The following cases and commentary, which address hematology, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 15).
Case 1: Leukemia and symptomatic anemia
A 72-year-old man is hospitalized because of dyspnea, anginal chest pain, and new-onset anemia. Chronic lymphocytic leukemia was diagnosed 2 years ago. He has not received specific therapy and has never required a blood transfusion.
On physical examination, the patient appears pale. Blood pressure is 110/80 mm Hg, pulse rate is 112/min, and respiration rate is 24/min. Diffuse cervical, axillary, and inguinal lymphadenopathy is present. There is no jugular venous distention. The lungs are clear. Abdominal examination reveals splenomegaly. There is no peripheral edema.
Laboratory studies show hemoglobin 6.0 g/dL (60 g/L), leukocyte count 55,000/µL (55 × 109/L) with 90% lymphocytes, platelet count 115,000/µL (115 × 109/L), reticulocyte count 12% of erythrocytes, total bilirubin 2.8 mg/dL (47.9 µmol/L), direct bilirubin 0.6 mg/dL (10.26 µmol/L), direct antiglobulin (Coombs test) positive for IgG, ABO/Rh blood type A positive.
A peripheral blood smear shows microspherocytes.
Corticosteroid therapy is begun, and a cross-match for two units of packed erythrocytes is ordered. However, no compatible units are available in the blood bank.
Which of the following is the most appropriate management at this time?
A. Begin erythropoietin
B. Schedule splenectomy
C. Transfuse one unit of A-positive packed erythrocytes
D. Transfuse one unit of O-negative packed erythrocytes
E. Withhold transfusion until a compatible unit of blood is available
Case 2: Hematuria and dyspnea
A 42-year-old man is hospitalized because of hematuria. The patient has a mechanical mitral valve and has been taking warfarin, 5 mg/d.
On physical examination, he is alert and appears pale. Blood pressure is 105/65 mm Hg, pulse rate is 96/min, and respiration rate is 16/min. The lungs are clear.
Laboratory studies show hemoglobin 8.0 g/dL (80 g/L), platelet count 200,000/µL (200 × 109/L), INR 7.0, activated partial thromboplastin time 28 s, urinalysis gross blood.
Three units of fresh frozen plasma are transfused over the next 4 hours. Halfway through the third unit, the patient develops severe dyspnea without chest pain or cough. Temperature is normal, blood pressure is 115/70 mm Hg, pulse rate is 104/min, and respiration rate is 28 min. Arterial oxygen saturation on ambient air is 86%. Bibasilar crackles are auscultated. There is no S3 on cardiac examination, jugular venous distention, or peripheral edema.
A chest radiograph shows bilateral pulmonary infiltrates. Serum B-type-natriuretic peptide level is normal.
Which of the following is the most likely diagnosis?
B. Aspiration pneumonia
C. Pulmonary embolism
D. Heart failure
E. Transfusion-related acute lung injury
Case 3: Post-DVT therapy
A 19-year-old female college student is treated for a deep venous thrombosis, which occurred after she took a long flight on her return from school. Her only medication is an oral contraceptive she began taking 6 months prior to the diagnosis.
The patient is instructed to stop taking oral contraceptives and is given therapy with low-molecular-weight heparin followed by warfarin to achieve a target INR of 2.5.
Which of the following is the best duration of anticoagulation for this patient?
A. Lifelong anticoagulation
B. 12 months
C. 3 to 6 months
D. 4 to 6 weeks
Case 4: Preoperative assessment
A 58-year-old man is evaluated for preoperative clearance prior to elective hernia surgery after a prolonged activated partial thromboplastin time (aPTT) is found on laboratory studies. Personal and family history of abnormal bleeding is negative. Medical history is otherwise noncontributory, and the patient takes no medications.
The vital signs and general screening examination are normal.
The inhibitor mixing study corrects the prolonged aPTT, and factor assays indicate an isolated factor XI deficiency with a value of 47% of normal (normal, 70% to 120%).
Which of the following is the most appropriate management?
A. Cancel surgery
B. Proceed to surgery with no preoperative treatment
C. Treat with factor VIII concentrate preoperatively
D. Treat with cryoprecipitate preoperatively
E. Treat with fresh frozen plasma therapy preoperatively
Case 5: Sickle cell disease and stroke
A 20-year-old black woman is evaluated in the hospital after admission 5 days ago with acute right hemispheric stroke. Medical history is significant for sickle cell disease complicated by multiple episodes of acute chest syndrome. Current medications are hydroxyurea and folic acid.
On physical examination, temperature is 37.5°C (99.5°F), blood pressure is 166/92 mm Hg, pulse rate is 112/min and regular, and respiration rate is 18/min. The cardiopulmonary examination is unremarkable. There are no carotid bruits. Right upper and lower extremity weakness and aphasia are noted on neurologic examination.
Laboratory studies indicate a hemoglobin level of 10.1 g/dL (101 g/L). An MRI shows an acute infarction in the territory of the right middle cerebral artery.
In addition to aspirin, which of the following is the most appropriate secondary prevention of stroke in this patient?
C. Angiotensin-converting enzyme inhibitor
D. Monthly erythrocyte transfusions
Case 6: Hematuria after pneumonia
A 70-year-old malnourished man with a 4-year history of Alzheimer dementia is admitted to the intensive care unit from the emergency department for treatment of community-acquired pneumonia and impending respiratory failure. He is inattentive and confused and has a weak productive cough. His only medications are donepezil and memantine.
Temperature was 38.3°C (101.0°F), blood pressure 100/62 mm Hg, pulse rate 110/min, and respiration rate 26/min; BMI was 18. Arterial oxygen saturation on ambient air was 92%. Pulmonary examination revealed crackles in the right lower lobe. A chest radiograph confirmed an extensive right lower lobe pneumonia.
The patient was treated with ceftriaxone and azithromycin, oxygen, and low-dose unfractionated heparin, 5000 U, three times daily. During the subsequent 48 hours he had several episodes of hypotension and oxygen desaturation that responded to intubation, mechanical ventilation, and intravenous fluids. By day 4, his serum creatinine level increased to 4.0 mg/dL (305.2 µmol/L) before returning to his hospital-admission value of 1.2 mg/dL (91.6 µmol/L) by day 7. On day 8 he was successfully extubated and transferred to the medicine ward. His wife agreed to his transfer to a nursing home.
At day 10 of hospitalization he is ready for transfer, but he is eating little and develops new bruising on his extremities and gross hematuria. Laboratory studies at the time show platelet count 152,000/µL (152 × 109/L), INR 7.7, activated partial thromboplastin time 46 s, thrombin time 16 s (control, 15 s), fibrinogen 450 mg/dL (4.5 g/L), D-dimer assay mildly elevated, mixing study corrects to near normal.
Which of the following is the most likely diagnosis?
A. Disseminated intravascular coagulation
B. Heparin toxicity
C. Presence of a lupus inhibitor
D. Vitamin K deficiency
Answers and commentary
Correct answer: C. Transfuse one unit of A-positive packed erythrocytes.
This patient with symptomatic anemia has severe autoimmune hemolytic anemia secondary to chronic lymphocytic leukemia (CLL) confirmed by positive direct antiglobulin (Coombs) test results and the peripheral blood smear showing microspherocytes. In the absence of pregnancy and previous blood transfusions, the likelihood of alloimmunization to erythrocyte antigens is extremely low. Because of the broad specificity of autoantibodies in patients with autoimmune hemolytic anemia, most donor erythrocytes will be incompatible on cross-match. In this situation, transfusion of ABO-/Rh-specific, but otherwise incompatible, blood is necessary and can be life-saving. The transfused donor erythrocytes will survive as long as the patient's own erythrocytes and will provide oxygen-carrying capacity until definitive therapy, such as corticosteroids, becomes effective.
Erythropoietin is not indicated in patients with an appropriate reticulocyte response.
Splenectomy may be used to treat idiopathic autoimmune hemolytic anemia in a patient who does not respond to corticosteroid therapy. However, surgery is rarely indicated for patients with autoimmune hemolytic anemia secondary to CLL because therapy for the leukemia also treats the anemia. Transfusion of O-negative (“universal”) blood is generally reserved for emergency situations in which the patient's ABO/Rh type is not known.
- Because severe autoimmune hemolytic anemia can be life-threatening, an incompatible blood transfusion should not be withheld in a patient with this disorder.
Correct answer: E. Transfusion-related acute lung injury.
This patient has transfusion-related acute lung injury (TRALI), which occurs most frequently within 6 hours of transfusion of plasma-rich blood components. TRALI is an often severe reaction from donor antileukocyte antibodies that react with the patient's leukocytes. In TRALI, antibody-mediated activation of leukocytes causes leukocyte aggregates to become trapped in the pulmonary capillary bed, leading to neutrophil degranulation, alveolitis, or noncardiogenic pulmonary edema that often progresses to acute respiratory distress syndrome. TRALI is characterized by dyspnea, hypoxemia, and diffuse pulmonary infiltrates on radiography occurring within 6 hours of transfusion in the absence of circulatory overload. Plasma is the blood component most frequently responsible for TRALI, but packed erythrocytes, platelets, and even blood derivatives may also be implicated. Clinical improvement in TRALI begins in 2 to 3 days unlike in typical cases of acute respiratory distress syndrome. Management of TRALI involves stopping the transfusion and providing respiratory support and vasopressors for hypotension.
The absence of fever or a precipitating event and a normal level of consciousness make aspiration pneumonia unlikely. Anaphylaxis and pulmonary embolism cause respiratory distress without pulmonary infiltrates on a chest radiograph, and anaphylaxis is often associated with wheezing or stridor. Heart failure is effectively ruled out by the absence of an S3 and jugular distention and a normal serum B-type-natriuretic peptide level.
- Transfusion-related acute lung injury (TRALI) is a respiratory distress syndrome that is temporally associated with transfusion of plasma-rich blood components.
Correct answer: C. 3 to 6 months.
In patients with venous thromboembolism (VTE) occurring secondary to transient risk factors such as in this patient, anticoagulation therapy should continue for 3 to 6 months, and in those with recurrent VTE, treatment should continue for more than 12 months. Although the appropriate duration of anticoagulation for idiopathic or recurrent VTE is not definitively known, extended-duration therapy is associated with significant benefit.
Treatment of 3 or 6 months' duration in patients with VTE secondary to transient risk is associated with similar risks for recurrent VTE. In one study in which patients with a second episode of VTE were enrolled exclusively, extended-duration (>12 months or indefinite) anticoagulant therapy was associated with fewer recurrences than was cessation of therapy after 6 months. For patients with idiopathic VTE (including those with recurrent VTE), extended-duration therapy was shown to decrease the relative risk for recurrence by 64% to 95%. Duration of therapy in the trials varied widely, from greater than 3 months, to 12 months, to up to 4 years. The results for extended-duration therapy reflect follow up only to 4 years; the risk–benefit ratio is not known for longer durations. Clinicians should weigh the benefits, harms, and patient preferences in deciding on the duration of anticoagulation.
This patient has two transient risk factors contributing to her deep venous thrombosis (DVT): a long airplane flight predisposing to venous stasis and oral contraceptives. Thus, a course of therapy for 3 to 6 months would be appropriate; 6 weeks would be considered too short and 12 months unnecessarily long. Decreasing warfarin treatment to 4 or 6 weeks results in a doubling of the rate of recurrent VTE compared with 6 months. Lifelong anticoagulation is unnecessary in a patient with transient, reversible risk factors for DVT.
- A 3- to 6-month regimen is adequate anticoagulation in a patient with a deep venous thrombosis caused by reversible risk factors.
Correct answer: B. Proceed to surgery with no preoperative treatment.
This patient may proceed to surgery with no preoperative treatment. Hematologic problems commonly encountered perioperatively include coagulopathy, thrombocytopenia, and anemia. Patients with a negative history for bleeding and normal physical examination findings undergoing low-risk procedures do not need screening for coagulopathy. Although routine screening for a bleeding disorder is not indicated unless there is a personal or family history suggestive of a problem, it was performed in this patient. Unexpected findings are uncommon, and even when present in a patient without a history of abnormal bleeding, rarely result in a change in preoperative management.
The relationship between an abnormal screening coagulation test and the risk of surgical bleeding is low in this group of patients. Because isolated factor XI deficiency, also called Rosenthal syndrome and hemophilia C, is seldom related to a bleeding tendency or is only a minimal bleeding risk at best, this patient who is undergoing minor surgery may proceed to surgery with no preoperative treatment; canceling surgery is also unnecessary.
Isolated factor XI deficiency is found most commonly in patients of Jewish ancestry from northern Europe (Ashkenazi ethnicity). Because factor VII in the extrinsic pathway can cross over and also activate factor IX in the intrinsic pathway, those factors higher up in the clotting cascade (factors XI and XII) are bypassed, resulting in relatively normal hemostasis.
- Patients with isolated factor XI deficiency seldom have a bleeding tendency and do not require prophylactic treatment prior to surgery.
Correct answer: D. Monthly erythrocyte transfusions.
The pathophysiology of stroke in patients with sickle cell disease is complex, involving adherent erythrocyte membranes, constricted arterioles, nitric oxide depletion, and other factors. Strokes recur in up to 70% of patients with sickle cell disease following an initial stroke if left untreated. Randomized trials have confirmed the ability of monthly erythrocyte transfusions (hypertransfusions) of two units per month in adults to decrease stroke recurrence by 50% in patients with sickle cell disease. In fact, in children at risk for stroke based on abnormal cranial Doppler flow measurements, such hypertransfusion therapy is an effective prophylactic treatment. Furthermore, increased stroke risk returns to baseline in children in whom transfusions are stopped once initiated.
Dipyridamole, clopidogrel, and angiotensin-converting enzyme inhibitors have a role in stroke prevention in patients with atherosclerotic disease; however, their role in patients with sickle cell disease remains undefined. Hydroxyurea would be continued, although its role in stroke prevention is unclear.
- Hypertransfusion can reduce the risk of stroke recurrence in patients with sickle cell disease by 50%.
Correct answer: D. Vitamin K deficiency.
Clotting factors II, VII, IX, and X, as well as protein C and protein S, require vitamin K–dependent gamma carboxylation for full activity. Dietary vitamin K is obtained primarily from the intake of dark green vegetables and is modified by gut flora to the active form. Interruption of bile flow prevents absorption of vitamin K. Antibiotic-related elimination of enteric bacteria limits intestinal sources of vitamin K, whereas warfarin directly antagonizes vitamin K activity. The prothrombin time (PT) is the first clotting time to become prolonged, but the activated partial thromboplastin time (aPTT) will also lengthen with further factor deficiencies. Therefore, a progressively prolonged PT (with the PT proportionately more prolonged than the aPTT) and a normal thrombin time in a malnourished patient receiving antibiotics should raise the suspicion for vitamin K deficiency. In adults with normal hepatic function, oral or subcutaneous vitamin K usually corrects the clotting times within 24 hours; intravenous vitamin K confers an increased risk for anaphylaxis. Fresh frozen plasma is used when urgent correction is required.
In this patient, the normal thrombin time and platelet count and elevated fibrinogen level are not suggestive of a diagnosis of disseminated intravascular coagulation (DIC) or liver disease. DIC would be a consideration in patients with a constellation of findings, including elevated levels of fibrin degradation products and/or fibrinogen D-dimer, sometimes accompanied by a prolonged PT, a decreased fibrinogen level, and thrombocytopenia.
Antibodies directed against clotting factors are rare but can result in potentially lethal, acquired bleeding disorders. Most such antibodies are considered idiopathic, but they may develop because of drugs or as part of an underlying illness, such as malignancy or autoimmune disorders (for example, systemic lupus erythematosus or rheumatoid arthritis). Diagnosis is made by identification of a protracted clotting time that does not correct with a mixing study. Quantifying the inhibitor by obtaining an inhibitor titer helps determine treatment options. Causes of such acquired bleeding disorders include the use of fibrin sealants during procedures, the presence of antiphospholipid antibodies, and the use of antibiotics. Because the PT/INR mixing study corrects to normal, a lupus inhibitor is excluded in this patient. In addition, low-dose heparin has no effect on INR and should not result in the clinical bleeding present in this patient. Finally, positive D-dimer results are to be expected in any hospitalized, ill patient with ongoing inflammation, and in the absence of any other findings, have no diagnostic significance.
- A progressively prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) (with the PT proportionately more prolonged than the aPTT) with a normal thrombin time in a malnourished patient who has received antibiotics is suggestive of vitamin K deficiency.