Clinical and laboratory diagnosis of TTP: an integrated approach

Abstract

Thrombotic thrombocytopenia purpura (TTP) is a rare, life-threatening disease with an incidence of approximately 2 persons per million per year. It is characterized by severe deficiency of the von Willebrand cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), leading to formation of platelet-rich thrombi in the microvasculature. Prompt initiation of appropriate therapy, particularly plasma exchange, may be life-saving. Diagnosis of TTP is challenging because of its diverse clinical manifestations, overlap in clinical presentation with other thrombotic microangiopathies, and limited availability of ADAMTS13 testing. Clinical prediction scores have been developed to estimate the pretest probability of severe ADAMTS13 deficiency and may be used as an adjunct to clinical judgment to guide initial management decisions. An ADAMTS13 activity level of less than 10% supports the diagnosis of TTP in appropriate clinical contexts, but many centers do not offer testing in-house and must send out the test to a reference laboratory with a turnaround time of several days. In such instances, initial management decisions must be made without the benefit of laboratory testing. In patients with TTP, inhibitor tests may be useful for distinguishing immune-mediated from congenital TTP. In this article, we review the epidemiology, natural history, and clinical presentation of TTP and laboratory assays for TTP including ADAMTS13 activity and inhibitor assays. We also describe an evidence-based approach to the evaluation of a patient with suspected TTP that integrates clinical and laboratory assessment.

Figure 1.

Predisposing conditions associated with TTP and their relative frequencies. Proportion of TTP cases according to predisposing etiology is shown. Percentages are approximate and are synthesized from published studies.^,,-

Figure 2.

Approach to the diagnosis of TTP. Our approach to the diagnosis of TTP involves 3 steps. In the initial step, obvious alternative causes of TMA are excluded. In the second step, if an obvious alternative cause is not present, the patient should be evaluated for TTP, using the PLASMIC score and measurement of ADAMTS13 activity. Our approach assumes that the ADAMTS13 activity result will not be immediately available and that the initial decision about whether to commence PEX must be made on clinical grounds alone. We recommend initiating PEX in patients with an intermediate- or high-risk PLASMIC score, whereas we recommend withholding PEX in those with a low risk score. The ADAMTS13 activity level is used to refine the diagnosis. An ADAMTS13 level of less than 10% confirms the diagnosis of TTP in patients with an intermediate- to high-risk PLASMIC score and supports the diagnosis in those with a low-risk PLASMIC score. The third step involves distinguishing immune-mediated from congenital TTP. We use clinical information, ADAMTS13 inhibitor/antibody assays, measurement of ADAMTS13 activity in remission, and ADAMTS13 mutation analysis to differentiate between these entities. This algorithm aims to provide general guidance to clinicians, but is not a substitute for clinical judgment, which should be individualized for each patient. APS, antiphospholipid syndrome; DIC, disseminated intravascular coagulation; HELLP, Hemolysis, Elevated Liver function tests, and Low Platelets.