Acquired autoimmune thrombotic thrombocytopenic purpura in a case of severe haemophilia A
Venue: Haemophilia the official journal of the World Federation of Hemophilia

Acquired thrombotic thrombocytopenic purpura (TTP) is a life threatening thrombotic disorder, affecting 3 10 per million residents  Deficiency of plasma ADAMTS13 activity, resulting from autoantibodies  is the primary cause of acquired TTP in adults. ADAMTS13 is a proteolytic enzyme that cleaves ultra large von Willebrand factor (ULVWF) into smaller sizes. When ADAMTS13's activity is inhibited by autoantibodies, ULVWF remains on endothelial surface and in circulation, which captures or binds flowing platelets and results in systemic platelet clumping, a characteristic feature of TTP. Clinically, TTP patients manifest with severe thrombocytopenia and microangiopathic haemolytic anaemia, in addition to varying degrees of multiorgan dysfunction. If left untreated, the mortality of TTP is nearly 90 100% Therapeutic plasma exchange (TPE) is the only effective initial therapy that reduces the mortality rate to 10 20%  Haemophilia A, however, is an X linked recessive bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII) It occurs in 1 of 5000 male births. Haemophilia A is classified as mild >5% moderate (1 5% and severe <1% based on the residual FVIII clotting activity [4] While TTP and haemophilia A are caused by completely different mechanisms, it is not known whether defect of a key component in the coagulation cascade (e.g. haemophilia A) would modulate the onset and progress of a thrombotic disorder (e.g. TTP) Here, we report a case of 56 year old African American male with acquired autoimmune TTP in the setting of severe to moderate haemophilia A. This case emphasizes the concept that haemophilia A is not protective against TTP pathogenesis. Instead, the lack of FVIII may be a potential risk factor for TTP. In April 2000, a 56 year old African American male with haemophilia A was admitted to an outside hospital with headaches and confusion. His past medical history includes positive hepatitis C, but negative human immunodeficiency virus (HIV) Although no lab reports were available for our review, per clinical notes, he was reported to have severe thrombocytopenia, elevated bilirubin and lactate dehydrogenase (LDH) and many schistocytes on his peripheral blood smear. His initial plasma FVIII activity was <1% Over the course of admission, his condition worsened, resulting in seizures and a brief period of being comatose. TTP was presumptively considered and TPE was initiated. Over 3 months of hospitalization, a total of 50 TPE procedures were performed with intermittent plasma transfusion, in addition to corticosteroids, rituximab, cyclophosphamide and splenectomy. Furthermore, the patient was also treated with prophylactic doses of plasma derived factor VIII concentrate to maintain his plasma levels at approximately 75 100% at all times. We did not observe any more bleeding in this case (both thrombocytopenia and factor VIII deficiency) than other haemophilia A patients without TTP. In December 2002, the patient experienced his first relapse, resulting in another prolonged course of hospitalization and similar treatment. In June 2007, the patient was hospitalized again for left sided weakness; brain imaging detected multiple cerebral infarctions. His initial platelet count was 13 000 lL 1 with numerous schistocytes on a peripheral blood smear. Plasma FVIII activity at that time was 2% Serum LDH was 415 U L 1 and creatinine was 0.8 mg L Plasma ADAMTS13 activity was reported as less than 5% (normal 67% and the inhibitor titre was 0.4 units (normal 0.4) The diagnosis of acquired autoimmune TTP was made. He received weekly rituximab infusions in addition to plasma infusion and achieved a complete remission within a few weeks. In June 2011, the patient experienced the third TTP relapse after pneumonia and sepsis. Platelet count was 44 000 lL Hb 10.7 g dL LDH 579 U L 1 and creatinine 1.1 mg dL Plasma ADAMTS13 activity was <5% and inhibitor titre was 0.6 units. Patent underwent clinical remission and follow up plasma ADAMTS13 activity in August 2011, November 2011 and September 2015 was 57% 71% and 43% respectively. These results essentially ruled out the Correspondence: Lance A. Williams III, MD or X. Long Zheng, MD, PhD, Division of Laboratory Medicine, Department of Pathology, University of Alabama at Birmingham, WP230 619 19th Street South, Birmingham, AL 35235, USA. Tel. +205 975 8161; fax: +205 975 4468;  lawrencewilliams@uabmc.edu or xzheng@uabmc.edu