Clinical Information

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare (estimated incidence of 3.7 cases per million) and potentially fatal thrombotic microangiopathy syndrome. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia (intravascular hemolysis and presence of peripheral blood schistocytes), with no apparent alternative explanation of these findings. Other clinical features may include neurological symptoms, fever, and acute kidney injury. A large majority of patients initially present with thrombocytopenia and peripheral blood evidence of microangiopathy and, in the absence of any other potential explanation for such findings, satisfy criteria for early initiation of plasma exchange, which is critical for patient survival. TTP may rarely be congenital (Upshaw-Shulman syndrome) but is far more commonly acquired or immune mediated. iTTP may be considered primary or idiopathic (the most frequent type) or associated with distinctive clinical conditions (secondary TTP) such as medications, hematopoietic stem cell or solid organ transplantation, sepsis, and malignancy.

The isolation and characterization of an IgG autoantibody frequently found in patients with iTTP clarified the basis of this entity and led to the isolation and characterization of a metalloprotease called ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13 repeats), which is the target for the IgG autoantibody, leading to a functional deficiency of ADAMTS13. Normally, ADAMTS13 cleaves the ultra-high-molecular-weight multimers of von Willebrand factor (VWF) at the peptide bond Tyr1605-Met1606 to disrupt VWF-induced platelet aggregation. The anti-ADAMTS13 IgG antibody interferes with this cleavage resulting in circulating ultra-high molecular weight multimers, microvascular occlusion, and leads to TTP.

The initial testing for diagnosis of TTP consists of testing for ADAMTS13 activity and, if indicated, assessment of an inhibitor against ADAMTS13. However, in the appropriate clinical circumstance, the decision to initiate plasma exchange should not be delayed pending results of this assay.

Approximately 35% of antibodies to ADAMTS13 are non-neutralizing. These will not be detected by a mixing study Bethesda type of assay but may foster enhanced clearance/reduction of ADAMTS13. Enzyme-linked immunosorbent assay ADAMTS13 antibody testing may be useful in determining congenital vs. immune TTP.(1)

Cohort studies have examined the prognostic impact of presence of ADAMTS13 IgG antibody in TTP. Although there are conflicting studies, the weight of evidence suggests that a low ADAMTS13 activity, an elevated Bethesda titer, presence of an IgG antibody and a low ADAMTS13 antigen are strong independent predictors of more severe disease, longer time to achieving remission and when present at remission a shorter time to relapse.