A 45-year-old woman with a history of developmental delay and mild mitral regurgitation who had recently had a fever attributed to a possible urinary tract infection presented to the ED with rectal pain and a small amount of bleeding from an apparent external hemorrhoid. Initial vital signs were stable, other than mild tachycardia. Physical exam was notable for mild scleral icterus, mild tachycardia with a systolic flow murmur, and an external hemorrhoid with heme-positive digital rectal exam.
Labs were significant for a mild leukocytosis (present over several years), a hemoglobin level of 6.9 g/dL (reference range, 11.5 to 14.5 g/dL), a platelet count of 15,000/µL (reference range, 140,000 to 450,000/µL), and a total bilirubin level of 5 mg/dL (reference range, 0.2 to 1 mg/dL). The patient's hemoglobin level and platelet count had been normal one year prior. Additional labs showed a very high lactate dehydrogenase (LDH) level, undetectable haptoglobin, a direct bilirubin level of 0.7 mg/dL, and a peripheral smear showing schistocytes, suggestive of hemolytic anemia (Figure).
Disseminated intravascular coagulation (DIC) did not seem likely given the patient's normal prothrombin and partial thromboplastin time and elevated fibrinogen level of 571 mg/dL (reference range, 180 to 500 mg/dL). The patient was admitted to the ICU for probable thrombotic thrombocytopenic purpura (TTP) and treated with plasma exchange and corticosteroids. After five days of treatment, her platelet count recovered and her LDH level normalized, and she was discharged home. An ADAMTS13 activity test taken at admission returned 10 days later at 7% (normal values >60%).
This patient had TTP, a clinical syndrome with a pentad including microangiopathic hemolytic anemia, thrombocytopenia, fever, renal disease, and neurologic dysfunction. Only a minority of patients (20% to 30%) have the entire pentad. There are no pathognomonic features of TTP, and the main complications are renal and neurologic dysfunction. The differential diagnosis includes hemolytic uremic syndrome, idiopathic thrombocytopenic purpura, DIC, sepsis, malignant hypertension, preeclampsia, and HELLP syndrome. It is helpful to exclude these diagnoses based on clinical presentation and laboratory tests. Some triggering factors for acquired TTP may include pregnancy, cancer, HIV, lupus, infection, and medications.
If untreated, approximately 95% of cases are fatal, but overall response rate to plasma exchange is 75% to 90%. This emphasizes the need for a high degree of clinical suspicion and early diagnosis. Pathophysiology involves the absence of von Willebrand factor cleaving enzyme (ADAMTS13), resulting in large von Willebrand multimers that lead to platelet aggregation and subsequent thrombocytopenia and microthrombi. TTP can be inherited (faulty production of ADAMTS13) or acquired (through ADAMTS13 antibodies).
Examination of the peripheral smear is crucial and will show evidence of hemolysis with fragmented red blood cells (schistocytes) and thrombocytopenia. After this has been established, the differential can be further narrowed by exclusion of other causes of hemolytic anemia. Urgent hematology consultation is advised for suspected cases. Treatment includes plasma-exchange therapy (aimed at replacing ADAMTS13) combined with corticosteroids. Newer adjunctive immunotherapy, approved by the FDA in January 2019, includes caplacizumab, which blocks the interaction between von Willebrand factor and platelets, leading to a faster normalization of the platelet count and reduced risk of death, recurrence, or a major thromboembolic event. Evidence supports use of rituximab in refractory TTP (which occurs in 10% to 42% of cases) or relapsing TTP (which occurs in 13% to 36%).
- The TTP pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, renal disease, and neurologic abnormalities is classic but presents in its entirety only in a minority of patients.
- Because TTP has a very high mortality rate if untreated, early recognition and treatment are critical and should involve plasma exchange and corticosteroids with or without immunotherapy.