You are working at a tertiary care center and a 55-year-old woman is transferred to you from an outside hospital for severe persistent thrombocytopenia of unknown origin. She initially presented one week ago with abdominal pain and underwent cholecystectomy. On arrival, she is mildly confused and tachycardic. The platelet count is 7K and the hemoglobin is 5.8. Your hematologist evaluates the peripheral blood smear and visualizes schistocytes meeting criteria for microangiopathic hemolytic anemia. The diagnosis of thrombotic thrombocytopenic purpura (TTP) is suspected. What causes TTP and what are the next steps in management? 

If untreated, TTP is fatal in 90% of patients and is considered a hematologic emergency. Thrombotic microangiopathy leads to platelet consumption and hemolysis causing end-organ dysfunction. TTP is caused by a deficiency of ADAMTS13, which is the enzyme that cleaves von Willebrand factor (VWF) throughout the blood vessels. Without it, VWF forms large multimers that bind platelets causing microthrombi and microvascular occlusion, leading to microangiopathic hemolytic anemia.  TTP can be hereditary or acquired. Acquired disease occurs when patients develop autoantibodies to ADAMTS13. Patients typically present with vague complaints such as fatigue, weakness, confusion, headache, abdominal pain, nausea, vomiting and diarrhea. Renal insufficiency is less common, and patients do not typically progress acute renal failure. The differential diagnosis includes preeclampsia, HELLP, severe HTN, endocarditis, HIV, CMV, RMSF, Malaria, Babesiosis, Aspergillosis, malignancies, rheumatic disease (lupus, systemic sclerosis, antiphospholipid syndrome), DIC and severe vitamin B12 deficiency. 

Important laboratory testing includes ECG, troponin, CBC, reticulocytes, BMP, LDH, LFTs, ADAMTS13, Coombs testing. An ADAMTS13 assay showing less than 10% normal plasma levels is required to establish the diagnosis of TTP, but is rarely available at clinical presentation. Of note, the ADAMTS13 activity assay must be sent prior to initiation of plasma exchange to avoid false negative results. Due to microangiopathic hemolytic anemia, patients typically have very high LDH, indirect bilirubin, and reticulocyte counts. The PLASMIC score can be used to help identify patients with TTP. 

PLASMIC score: 

Platlet count < 30k

Hemolysis

Reticulocyte > 2.5

Undetectable haptoglobin

Indirect bilirubin > 2

MCV < 90

Creatinine < 2

INR < 1.5

No active cancer

No solid organ or stem cell transplant

Score: 

0-4 points: Low probability

5 points: Intermediate probability 

6-7 points: High probability 

Treatment for TTP requires emergent initiation of plasma exchange (PEX) and should be started within 4 to 6 hours of diagnosis in nearly all patients with thrombotic microangiopathic hemolytic anemia with schistocytes, peripheral thrombocytopenia and organ dysfunction, in the absence of an obvious alternative diagnosis. Plasma infusion can be used as a temporizing measure until the initiation of PEX. Treatment continues until the platelet count has normalized for at least two days. It is important to avoid platelet transfusion, as it may worsen symptoms. Corticosteroids are recommended in combination with PEX as first-line treatment to suppress antibody formation. Rituximab and cyclosporine have been found to be beneficial in immune-mediated TTP. Patients require close monitoring early in the disease course, as sudden death can occur from cardiac microvascular occlusion, arrhythmia or cardiogenic shock. Cardiac ischemia is among the most common causes of death in patients with TTP. Neurologic impairment is also associated with worse outcome and can range from headache to stroke and coma. Expert consensus suggests that all patients with TTP should be admitted to the ICU for PEX initiation. Relapse occurs in up to 50% of patients. 

Resources: 

Azoulay E, et al. Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive Care Med 2019;45:1518-1539.

L. A. Dixon & R. R. Hemphill. (2016). Section18: Hematologic and Oncologic Disorders. In Tintinalli's Emergency Medicine: A Comprehensive Study Guide (8th ed., pp. 1515-1516). New York, NY: McGraw-Hill Education.

Paydary K, et al. Diagnostic accuracy of the PLASMIC score in patients with suspected thrombotic thrombocytopenic purpura: A systematic review and meta-analysis. Transfusion 2020; Aug 5: online ahead of print.