MKSAP quiz on TTP-HUS


Case 1: Abdominal pain, fever, and bleeding

A 45-year-old woman is evaluated in the emergency department for a 1-day history of abdominal pain and fever. She also reports unexpected, heavy menstrual bleeding of 1 day's duration and easy bruising of 2 days' duration. Medical and family histories are unremarkable, and she takes no medications.

On physical examination, the patient is oriented to person and place, but not time. Temperature is 38.1 °C (100.6 °F), blood pressure is 170/98 mm Hg, pulse rate is 110/min, and respiration rate is 20/min. Other than confusion, neurologic examination is normal. Subconjunctival hemorrhages are present. Cardiopulmonary examination is normal. Abdominal examination reveals tenderness to palpation without guarding or rebound. Pelvic examination shows blood in the vaginal vault with no cervical motion tenderness or adnexal masses.

Laboratory studies show hematocrit 26%, leukocyte count 10,300/µL (10.3 × 109/L), platelet count 24,000/µL (24 × 109/L), reticulocyte count 8.3% of erythrocytes, bilirubin, total 2.3 mg/dL (39.3 µmol/L), creatinine 3.2 mg/dL (283 µmol/L), and lactate dehydrogenase 1500 U/L.

Which of the following is the most appropriate diagnostic test to perform next?

A. ADAMTS13 activity level
B. Osmotic fragility test
C. Peripheral blood smear
D. Stool Shiga toxin assay

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Case 2: Diarrhea complications

A 23-year-old woman is hospitalized for a 2-day history of diarrhea. In the last 24 hours, there has been blood in the stools. She has had abdominal cramping but reports no fevers or chills. She eats only organically grown foods and drinks unpasteurized milk.

On physical examination, temperature is 36.8 °C (98.2 °F), blood pressure is 115/72 mm Hg, pulse rate is 86/min, and respiration rate is 18/min. She has mild abdominal pain diffusely on palpation.

The patient's stool shows visible bright red blood streaking.

Which of the following is the most common complication associated with this patient's dysentery?

A. Aortitis
B. Guillain-Barré syndrome
C. Hemolytic uremic syndrome
D. Mesenteric adenitis
E. Reactive arthritis

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Case 3: Edema and history of bloody diarrhea

A 35-year-old woman is evaluated in the emergency department for new-onset lower extremity edema. She notes a 1-week history of progressive shortness of breath and fatigue. She attended a picnic 10 days ago and subsequently developed bloody diarrhea, which has largely subsided. Medical history is otherwise unremarkable, and she takes no medications.

On physical examination, temperature is 37.8 °C (100.0 °F), blood pressure is 190/90 mm Hg, pulse rate is 100/min, and respiration rate is 20/min. BMI is 27. There is no skin rash. Cardiopulmonary examination is normal. The abdomen is diffusely tender but without rebound. Bilateral lower extremity edema is noted to the level of the mid calves. On neurologic examination, mental status is normal, and there are no other focal findings.

Laboratory studies show hemoglobin 7.0 g/dL (70 g/L), platelet count 50,000/µL (50 × 109/L), and creatinine 7.2 mg/dL (636.5 µmol/L). Urinalysis shows 2+ blood, 1+ protein, 0-2 erythrocytes/hpf, and 0-2 leukocytes/hpf.

Which of the following is the most appropriate next step in diagnosis?

A. ADAMTS13 activity level
B. Kidney biopsy
C. Peripheral blood smear
D. Urine protein electrophoresis

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Case 4: Thrombocytopenia in pregnancy

A 35-year-old woman is evaluated for worsening thrombocytopenia; she is pregnant at 36 weeks' gestation. Medical history is significant for immune thrombocytopenic purpura. Previous platelet counts during this pregnancy have been 80,000 to 100,000/µL (80-100 × 109/L). Her only medication is a prenatal vitamin.

On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 165/110 mm Hg, pulse rate is 95/min, and respiration rate is 18/min. Abdominal examination reveals mild right upper quadrant discomfort on palpation. Reflexes are normal, and no clonus is observed. She has lower extremity edema to the level of the knees bilaterally.

Laboratory studies show hemoglobin 10.5 g/dL (105 g/L), platelet count 21,000/µL (21 × 109/L), alanine aminotransferase 480 U/L, aspartate aminotransferase 600 U/L, creatinine 1.2 mg/dL (106.1 μmol/L), and urinalysis 3+ protein.

Image from MKSAP 17
Image from MKSAP 17

A peripheral blood smear is shown (Figure).

Which of the following is the most appropriate management of this patient's thrombocytopenia?

A. Emergent delivery
B. Intravenous immune globulin
C. Plasma exchange
D. Prednisone

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Answers and commentary

Case 1

Correct answer: C. Peripheral blood smear.

The most appropriate diagnostic test to perform at this time is a peripheral blood smear. This patient likely has thrombotic thrombocytopenic purpura (TTP). TTP should be suspected in patients who have microangiopathic hemolytic anemia, characterized by schistocytes on the peripheral blood smear and increased serum lactate dehydrogenase levels, and thrombocytopenia. A peripheral blood smear is essential to determine whether the anemia is caused by a microangiopathic hemolytic process as indicated by the presence of schistocytes. Patients may also have fever; kidney manifestations such as hematuria, elevated creatinine level, and proteinuria; and fluctuating neurologic manifestations, but the absence of these symptoms does not exclude the diagnosis.

Assays for ADAMTS13 activity and inhibitor titer are available but are best used for prognosis rather than to guide therapy, because TTP requires immediate treatment that cannot be delayed until laboratory test results are available. Low activity levels and a positive inhibitor titer confer a higher risk for relapse.

An osmotic fragility test is used to evaluate for hereditary spherocytosis, which can produce hemolysis in the setting of an acute infection. However, hereditary spherocytosis does not cause thrombocytopenia, kidney injury, or mental status changes.

TTP can overlap with hemolytic uremic syndrome (HUS), which usually occurs in children. HUS may be precipitated by an infectious diarrheal illness, especially Escherichia coli O157:H7 or Shigella species. These bacteria elaborate a toxin that resembles antigens on renal endothelial cells and bind and cause renal cell death. It is not clinically helpful to attempt to distinguish between TTP and HUS, because many patients with HUS respond to plasma exchange, the treatment for TTP.

Key Point

  • Thrombotic thrombocytopenic purpura is a clinical diagnosis that requires the presence of thrombocytopenia and microangiopathic hemolytic anemia, which is confirmed by schistocytes on the peripheral blood smear.

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Case 2

Correct answer: C. Hemolytic uremic syndrome.

This patient with dysentery most likely has Escherichia coli infection and is at risk for hemolytic uremic syndrome (HUS). E. coli O157:H7, a Shiga toxin–producing E. coli (STEC) serotype, is the most common cause of acute bloody diarrhea in the United States. It differs from other causes of dysentery in that fever is distinctly uncommon. STEC organisms are widespread in the gastrointestinal tract of domesticated animals, particularly cattle, and cause disease through ingestion of contaminated food or, as in this case, unpasteurized milk. One of the most serious complications of STEC infection is the development of HUS, which occurs in 5% to 10% of cases, most frequently in children. HUS is a form of thrombotic microangiopathy characterized by fever, hemolytic anemia, consumptive thrombocytopenia, neurologic findings, and kidney failure. Antibiotic and antimotility therapies are both associated with increased risk for HUS and should not be prescribed when there is clinical concern for STEC gastrointestinal disease.

The other choices are complications associated with bacterial causes of dysentery, but unlike STEC infections, these are usually associated with fevers. Aortitis is an inflammation of the aortic wall and can potentially be caused by Salmonella infection, which has a propensity for causing endovascular infection, particularly when there is significant atherosclerosis or graft material. Guillain-Barré syndrome is a rare complication of Campylobacter infection, occurring in less than 1% of cases; however, up to 40% of cases of Guillain-Barré are triggered by an antecedent Campylobacter infection. Several strains of Yersinia cause infection of the mesenteric lymph nodes and can mimic acute appendicitis. Grossly bloody stools are uncommon with Yersinia infection. Reactive arthritis can occur following Campylobacter, Shigella, Salmonella, or Yersinia infections in patients who are positive for the HLA-B27 gene.

Key Point

  • One of the most serious complications of Escherichia coli O157:H7 infection is hemolytic uremic syndrome, with this risk increased if antibiotics or antimotility therapy is administered.

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Case 3

Correct answer: C. Peripheral blood smear.

The next step in diagnosis is a peripheral blood smear. This patient has findings suggestive of Shiga toxin–associated hemolytic uremic syndrome (HUS). This is a diarrhea-associated syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and kidney failure caused by Shiga toxin–producing Escherichia coli, typically with serotypes O157:H7, O104:H4, and, less commonly, Shigella dysenteriae. Shiga toxin binds to endothelial cells, triggering thrombosis and resulting in a thrombotic microangiopathy. It also binds to renal mesangial cells, podocytes, and renal tubular cells, causing direct damage. These actions lead to acute kidney injury (AKI). Although this patient has a consistent clinical history, a peripheral blood smear is essential to determine whether the anemia is caused by a microangiopathic hemolytic process as indicated by the presence of schistocytes. Stool cultures may reveal the offending organism. Treatment is primarily supportive, and many patients require dialysis.

ADAMTS13 is a metalloprotease enzyme that cleaves von Willebrand factor; low activity levels are supportive of a diagnosis of thrombotic thrombocytopenic purpura (TTP). Although this would be a reasonable study in this patient if a likely diagnosis of Shiga toxin–associated HUS were less clear to assess for the possibility of TTP, confirmation of true thrombocytopenia and microangiopathic hemolytic anemia would be an initial diagnostic step before additional testing.

Kidney biopsy would show evidence of capillary thrombosis as well as glomerular and tubular damage, but it is not necessary to establish the diagnosis of Shiga toxin–associated HUS.

Urine protein electrophoresis may be useful in evaluating AKI due to monoclonal urine immunoglobulin light chains (Bence Jones proteins). Although a plasma cell disorder may cause anemia and AKI due to precipitation of light chains in the renal tubule (myeloma kidney), it is not a cause of microangiopathic hemolytic anemia or thrombocytopenia as seen in this patient.

Key Point

  • Shiga toxin–associated hemolytic uremic syndrome is a diarrhea-associated syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and kidney failure caused by Shiga toxin–producing Escherichia coli.

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Case 4

Correct answer: A. Emergent delivery.

The most appropriate management for this patient's thrombocytopenia is immediate delivery of the fetus, because she has HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome. Although she has a history of immune thrombocytopenic purpura (ITP), and her platelet counts have been low throughout the pregnancy, her markedly decreased platelet count is worrisome and could indicate development of another condition. Worsening anemia, right upper quadrant pain, hypertension, proteinuria, and elevated liver enzymes are more consistent with a microangiopathy of pregnancy (HELLP syndrome, preeclampsia, thrombotic thrombocytopenic purpura [TTP]) rather than worsening ITP. Her clinical picture is more consistent with preeclampsia (new-onset hypertension at >20 weeks' gestation) with proteinuria or the HELLP syndrome. The relationship between preeclampsia and HELLP syndrome is unclear; HELLP syndrome occurs in 10% to 20% of women with preeclampsia but occasionally in some patients without hypertension or proteinuria. The primary treatment for both conditions, particularly in advanced pregnancy, is urgent delivery. Platelet counts tend to recover quickly after delivery; persistent thrombocytopenia several days after delivery should raise concern for another diagnosis, such as thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS).

Administering intravenous immune globulin is not indicated as a treatment for thrombocytopenia associated with preeclampsia and HELLP syndrome.

Plasma exchange can be undertaken if TTP is present earlier in the pregnancy before delivery is a viable option, but would not be a preferred treatment strategy in a patient in whom delivery is appropriate. Plasma exchange would be indicated if thrombocytopenia persisted after delivery and TTP-HUS were diagnosed.

Glucocorticoids such as prednisone are not indicated for microangiopathy of pregnancy. Additionally, if used as a treatment for ITP, prednisone typically takes 48 to 72 hours for effectiveness. Therefore, treatment with prednisone would not be appropriate in this patient.

Key Point

  • Immediate delivery of the fetus is the best management approach for pregnant women experiencing thrombotic microangiopathy of pregnancy.