17. A 31-year-old woman presents to you for follow-up after a visit to the emergency department 1 week ago.
The patient went to the emergency department because of severe right upper quadrant pain of 2 days’
duration. An abdominal CT was normal—there was no evidence of biliary disease, nephrolithiasis, or pelvic disease. The patient was sent home that day with minimal pain control. She now states that her abdominal pain has persisted and is unimproved. She also states that she now has bloody urine in the morning and that she has developed severe lower extremity swelling and abdominal distention. Physical examination is significant for marked ascites, tender hepatomegaly, and 3+ bilateral lower extremity pit-ting edema. You order magnetic resonance imaging of the abdomen, which reveals the presence of a hepatic vein thrombosis.
Which of the following statements regarding paroxysmal nocturnal hemoglobinuria (PNH) is true?
❑ A. PNH is the result of a mutation that causes a deficiency of a mem-brane-anchoring protein, which in turn results in an inability to prop-erly modulate complement attack
❑ B. PNH causes anemia but has no effect on other cell lines
❑ C. PNH can cause thromboses in unusual sites, such as in the mesenteric or hepatic vein; however, lower extremity thromboses and associated pulmonary emboli are not seen
❑ D. The diagnosis of PNH is a diagnosis of exclusion because there are no specific tests available for PNH
Key Concept/Objective: To know the clinical characteristics of PNH
The mutation associated with PNH results in a deficiency of the membrane-anchoring pro-tein phosphatidylinositol glycan class A. Normal human erythrocytes, and probably platelets and neutrophils, modulate complement attack by at least three glycosylphos-phatidylinositol (GPI) membrane-bound proteins: DAF (CD55), C8-binding protein (C8BP), and MIRL (CD59). Because the defective synthesis of GPI affects all hematopoietic cells, patients with PNH may have variable degrees of anemia, neutropenia, or thrombo-cytopenia, or they may have complete bone marrow failure. Recurrent venous occlusions lead to pulmonary embolism and hepatic and mesenteric vein thrombosis, possibly
result-ing from the release of procoagulant microparticles derived from platelets. Diagnosis is made by specific tests based on fluorescence-activated cell sorter analysis using antibodies that quantitatively assess DAF (CD55) and particularly MIRL (CD59) on the erythrocyte or on the leukocyte surface. (Answer: A—PNH is the result of a mutation that causes a deficiency of a membrane-anchoring protein, which in turn results in an inability to properly modulate complement attack)
18. A 48-year-old black man presents to the emergency department for evaluation of severe fatigue. He has been HIV positive for several years. He reports that his last known CD4+T cell count was “around 100.”
The patient is receiving drugs for prophylaxis against Pneumocystis carinii pneumonia (PCP). He was in his usual state of moderate health until 2 days ago. His only complaints are severe fatigue and some dys-pnea on exertion. He denies having fever, chills, cough, abdominal pain, or dysuria. He states that his doctor recently changed his “PCP pill” because of a persistent rash. A chest x-ray is within normal lim-its. Laboratory values are remarkable for a hematocrit of 22% and a urinalysis that shows 4+ blood and 0–2 RBCs.
Which of the following statements regarding glucose-6-phosphate dehydrogenase (G6PD) deficiency is true?
❑ A. G6PD is an enzyme that catalyzes the conversion of adenosine diphos-phate (ADP) to adenosine triphosdiphos-phate (ATP), a powerful reducing agent
❑ B. G6PD deficiency is very rare in the United States
❑ C. G6PD deficiency occurs with equal frequency in males and females
❑ D. Potential users of dapsone should be screened for G6PD deficiency
Key Concept/Objective: To understand the function of G6PD and the epidemiology of G6PD deficiency
G6PD is the first enzyme in the pentose phosphate pathway, or hexose monophosphate shunt. It catalyzes the conversion of the oxidized form of nicotinamide-adenine dinu-cleotide phosphate (NADP+) to the reduced form (NADPH), which is a powerful reducing agent. NADPH is a cofactor for glutathione reductase and thus plays a role in protecting the cell against oxidative attack. G6PD deficiency is one of the most common disorders in the world; approximately 10% of male blacks in the United States are affected. The gene for G6PD is on the X chromosome at band q28; males carry only one gene for this enzyme, so those males that are affected by the disorder are hemizygous. Females are affected much less frequently because they would have to carry two defective G6PD genes to show clini-cal disease of the same severity as that in males. Dapsone, which is capable of inducing oxidant-type hemolysis, has increasingly come into use as prophylaxis for PCP in patients infected with HIV. Therefore, it is important to screen potential users of dapsone for G6PD deficiency with the standard enzymatic tests. (Answer: D—Potential users of dapsone should be screened for G6PD deficiency)
19. A 25-year-old black man comes for a routine office visit. You have followed the patient for many years for his sickle cell disease. The patient takes very good care of himself and has only required hospital admission four times in the past 5 years. Two of these admissions occurred in the past 6 months. You feel that the patient’s clinical course is worsening. He has recently required the addition of narcotics to his home regimen of nonsteroidal anti-inflammatory drug therapy. The patient states that he now has moderately severe pain in long bones two to three times monthly. He has also developed worsening left hip pain over the past month.
Which of the following statements regarding sickle cell disease is true?
❑ A. In patients with homozygous sickle cell disease, roughly 50% of total hemoglobin is hemoglobin S
❑ B. Risk factors that predispose to painful crises include a hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high reticu-locyte count
❑ C. The most definitive test for the diagnosis of sickle cell anemia is the sodium metabisulfite test
❑ D. Hydroxyurea has never been shown to be of benefit in the therapy of sickle cell disease
Key Concept/Objective: To know the clinical features of sickle cell disease
Sickle cell disease develops in persons who are homozygous for the sickle gene (HbSS), in whom 70% to 98% of hemoglobin is of the S type. About 0.2% of African Americans have sickle cell anemia. Risk factors that predispose to painful crises include a hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high reticulocyte count. Conversely, the low hematocrit in sickle cell anemia reduces blood viscosity and is protective. The most definitive tests for sickle cell anemia are hemoglobin electrophoresis or high-per-formance liquid chromatography, which indicate the relative percentages of HbS and HbF.
Hydroxyurea produces an increase in F reticulocyte and HbF levels. In a phase III trial, patients treated with hydroxyurea (starting dosage, 15 mg/kg/day) had fewer painful crises, fewer admissions for crisis, and fewer episodes of acute chest syndrome and required fewer transfusions than patients given a placebo. There was no effect on stroke; however, after 8 years of follow-up, mortality was reduced by 40%. (Answer: B—Risk factors that predis-pose to painful crises include a hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high reticulocyte count)
20. A 47-year-old woman presents to your office with a complaint of severe fatigue, weakness, and dyspnea on exertion. She has had these symptoms for 2 days. The patient denies having fever, chills, weight changes, or dysuria. Her medical history is significant for pernicious anemia and hypothyroidism.
Results of thyroid studies were within normal limits 1 week ago. Her physical examination is positive for mild icterus and hepatosplenomegaly. CBC is normal, with the exception of a hematocrit of 21%. Her hematocrit was 36% 3 months ago. Liver function tests show the total bilirubin level to be 4.6 mg/dl and the indirect bilirubin level to be 4.2 mg/dl. Other results are within normal limits. A direct Coombs test is positive.
Which of the following statements regarding autoimmune hemolytic anemia is true?
❑ A. Autoimmune hemolytic anemia typically results in intravascular hemolysis
❑ B. Autoimmune hemolytic anemia may be idiopathic or secondary to dis-orders such as systemic lupus erythematosus, chronic lymphocytic leukemia (CLL), HIV infection, or hepatitis C infection
❑ C. Most patients with autoimmune hemolytic anemia are cured with steroid therapy
❑ D. Splenectomy is curative for those patients who do not respond to sim-ple steroid therapy
Key Concept/Objective: To understand the clinical features and chronic nature of autoimmune hemolytic anemia
Intravascular hemolysis in autoimmune hemolytic anemia is rare and indicates that an extremely rapid rate of erythrocyte destruction is occurring or that the extravascular removal mechanisms have been overwhelmed. Erythrocytes sensitized to IgG alone are usually removed in the spleen, whereas RBCs sensitized to IgG plus complement or to complement alone are generally destroyed in the liver, because hepatic Kupffer cells carry receptors specific for complement component C3b. Both an idiopathic variety of autoim-mune hemolytic anemia and a variety that occurs secondary to other disorders have been described. Such primary disorders include systemic lupus erythematosus, non-Hodgkin lymphoma (especially chronic lymphocytic leukemia), Hodgkin disease, cancer, myeloma, dermoid cyst, HIV infection, angioimmunoblastic lymphadenopathy with dysproteine-mia, hepatitis C infection, and chronic ulcerative colitis. Approximately 20% of patients remain well indefinitely after steroid therapy, but the majority suffer from a chronic, treacherous disease that can produce sudden relapses with abrupt anemia. If the
cortico-steroid dose required for long-term therapy produces significant morbidity, one can pro-ceed empirically either to splenectomy or to the use of immunosuppressive agents.
Splenectomy rarely results in extended remission but is valuable as a prednisone-sparing measure. (Answer: B—Autoimmune hemolytic anemia may be idiopathic or secondary to disorders such as systemic lupus erythematosus, chronic lymphocytic leukemia [CLL], HIV infection, or hepatitis C infection)
21. A 19-year-old African-American man comes to establish primary care. He knows that both of his parents are carriers of sickle cell anemia. He also knows that one of the parents has a second hemoglobin defect.
He has never experienced pain crises.
Which of the following compound heterozygote states, if present, would make the patient susceptible to symptoms such as pain crises and avascular necrosis?
❑ A. HbS/HbC
❑ B. HbS/HbE
❑ C. HbS/α-thalassemia
❑ D. HbS/α+-thalassemia
❑ E. HbS/α0-thalassemia
Key Concept/Objective: To understand the mechanisms of sickling and the protective role of glo-bin chains
Certain physiologic stresses make deoxygenated HbS more likely to polymerize and pre-cipitate, forming a gel-like substance. Known stressors are a low pH, an increase in the level of intracorpuscular hemoglobin (MCHC), a high concentration of HbS, a low concentra-tion of HbF, and slow transit time. Patients with α+-thalassemia traits produce enough αA -globin chains to maintain an HbA concentration greater than 25%, thus decreasing the amount of HbS. Patients with α-thalassemia tend to have lower levels of MCHC and, thus, decreased concentrations of HbS. HbE is an unstable hemoglobin in which lysine is sub-stituted for glutamic acid in position 26 of the α-globin chain. Heterozygous patients are asymptomatic. Homozygous patients present with a clinical picture similar to that of patients with α+-thalassemia. Similarly, patients with HbS/HbE have a clinical picture sim-ilar to that of patients with HbS/α+-thalassemia. In patients with HbS/HbC, 50% of the hemoglobin is HbS. Although HbS/HbC disease is less severe than HbSS disease, patients with HbS/HbC frequently tend to have avascular necrosis of the femoral head. Patients with α0-thalassemia have a very low concentration of HbA; in these patients, HbS consti-tutes more than 50% of the intracorpuscular hemoglobin. In extreme cases, the clinical picture of α0-thalassemia is identical to that of HbSS. As HbS decreases, the clinical picture comes to resemble that of patients with HbS/HbC disease. (Answer: E—HbS/α0-thalassemia)
22. A 38-year-old African-American man is admitted to the hospital with congestive heart failure (CHF) of new onset. He is noted to have a blood pressure of 210/140 mm Hg. Therapy with intravenous furosemide, intravenous nitroglycerin, and oral angiotensin-converting enzymes controls his symptoms and blood pressure over the next 48 hours. On the third day, a 10% drop of his hematocrit is noted.
Laboratory data show the following: Hb, 11 g/dl (admission Hb, 14.5 g/dl); Hct, 35% (admission Hct, 45%); total bilirubin, 3.5 mg/dl (indirect, 2.8 mg/dl); LDH, 550 mg/dl; haptoglobin level, undetectable.
Which of the following tests is most likely to establish the diagnosis?
❑ A. A test for immune hemolysis (i.e., direct Coombs test, indirect Coombs test, or both)
❑ B. A test for membrane fragility (i.e., sucrose lysis test)
❑ C. A test for red cell enzyme deficiency (e.g., pyruvate kinase assay)
❑ D. Hemoglobin electrophoresis
Key Concept/Objective: To understand hemolysis secondary to use of oxidating agents (furosemide and nitroglycerin) and the timing of the G6PD assay
This patient experienced an episode of acute hemolysis after being hospitalized. It is like-ly that this is a case of drug-induced hemolike-lysis. There are several mechanisms by which drugs can induce hemolysis; two well-recognized mechanisms are immunologic media-tion (e.g., hemolysis caused by penicillin and methyldopa) and an increase in oxidative stress on red cells. Oxidative stress can occur as a result of hemoglobins becoming unsta-ble or through a decrease in reduction capacity (as would result from G6PD deficiency).
Penicillins and cephalosporins produce immune hemolysis by acting as a hapten in the red cell membrane. The protein/drug complex elicits an immune response. An IgG anti-body is generated that acts against the drug-red cell complex. In such patients, the direct Coombs test is positive, but the indirect Coombs test is negative. Other drugs induce hemolysis by altering a membrane antigen. IgG autoantibodies that cross-react with the native antigen are produced. The direct Coombs test is also positive in this form of drug reaction. Methyldopa is the classic example of this form of interaction, although other drugs such as procainamide and diclofenac have been clearly implicated. Diclofenac can produce massive hemolysis with concomitant disseminated intravascular coagulation and shock. Sucrose lysis is still used to screen for membrane fragility. The most common dis-order associated with this abnormality is paroxysmal nocturnal hemoglobinuria (PNH).
The lack of associated cytopenias, the acuteness of the onset of symptoms, and the lack of history of venous thrombosis (especially thrombosis at unusual sites such as the inferior vena cava or the portal mesenteric system or thrombosis that produces Budd-Chiari syn-drome) makes PNH an unlikely cause of this patient’s symptoms. Some unstable hemo-globins, such as HbE, are susceptible to hemolysis from oxidative stress. This patient was exposed to both furosemide (a drug with a sulfa moiety) and nitroglycerin. This hemoglo-binopathy is diagnosed by hemoglobin electrophoresis. However, this disease is seen almost exclusively in individuals from Southeast Asia (Cambodia, Thailand, and Vietnam).
The most likely diagnosis in this case is G6PD deficiency. This enzymopathy affects 10%
of the world population. It is commonly seen in African Americans. The red cell becomes hemolyzed when exposed to an oxidative stress. Older red cells are more susceptible to hemolysis because levels of G6PD decrease as red cells age. The results of the G6PD assay should be interpreted carefully. On occasion, the results of the G6PD assay will be normal in patients with G6PD deficiency; this occurs when the assay detects G6PD in very young cells (reticulocytes) that are being released as a result of the brisk hemolysis. (Answer: D—
Hemoglobin electrophoresis)
23. A 17-year-old African-American woman is referred to you from the blood bank for evaluation of micro-cytic anemia detected at the time of screening for blood donation. She is unaware of this problem. She has no symptoms of fatigue or dyspnea. Her menstrual period appears to be normal in frequency and volume of blood loss. There is no history of GI bleeding. She has not been pregnant before. Her physi-cal examination is unremarkable. Her laboratory values are as follows: Hb, 10.5 g/dl; Hct, 32%; MCV, 61;
WBC, 7,500 with normal differential; platelet count, 235,000; peripheral smear shows hypochromia and microcytosis; red cell count, 5 million cells/mm3; Hb electrophoresis: HbA, 97%; HbA2, 2%; HbF, < 1%.
What is the most likely diagnosis for this patient?
❑ A. Iron deficiency anemia
❑ B. α-Thalassemia minor
❑ C. Heterozygous α-thalassemia-1
❑ D. Hemoglobin H disease
❑ E. Homozygous α-thalassemia-2
Key Concept/Objective: To understand the interpretation of the red cell count in patients with anemia, the results of hemoglobin electrophoresis in patients with thalassemia, and differences in genotype among the thalassemias
Microcytic and hypochromic anemia is common in clinical practice. The most likely cause is iron deficiency anemia, especially in women of childbearing age. In iron deficiency ane-mia, the production of red cells is deficient. Thus, the red cell count tends to be low when anemia is present. This patient has a normal red cell count and mild to moderate anemia.
This combination should suggest a problem in red cell production. Both α- and
β-tha-lassemia can present as an asymptomatic microcytic/hypochromic anemia. In β-tha-lassemia, there is a decrease in production of β-globin chains. The α-globin chains are pro-duced in normal amounts and combine with other globin chains. As such, HbA2 produc-tion is increased. This change in hemoglobin patterns enables the diagnosis of β-tha-lassemia to be made through use of hemoglobin electrophoresis. With α-thaβ-tha-lassemias, the hemoglobin electrophoresis pattern is normal. This globin chain is under control of two different loci with a total of four alleles. The absence of both the α-globin gene and the β-globin gene causes hemoβ-globin Barts syndrome during fetal life. This hemoβ-globinopathy results in children being born with hydrops fetalis. When three alleles are missing, the patient develops HbH disease. This disease is seen exclusively in patients of Mediterranean origin and is characterized clinically by chronic hemolysis and the presence of splenomegaly. All three features are absent in this patient. Of the two remaining possibil-ities, we can conclude that the patient has α-thalassemia-2 because of the ethnic origin.
This disease is characterized by homozygous inheritance (--α/-- α) and is seen exclusively in African Americans. The heterozygous patient of this genotype (--α/α α) is the silent car-rier. On the other hand, patients with α-thalassemia-1 have lost two α-chain genes in one chromosome (-- --/α α). This genotype is seen almost exclusively in Asians. (Answer: E—
Homozygous α-thalassemia-2)
For more information, see Schrier SL: 5 Hematology: IV Hemoglobinopathies and Hemolytic Anemias. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds.
WebMD Inc., New York, April 2004