Posted August 1, 2012
Cherie Paquette, MD
CAP Molecular Oncology Committee
Thrombotic thrombocytopenic purpura (TTP) is a rare medical emergency requiring a high clinical index of suspicion, assisted by targeted laboratory testing, for diagnosis. With only 4.5 cases per million people per year and nonspecific symptoms, TTP may be difficult to distinguish from more common conditions such as sepsis, malignancy, medication side effects, etc.1 If the condition is untreated, the mortality rate can be as high as 90% secondary to microangiopathic end-organ damage.2 The classic clinical pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal dysfunction, and fever are present in a minority of TTP cases. Only the first two of the pentad are needed for a presumptive diagnosis, and they are sufficient to consider immediate plasma exchange, day or night. This article will discuss strategies for clinical laboratory testing to diagnose this potentially rapidly fatal condition as quickly and definitively as possible.
Commonly ordered tests and their respective results supporting microangiopathic hemolytic anemia are listed below:
|Peripheral blood smear review||Schistocytes present|
When considering TTP, it is important to communicate this on the laboratory requisition and to order a smear review, as automated methods will not flag schistocytes. Regarding additional testing, a negative direct antibody (Coombs) test and normal coagulation markers argue against an autoimmune hemolytic anemia and disseminated intravascular coagulation, respectively. A specimen should be sent for ABO blood type in anticipation of future plasma request if exchange therapy is initiated.
An ADAMTS13 assay should be considered early in the process using a sample collected prior to the administration of any blood products. Approximately 75% of TTP cases have a low ADAMTS13 level or ADAMTS13 inhibitor. The inability to breakdown ultra-large von Willebrand factor by ADAMTS13 leads to enhanced platelet aggregation at the endothelial cell surface, microvascular occlusion, and mechanical injury to erythrocytes.3 Assays for ADAMTS13 are typically available at large hospitals and reference laboratories, with results reported within days. A recent study found that four routine clinical tests correlated with low (<15%) ADAMTS13: elevated indirect bilirubin and reticulocytes, thrombocytopenia, and normal to minimally elevated creatinine; however, this is not a substitute for the ADAMTS13 test.4
A low or inhibited ADAMTS13 helps confirm the diagnosis of TTP, but more importantly the results inform future management: if severely deficient (usually less than 10%), close monitoring is needed due to a significantly increased relapse risk. Approximately 8% of all patients relapse, with a 30% relapse rate for those with severe ADAMTS13 deficiency.3,5 In the short term, the ADAMTS13 results help rule out conditions with clinical overlap, such as hemolytic-uremic syndrome.
With modern plasma exchange, approximately 70% of patients survive with treatment for TTP.5 When diagnosed in time and with prompt initiation of treatment, this historically deadly disease now has a much improved prognosis. The initiation of proper laboratory testing requires physicians to have a high index of suspicion for TTP; and proper test selection, timing, and interpretation is facilitated by collaboration with pathologists in the laboratory.
- Terrell DR, Williams LA, Vesely SK, Lämmle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost. 2005;3(7):1432–1436.
- Shepard KV, Bukowski RM. The treatment of thrombotic thrombocytopenic purpura with exchange transfusions, plasma infusions, and plasma exchange. Semin Hematol. 1987;24(3):178–193.
- Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112(1):11–18.
- Bentley MJ, Lehman CM, Blaylock RC, Wilson AR, Rodgers GM. The utility of patient characteristics in predicting severe ADAMTS13 deficiency and response to plasma exchange. Transfusion. 2010;50(8):1654–1664.
- Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115(8):1500–1511.
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