysis in the setting of viral infections. (Choice A) Glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency anemia usually follows oxidative stress. Common triggers include drugs (sulfonamide or antimalarial agents), fava beans, and infections (viral hepatitis, pneumonia, or typhoid). Peripheral smears of G6PD deficiency anemia show bite cells and Heinz bodies, not spherocytes. (Choice B) An imbalance between alpha globin and beta globin chain production results in thalassemia. In this patient, the peripheral smear has no morphologic variants associated with thalassemia, such as target cells or hypochromic microcytes. (Choice C) A nuclear maturation defect due to defective DNA synthesis is the pathophysiologic mechanism of megaloblastic anemia, which is most commonly caused by vitamin B12 and folic acid deficiencies. In this patient's peripheral smear, small spherocytes are primarily seen and not the enlarged oval cells and hypersegmented neutrophils of megaloblastic anemia. (Choice D) Polymerization of hemoglobin occurs in sickle cell anemia. A missense mutation in the beta globin chain leads to the production of hemoglobin S, which has the capacity to polymerize in deoxygenated states. This polymerization leads to red blood cell membrane injury and deformation to a "sickle" shape seen on peripheral smear. Educational objective: Hereditary spherocytosis results from red cell cytoskeleton abnormalities, most commonly spectrin and ankyrin. Hemolytic anemia, jaundice, and splenomegaly are classic manifestations. Spherocytes are seen on peripheral blood smear.

A 63-year-old man comes to the emergency department due to abdominal pain. Physical examination shows abdominal tenderness without guarding or rebound. His laboratory test results are as follows: Hemoglobin 8.9 g/dL Platelets 134,000/mm3 Total bilirubin 6.3 mg/dL Lactate dehydrogenase7 40 U/L Haptoglobin Low On further investigation, magnetic resonance angiography of the abdomen reveals mesenteric vein thrombosis. Flow cytometry shows absence of CD55 on the surface of red blood cells. Which of the following is the most likely pathologic renal finding in this patient? Cast nephropathy Hemosiderosis Interstitial nephritis Membranous glomerulonephritis Minimal change disease

This patient's presentation is consistent with paroxysmal nocturnal hemoglobinuria (PNH), a disorder due to complement-mediated hemolysis. PNH is usually due to a mutated phosphatidylinositol glycan class A (PIGA) gene, which helps synthesize the glycosylphosphatidylinositol (GPI) anchor protein. This protein helps attach several cell surface proteins (eg, CD55 decay accelerating factor, CD59 MAC inhibitory protein) that inactivate complement. Absence of these proteins leads to uncontrolled complement-mediated hemolysis. Manifestations of PNH include the following: Fatigue and jaundice due to hemolytic anemia (elevated bilirubin and lactate dehydrogenase, low haptoglobin, hemoglobinuria [which may be nocturnal]) Thrombosis at atypical sites (eg, hepatic, portal, or cerebral veins) possibly due to the release of prothrombotic factors from lysed red blood cells and platelets (mesenteric vein thrombosis may explain this patient's abdominal pain) Pancytopenia due to stem cell injury Chronic hemolysis with breakdown of iron-containing erythrocytes can also lead to iron deposition in the kidney (hemosiderosis), which can interfere with proximal tubule function and cause interstitial scarring and cortical infarcts. The hemosiderosis combined with microvascular thrombosis can increase the risk of chronic kidney disease. (Choices A and C) Cast nephropathy is usually seen in multiple myeloma and is due to large amounts of monoclonal free chain deposition in the kidney. Interstitial nephritis (inflammation in the area surrounding the renal tubules) is most commonly due to drugs (eg, analgesics, antibiotics), recent infection, or systemic conditions (eg, sarcoidosis). (Choices D and E) Membranous glomerulonephritis can be associated with systemic lupus erythematosus, drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), hepatitis B and C, or solid tumor malignancies (eg, lung, prostate, gastrointestinal). Minimal change disease can be associated with drugs (eg, NSAIDs), hematologic malignancies (eg, lymphoma, leukemia), or allergens (eg, fungi). Educational objective: Paroxysmal nocturnal hemoglobinuria is due to a gene defect that leads to uncontrolled complement-mediated hemolysis. The classic triad includes hemolytic anemia (hemoglobinuria), pancytopenia, and thrombosis at atypical sites. Chronic hemolysis can cause iron deposition in the kidney (hemosiderosis).

A 20-year-old man is evaluated for recurrent episodes of jaundice. He was separated from his parents at a young age and is unaware of any family medical history. The patient resided in several foster homes throughout his childhood but currently lives alone. His temperature is 36.7 C (98 F), blood pressure is 120/80 mm Hg, and pulse is 72/min. Physical examination shows pallor, icterus, and mild splenomegaly. There is no lymphadenopathy or hepatomegaly. The remainder of the physical examination is normal. Laboratory test results are as follows: Hemoglobin 9g/L Platelets 198,000/mm3 Leukocytes 6500/mm3 Lactate dehydrogenase Increased Total bilirubin 3.4 mg/dL Direct bilirubin 0.2 mg/dL Aspartate aminotransferase (AST) 25 U/L Alanine aminotransferase (ALT) 30 U/L Direct Coombs test Negative When the patient's red blood cells are incubated in a hypotonic solution with glycerol, hemoglobin is released. The control sample does not release hemoglobin. This patient is at greatest risk of developing which of the following? Autoimmune disease Autoinfarction of the spleen Avascular necrosis of the femur Hemolysis from consumption of fava beans Pigmented gallstones

This patient's presentation with anemia, elevated lactate dehydrogenase, and indirect hyperbilirubinemia suggests hemolytic anemia. The lysing of blood cells when incubated in hypotonic saline with glycerol describes a positive acidified glycerol lysis test, the diagnostic test for hereditary spherocytosis (HS). Spherocytes demonstrate increased osmotic fragility in this test due to their decreased surface area to volume ratio. HS is the most common hemolytic anemia due to a red blood cell (RBC) membrane defect. The mutation in HS most often affects spectrin and ankyrin, the plasma-membrane scaffolding proteins. Patients with HS present with hemolytic anemia, jaundice, and splenomegaly. Pigmented gallstones are a complication of any hemolytic anemia. In chronic hemolysis, the increased bilirubin from lysed RBCs precipitates as calcium bilirubinate, forming pigmented stones in the gallbladder. Patients with HS may also present with aplastic crises due to parvovirus B19 infection. (Choice A) Autoimmune hemolytic anemia (AIHA) results in findings similar to those seen in HS (eg, indirect hyperbilirubinemia, elevated lactate dehydrogenase, spherocytes on peripheral blood smear). In contrast to HS, AIHA is not heritable, and patients have a positive direct antiglobulin (Coombs) test along with a propensity to develop autoimmune disease (eg, systemic lupus erythematosus). (Choices B and C) The abnormal adhesion of sickle cell RBCs to the endothelium and the subsequent obstruction of small blood vessels lead to various injuries, which include splenic autoinfarction and femoral avascular necrosis. A positive acidified glycerol lysis test classically describes HS, not sickle cell anemia. (Choice D) Glucose-6-phosphate dehydrogenase (G6PD) deficiency presents with hemolytic anemia and indirect hyperbilirubinemia usually following oxidative stress. Common triggers include drugs (sulfonamide or antimalarial agents), fava beans, and infections (viral hepatitis, pneumonia, or typhoid). Peripheral smears of G6PD deficiency anemia show bite cells and Heinz bodies, not spherocytes. Educational objective: Hereditary spherocytosis results from red cell cytoskeleton abnormalities, most commonly in the proteins spectrin and ankyrin. Increased osmotic fragility on acidified glycerol lysis testing confirms the diagnosis. Hemolytic anemia, jaundice, and splenomegaly are classic manifestations. Complications include pigmented gallstones and aplastic crises from parvovirus B19 infection.

A 25-year-old woman comes to the office due to significant fatigue. Several weeks ago, the patient had a weeklong episode of intermittent fever and severe body aches. Over the last 2 weeks, she has been too tired to complete her normal jogging routine in the mornings and has had to take naps after returning home from work. The patient has no chronic medical conditions and takes no medications. Temperature is 37.2 C (99 F), pulse is 110/min, and respirations are 20/min. Examination shows pale lips and conjunctivae. The abdomen is soft and there is no hepatosplenomegaly. Examination of the extremities is unremarkable, and no lymphadenopathy is present. Laboratory results are as follows: Hemoglobin 7.0 g/dL Mean corpuscular volume 90μm^3 Reticulocytes 0.1% Platelets 40,000/mm3 Leukocytes 2,000/mm3 PT 13 sec PTT 30 sec Peripheral blood smear reveals normocytic, normochromic red blood cells, and other cell types appear morphologically normal. This patient's bone marrow biopsy would most likely show which of the following patterns? Hypercellular marrow filled with numerous blast forms Hypercellular marrow with increased granulocytes Hypocellular marrow filled with fat and stroma Hypocellular marrow with extensive fibrosis Large promyelocytes containing Auer rods

Aplastic anemia is a form of bone marrow failure caused by direct toxic injury or cytotoxic T-cell destruction of multipotent hematopoietic stem cells in the bone marrow. Because these stem cells generate progenitor cells that produce all blood cells, damage results in a dramatic reduction of immature and mature blood cells in the bone marrow and peripheral blood. This is reflected on bone marrow biopsy as marked hypocellularity with an abundance of fat cells and other marrow stroma; aspiration classically produces a "dry tap." Although aplastic anemia is usually idiopathic (no clear cause), it can be triggered by viral infection (eg, hepatitis, HIV), chemical or radiation exposure, or medications (eg, carbamazepine). Patients typically have manifestations of pancytopenia such as severe fatigue and pale mucous membranes (anemia), bleeding/bruising (thrombocytopenia), or infection (eg, leukopenia). No significant extramedullary hematopoiesis occurs (eg, no splenomegaly) because few hematopoietic stem cells continue to function. (Choice A) Acute leukemias (eg, acute myeloid leukemia) are usually associated with a hypercellular marrow with increased blasts. Although anemia and thrombocytopenia may be present, most patients have mild leukocytosis. In addition, blasts would be seen on peripheral smear. (Choice B) Chronic myeloid leukemia, a myeloproliferative neoplasm of granulocytes associated with the BCR-ABL fusion gene, is marked by a hypercellular marrow with increased granulocytes and megakaryocytes. Patients typically have significant peripheral leukocytosis and thrombocytosis; in addition, hepatosplenomegaly is generally present. (Choice D) Myelofibrosis, a chronic hematopoietic neoplasm, is marked by hypocellular marrow with extensive fibrosis. Although pancytopenia is typically present, peripheral blood smear usually shows teardrop-shaped and nucleated erythrocytes; significant extramedullary hematopoiesis also occurs, so dramatic splenomegaly is usually present. (Choice E) Acute promyelocytic leukemia is associated with promyelocytes with Auer rods (rod-shaped cytoplasmic inclusions). This type of acute myeloid leukemia is characterized clinically by disseminated intravascular coagulation (acquired hypercoagulability and bleeding), which is not seen in this patient (normal PT and PTT); immature leukocytes would also be seen on peripheral smear. Educational objective: Aplastic anemia is a form of bone marrow failure due to destruction of multipotent hematopoietic stem cells. It is marked by pancytopenia and profound hypocellularity of the bone marrow with an abundance of fat cells and stroma. Impaired reticulocytosis and an absence of splenomegaly are important features.

A 12-year-old girl is brought to the emergency department due to several days of worsening exertional dyspnea and lethargy. The patient has a history of sickle cell disease and takes hydroxyurea. Physical examination shows mucosal pallor and a systolic ejection murmur. Laboratory studies reveal a hemoglobin level of 5.6 g/dL. Bone marrow biopsy is performed and demonstrates decreased erythroid precursors and giant pronormoblasts containing inclusions, as shown below. Big blue cell with circle and a faint circle within the faint circle, surrounded by RBCs Which of the following is the most likely cause of this patient's current condition? Acute viral infection Dietary folate deficiency Medication averse effects Secondary iron overload Toxic chemical exposures

ID:15562 review image This patient's symptomatic anemia (lethargy, exertional dyspnea, mucosal pallor, ejection murmur) and bone marrow biopsy showing decreased erythropoiesis (reduced erythrocyte precursors) raise suspicion for transient aplastic crisis due to acute parvovirus B19 infection. Parvovirus is a small, nonenveloped, DNA virus transmitted via the respiratory route that primarily attacks erythroid progenitor cells due to tropism for an erythrocyte cell surface receptor (P blood group antigen). Infection of erythroid progenitor cells prevents red blood cell maturation, leading to formation of abnormal giant pronormoblasts (several times larger than surrounding red blood cells) with glassy, intranuclear viral inclusions. The drop in red cell production often leads to a transient (1-2 week) drop in hematocrit. Although many patients are asymptomatic, individuals with underlying hemoglobin disorders (eg, sickle cell anemia) sometimes develop symptomatic anemia. (Choice B) Folate deficiency can be seen in patients with sickle cell disease due to increased erythropoiesis in response to chronic anemia. However, folate deficiency is characterized by macrocytic anemia and hypersegmented neutrophils; giant pronormoblasts with inclusions would not be seen. (Choice C) Hydroxyurea can sometimes interfere with normal erythropoiesis and result in macrocytic anemia. However, it is not associated with giant pronormoblasts with intranuclear inclusions. (Choice D) Patients with sickle cell disease who require repeated blood transfusion can sometimes develop secondary iron overload. Bone marrow biopsy would show increased iron stores. (Choice E) Exposure to toxic chemicals (eg, industrial solvents/chemicals, insecticides) can lead to aplastic anemia. However, bone marrow biopsy would show hypocellular marrow with a decrease in all cell types; the remaining hematopoietic cells would be morphologically normal. Educational objective: Parvovirus B19 infection can cause transient aplastic crisis, particularly in those with underlying hemoglobin disorders such as sickle cell anemia. Patients develop symptomatic anemia (eg, exertional dyspnea, fatigue, low hematocrit) due to inhibition of erythropoiesis by the virus. Bone marrow examination will show giant pronormoblasts with glassy, intranuclear viral inclusions.

A 35-year-old woman comes to the office due to reduced energy and fatigue. She reports heavy menstrual bleeding over the past 6 months. The patient is found to have hypochromic microcytic anemia. Iron supplementation is prescribed. A week later, a peripheral blood smear shows numerous enlarged red blood cells that have a bluish hue on Wright-Giemsa staining. The bluish color of these red blood cells is best explained by the presence of which of the following? Golgi apparatus Hemoglobin precipitates Histones Mitochondria Nuclear remnant Ribosomal RNA

This patient has iron deficiency anemia (most likely due to menstrual blood loss), characterized by the presence of microcytic (ie, small), hypochromic (ie, pale) red blood cells (RBCs). Patients with iron deficiency anemia who receive iron replacement therapy experience enhanced erythropoiesis and accelerated release of reticulocytes into the bloodstream as the bone marrow attempts to correct the anemia. Reticulocytes (immature RBCs) are anucleate (like mature RBCs) but are enlarged and have a blue-gray hue on Wright-Giemsa staining. This bluish color (ie, polychromatophilia) is due to the presence of large amounts of ribosomal RNA necessary for adequate hemoglobin synthesis. The ribosomal RNA can be distinguished using a supravital stain that binds RNA (eg, new methylene blue) and appears as a blue, reticular (ie, net-like) substance. Ribosomal RNA is gradually degraded as the reticulocyte matures. After spending a day or more in the bloodstream, the maturation process is complete, and the reticulocyte transforms into a mature RBC, which has a lifespan of approximately 120 days. (Choices A and D) Young reticulocytes contain organelles necessary for cell development, including mitochondria and remnants of Golgi apparatus, which are also removed as the reticulocyte matures. However, it is the ribosomal RNA that imparts the bluish color on Wright-Giemsa staining. (Choice B) Heinz bodies consist of denatured hemoglobin precipitate and are associated with glucose-6-phosphate dehydrogenase deficiency. They cannot be seen on Wright-Giemsa staining but appear as round, peripheral RBC inclusions using a supravital stain. (Choice C) Histone proteins are found in the nucleus. During erythropoiesis, the erythroblast ejects its nucleus, forming a reticulocyte; because the reticulocyte does not have a nucleus, it does not contain histones. (Choice E) Howell-Jolly bodies are nuclear remnants visible on Wright-Giemsa staining as purple, round, peripheral RBC inclusions. They are associated with asplenia or hyposplenia because the spleen typically removes these nuclear remnants. Educational objective: Reticulocytes (immature red blood cells) appear as blue-gray (ie, polychromatophilic) red blood cells on Wright-Giemsa staining due to the presence of ribosomal RNA. In patients with iron deficiency anemia, iron supplementation results in increased bone marrow erythropoiesis and accelerated release of reticulocytes into the bloodstream.

A 23-year-old African American man comes to the emergency department due to back and lower extremity pain for 2 days. He has had several similar episodes over the last 15 years that have required hospitalization. His pain is not responsive to over-the-counter analgesics, and review of his prior records shows that he has needed treatment with opioids for adequate pain relief. The patient does not use tobacco, alcohol, or illicit drugs. On physical examination, he has scleral icterus and tenderness over his lower back and long bones of his thighs. Laboratory evaluation shows a hemoglobin level of 6.7 g/dL. Histopathologic evaluation of this patient's spleen is most likely to reveal which of the following? Congestion Cyst formation Fibrosis and atrophy Infiltration White pulp hyperplasia

This patient with frequent episodes of bony pain likely has sickle cell disease (SCD), an autosomal recessive condition characterized by hemolytic anemia and vaso-occlusion. The hemolytic anemia causes jaundice (due to unconjugated hyperbilirubinemia) and promotes formation of pigmented gallstones. Vaso-occlusion by sickled red blood cells occurs in various tissues, causing hypoxia and acidosis (vaso-occlusive pain episodes). Microvascular occlusion nearly always affects the spleen due to the trapping of sickle cells by the rigid splenic cords; autoinfarction begins in early childhood and can precipitate splenic sequestration crisis in infants. However, repeated infarction eventually leads to significant scarring, fibrosis, and atrophy of the spleen, which would likely be present in this adult patient. Asplenic patients are more susceptible to infections with encapsulated bacteria (eg, group B Streptococcus, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, Salmonella typhi). (Choice A) Splenic congestion occurs during a splenic sequestration crisis (marked hemoglobin decrease, rapidly enlarging spleen), which develops due to vaso-occlusion within the cords of Billroth and splenic pooling of erythrocytes. However, repeated infarction leads to functional asplenia and autosplenectomy (splenic atrophy) by late childhood/adolescence. (Choices B and D) Splenic cyst formation typically occurs due to infection. Splenic infiltration can be seen with metastatic neoplasms but is not a feature of SCD. (Choice E) The white pulp of the spleen is composed of lymphoid tissue. Lymphoid hyperplasia may represent infection or malignancy. Educational objective: Sickle cell disease is characterized by repeated splenic infarctions that ultimately result in splenic atrophy and fibrosis, a process that is typically complete by late childhood/adolescence. After autosplenectomy, patients are predisposed to infections with encapsulated bacterial organisms.

A 30-year-old woman comes to the emergency department with sudden-onset abdominal pain and ascites. Laboratory studies show anemia, reticulocytosis, leukopenia, and thrombocytopenia. Flow cytometry of the patient's peripheral blood cells using the appropriate monoclonal antibodies shows CD55 and CD59 deficiency. CT scan of the abdomen shows hepatic vein thrombosis. Which of the following is the most likely cause of this patient's anemia? Complement activation Factor V mutation Intracellular dehydration Mutation in beta globin chain Splenic sequestration

This patient's combination of hemolytic anemia, hypercoagulability (eg, hepatic vein thrombosis), and pancytopenia are characteristic of paroxysmal nocturnal hemoglobinuria (PNH). Despite the name, hemolysis has been shown to occur at low baseline levels throughout the day, with exacerbations caused by a variety of inflammatory triggers (eg, infections, surgery). PNH is caused by an acquired mutation of the PIGA gene within a clonal population of multipotent hematopoietic stem cells. This gene is involved in the synthesis of the glycosylphosphatidylinositol (GPI) anchor, a glycolipid necessary for the attachment of several cell-surface proteins, including CD55 (decay-accelerating factor) and CD59 (MAC inhibitory protein). These proteins help inactivate complement and prevent the membrane attack complex from forming on normal cells. Absence of the GPI anchor results in CD55 and CD59 deficiency and complement-mediated hemolysis. The hemolysis occurs more often at night because complement activity is increased during sleep due to lower blood pH. Patients also develop thrombotic complications (eg, Budd-Chiari syndrome), likely due to release of free hemoglobin and other prothrombotic factors from lysed red blood cells and platelets. PNH is often associated with pancytopenia and aplastic anemia (possibly due to autoimmune attack against GPI-antigens on stem cells). Flow cytometry is the gold standard for the diagnosis of PNH and will show absence of the GPI anchor and CD55 and CD59 deficiency. (Choice B) Factor V mutation can result in an aberration called factor V Leiden, which is resistant to cleavage by activated protein C. Patients with factor V Leiden are at increased risk of thrombotic events, but hemolytic anemia and pancytopenia are not seen. (Choice C) Intracellular dehydration occurs during the pathogenesis of sickle cell anemia and spherocytosis. (Choice D) Mutations affecting the beta globin chain cause β-thalassemia. (Choice E) Splenic sequestration is a common complication of sickle cell anemia. Educational objective: The triad of hemolytic anemia, hypercoagulability (resulting in thrombosis), and pancytopenia suggests paroxysmal nocturnal hemoglobinuria (PNH). PNH results from an acquired mutation in the PIGA gene that causes absence of the glycosylphosphatidylinositol anchor and associated deficiency of CD55 and CD59 complement inhibitor proteins.