PB0300 - Refractory Acquired Thrombocytopenic Thrombotic Purpura with Genetic Polymorphism Complement System

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is caused by autoantibody-mediated inhibition of the protease ADAMTS13. Lack of functional protease leads to ultralarge von Willegrand Factor multimers and platelet activation, with systemic thrombi. The role of complement dysregulation, well identified in other syndromes, has been discussed in TTP. This leads to the concept of a variety of mixed clinical presentations and outcomes, in which pathological mechanisms are intertwined. Novel therapies for refractory TTP include bortezomib and, anti-VWF nanobody, and eculizumab.

Aims: We present a case of refractory TTP, in which variants in complement genes were observed.

Methods: ADAMSTS13 activity was analyzed by a chromogenic test measured with ELISA (normal >40%). Quantification of antibodies IgG against ADAMTS13 was obtained by ELISA with IMUBIND, and defined as positive >=9.6 U/mL. Sanger sequencing of the whole ADAMTS13 gene was performed (cDNA sequence ENST00000371929). Genetic study of complement was made by NGS.

Results: A 19-year-old pregnant presented at delivery with anemia (6.6 g/dL), thrombocytopenia (7000 /µL), schistocytes. aTTP was diagnosed (0% ADAMTS13 activity). Plasma exchange (PEX), methylprednisolone iv (500 mg daily x 3, tapering), and rituximab (375mg/m2 x 4) were given, with no response. Therapy was intensified: corticoids (1 g/24 h x 3), PEX twice a day, vincristine (1.6 mg three doses). On day +20 caplacizumab was started. Platelet count rose until normal levels, ADAMTS13 activity persisted 0%. Anti-ADAMTS13 antibodies were negative. ADAMTS13 gene sequencing was normal. After three cycles of bortezomib (1.3 mg/m2 x 4) ADAMTS13 activity was 24%, on day +209. ADAMTS13 activity was 58.6% on day +291, remaining >40% since then. Genetic study of complement was performed, finding a carrier status for atypical Hemolytic Uremic Syndrome in heterozygosis (MCPggaac/MCPaaggt).

Conclusion(s): Bortezomib is effective in refractory aTTP.
Caplacizumab is a safe therapy even in long-term scheduling.
Severe refractory cases may involve associated polymorphisms in the complement system.