What is thrombotic thrombocytopenic purpura (TTP)?

Answer

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome characterized by neurologic symptoms (fever, renal impairment, thrombocytopenia, hemolytic anemia, and microvascular thrombosis) that result in variable degrees of tissue ischemia and infarction. Large-vessel thrombosis is uncommon.

The pathogenesis of TTP involves a relationship between the actions of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13) and platelet adherence to the extracellular vascular matrix. ADAMTS13 is a plasma zinc metalloprotease that cleaves von Willebrand factor (vWF) in the process of coagulation. A deficiency of ADAMTS13 creates a propensity for increased vWF-platelet aggregation that results in the intravascular thrombosis seen in TTP.

While levels of ADAMTS13 are very helpful in a definitive diagnosis, assay results take days in most centers and should not be waited upon to start plasmapheresis. In a clinically suggestive picture, elevated lactate dehydrogenase (LDH) and the presence of schistocytes on peripheral smear are sufficient starting points for emergent treatment.

ADAMTS13 deficiency can be caused by a genetic mutation or acquired autoimmune inhibitors. Hereditary TTP is a rare autosomal recessive disorder caused by ADAMTS13 mutations that result in the absence or severe deficiency of the plasma metalloprotease ADAMTS13. Patients with hereditary TTP may appear to be healthy, but their increased risk of critical thrombosis is always present.^[40] More than 200 ADAMTS13 mutations, spread over all ADAMTS13 protein domains, have been identified in patients with hereditary TTP. Diagnosis of hereditary TTP is confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles.^[41]

Several drugs have been implicated in the development of inhibitors and clinical TTP, including cyclosporine, mitomycin-C, ticlopidine, simvastatin, atorvastatin (Lipitor), and clopidogrel (Plavix). Human immunodeficiency virus (HIV) infection has also been associated with TTP.

Therapeutic plasma exchange with 40 mL fresh frozen plasma (FFP)/kg of body weight is the treatment of first choice in acute TTP and thrombotic thrombocytopenic purpura–adult hemolytic uremic syndrome (TTP-HUS). FFP replenishes the deficient ADAMTS13, while plasma exchange removes some of the pathogenic autoantibodies and endothelial-stimulating cytokines. Octaplas—a pooled plasma (human) blood product that has been treated with a solvent detergent process—provides a viable alternative to single-donor FFP and provides a reduced risk of certain viral transmissions.

McCarthy et al have treated more than 160 patients using FFP, solvent detergent (SD), and cryosupernatant as the exchange media.^[44]They showed that SD plasma has value in virtually eliminating all allergic reactions during treatment. Approximately 80% of patients respond to plasma exchange therapy.

Rituximab, a monoclonal antibody against CD20 present in B-lymphoid cells, has been successfully used in treating patients with acquired TTP who had failed to respond to plasma exchange.

Caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between vWF multimers and platelets and has shown efficacy in the treatment of acquired TTP. However, a subgroup of patients who had persistent ADAMTS13 deficiency had a relapse soon after treatment with caplacizumab was stopped, which suggests that monitoring of ADAMTS13 could be useful to guide the continuation of therapy. ^[46]

In the phase III HERCULES trial to study the efficacy and safety of caplacizumab in patients with acquired TTP, aplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo.^[47]

Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup of good responders to plasma exchange. High-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Knovich et al have developed an ADAMTS13 assay suitable for guiding the treatment of patients with suspected TTP.^[48]Recombinant ADAMTS13 may provide specific and more efficacious treatment of patients with TTP. Antiplatelet agents to inhibit the interaction between vWF and platelets are also being studied.^[49]

In a review of membrane plasma exchange for the treatment of idiopathic TTP, Marn Pernat et al reported 52 of their 56 patients (93%) had an excellent response to treatment, with 48 (86%) of them experiencing complete remission (platelet count > 100 x 10⁹/L). The patients (36% of whom were found to have renal impairment) underwent membrane plasma exchange 1-2 times daily until their platelet count normalized, with 1-1.5 plasma volumes (3606 +/- 991 mL) being replaced with FFP during each procedure. Overall, 1066 plasma exchange procedures were performed in this group of patients, with each patient undergoing an average of 19 +/- 17 procedures.^[50]

Four patients died after having received only 1-3 procedures; 6 patients who had had a complete remission suffered 1-5 relapses annually during the follow-up period, 1 of whom died of acute hemolytic reaction while undergoing tapering of plasma exchange procedures. In addition, 3 patients required additional splenectomy. The authors concluded that the use of plasma exchange with FFP "as a mandatory, up-to-date therapy" is supported by their data.^[50]

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