Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

Abstract

Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL^-1 ) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL^-1 ) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP.

Keywords: diagnosis; pathology; therapeutics; thrombotic microangiopathies; von Willebrand factor.

Fig. 1. Historic prospective of TTP research

Several landmark discoveries have been made since the initial case report in 1924, leading to understanding pathogenesis of TTP, basic biology of ADAMTS13 metalloprotease, and the association of ADAMTS13 abnormality with other arterial and inflammatory diseases. Here, VWF-cp denotes VWF-cleaving protease.

Fig. 2. Algorithm for differentiating TTP from aHUS and their therapeutic modalities

Plasma ADAMTS13 activity <10 IU/dL is the single most important test for differentiating TTP from aHUS after excluding other known causes of TMA, including disseminated intravascular coagulation (DIC), mechanic valves, and malignant hypertension (MHTN). Other clinical features including the platelet counts (<30×10⁹/L), degree of renal injury (creatine<2.2 mg/dL), and swift response to plasma exchange therapy are also crucial for the initial diagnosis before ADAMTS13 activity becomes available. The asterisk (*) indicates that the cut-off value may vary from laboratory to laboratory depending on the assay used. The double asterisks (**) indicate that ADAMTS13 activity in non-TTP patients is usually much higher than 10 IU/dL.