Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers

Abstract

Although outstanding progress has been made in understanding the pathophysiology of thrombotic thrombocytopenic purpura (TTP), knowledge of the immunopathogenesis of the disease is only at an early stage. Anti-ADAMTS13 auto-antibodies were shown to block proteolysis of von Willebrand factor and/or induce ADAMTS13 clearance from the circulation. However, it still remains to identify which immune cells are involved in the production of anti-ADAMTS13 autoantibodies, and therefore account for the remarkable efficacy of the B-cell depleting agents in this disease. The mechanisms leading to the loss of tolerance of the immune system towards ADAMTS13 involve the predisposing genetic factors of the human leukocyte antigen class II locus DRB1*11 and DQB1*03 alleles as well as the protective allele DRB1*04, and modifying factors such as ethnicity, sex and obesity. Future studies have to identify why these identified genetic risk factors are also frequently to be found in the healthy population although the incidence of immune-mediated thrombotic thrombocytopenic purpura (iTTP) is extremely low. Moreover, the development of recombinant ADAMTS13 opens a new therapeutic era in the field. Interactions of recombinant ADAMTS13 with the immune system of iTTP patients will require intensive investigation, especially for its potential immunogenicity. Better understanding of iTTP immunopathogenesis should, therefore, provide a basis for the development of novel therapeutic approaches to restore immune tolerance towards ADAMTS13 and thereby better prevent refractoriness and relapses in patients with iTTP. In this review, we address these issues and the related challenges in this field.

Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine

“…40,44 The pathophysiological mechanisms underlying the different scenarios in iTTP observed after treatment with rituximab (ie, durable response, temporary response with subsequent recurrence of anti-ADAMTS13 autoantibodies, refractoriness) as well as the specific B-and T-cell and plasma cell subpopulations involved still remain to be elucidated. 45 Future studies should also assess whether rituximab selects for survival of long-lived plasma cells involved in the production of anti-ADAMTS13 autoantibodies, which would raise new therapeutic challenges. 46,47 Splenectomy has also been reported to decrease relapses with an acceptable safety profile and may therefore represent an alternative to rituximab.…”

Understanding the Health Literacy in Patients With Thrombotic Thrombocytopenic Purpura

“…Lastly, patients were globally unaware of the controllable key factors associated with relapse, especially pregnancy. 32 – 34 Finally, an important finding of this work is that a high proportion of patients did not answer the question regarding what to do in case of an emergency setting. This finding challenges our information and needs efforts from practitioners to clarify the requested actions in case of unusual symptoms including bleeding and neurological symptoms, but also unusual fatigue.…”

Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management

“…The most common isotype class of anti-ADAMT13 autoantibodies are IgG, followed by IgA and IgM (20% of cases). Among the IgG isotype, the IgG4 subclass is most common, followed by IgG1 [ 83 , 91 , 94 , 95 , 96 , 97 , 98 ]. During acute episodes of iTTP, approximately 75% of cases have detectable free anti-ADAMTS13 IgG [ 29 ].…”