Background: A syndrome of MAHA, thrombocytopenia and microthrombosis (MAHATT) can result from a variety of etiologies. Making an accurate diagnosis is important to guide treatment decisions and to inform prognosis. Our centre is one of the two adult apheresis centres serving a catchment area of over 5 million people. Our centre maintains database of all patients who were referred for investigation and treatment of MAHATT.
Materials and Methods: ADAMTS13 testing was performed at our centre by a qualitative collagen binding assay before 2011 and by ELISA (Technoclone GmbH, Viennna) after 2011. Complement genetics studies included screening CFI, CFH, CFB, CD46/MCP, CFHR5, C3, APLN and THBD genes and were performed at the Hospital for Sick Children, Toronto. Complement protein and function studies were performed at the laboratories of the University of Heidelberg, Heidelberg and St. Justine Hospital, Montreal.
Results: Between January 1 2010 and December 31 2015, 78 patients were referred with a presumed diagnosis of TTP for apheresis. On presentation, all patients had evidence of MAHA, thrombocytopenia and organ involvement. Five additional patients had a history of MAHATT and were referred for a second opinion.
2 patients did not have ADAMTS13 done and died during admission. The remaining 81 patients could be divided into 4 groups.
Group 1 (TTP). 34 patients were found to have severe ADAMTS13 deficiency (activity less than 5%) and were diagnosed with TTP. Three additional patients were included in this Group despite having ADAMTS13>5% on presentation: one with relapse of immune TTP and two with known hereditary TTP. All were treated with apheresis. Only one patient required IHD (3%) and 36/37 (97%) survived to discharge.
Group 2 (definite secondary thrombotic microangiopathy). 15 patients had been given alternative diagnoses: cancer 5, STEC-HUS 4, scleroderma 3, drug-associated TMA 2 and hemaphagocytic syndrome 1. 6/15 (40%) required dialysis and 9/15 (60%) survived to discharge.
Group 3 (possible secondary thrombotic microangiopathy). In 16 patients, MAHATT was associated with other risk factors including autoimmune disease 5, acute pancreatitis 3, malignant hypertension 3, postpartum state 2, post-splenectomy 1, post-alloBMT/sepsis 1, and dyskeratosis congenita/post-alloBMT 1. 11 patients had complement genetics screen and in 10 cases the results were normal. 7/16 (44%) required dialysis and all patients survived to discharge.
Group 4 (complement-mediated HUS). 13 patients were diagnosed with cm-HUS. All patients had MAHATT and acute kidney injury. 11/13 had complement genetics screen and in 7/11 the results were normal. 5 patients underwent anti-CFH antibody testing; 2 patients had detectable anti-CFH antibodies. Both of these patients had normal genetics screen. Thus, in 6/11 (55%) patients a complement abnormality has been identified on diagnostic testing. 8/13 (62%) required hemodialysis and all patients survived to discharge.
Of note, 4/83 patients had SLE. TMA was attributed to immune TTP (2 cases), lupus flare/vasculitis (1) and cm-HUS due to anti-CFH antibody (1). In these patients SLE was diagnosed from 13 years earlier to 4 years after presentation with MAHATT.
Conclusions: TTP accounted for the majority of patients referred with MAHATT to our centre and was generally associated with excellent short-term outcomes. The worst mortality was observed in patients with definite secondary TMA (40%) and dialysis requirement was highest in the cm-HUS group (62%). Anti-CFH antibody testing and complement genetics screen was positive in about 50% of patients diagnosed with cm-HUS. SLE in patients with MAHATT is not common (5%) and may result from different pathogenic processes. Timely diagnosis and appropriate management are imperative to minimizing morbidity and mortality in this vulnerable patient population.
Pavenski:Alexion Pharmaceuticals Inc.: Honoraria, Other: attended an entity's advisory boards. Sholzberg:Shire (previously Baxter, Baxalta): Honoraria, Research Funding; Novonordisk: Honoraria.
Asterisk with author names denotes non-ASH members.