Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura

The pathophysiology of thrombotic thrombocytopenic purpura (TTP) is not wel l understood. Recent studies have described a platelet aggregating factor w hich has been characterized as a calcium-dependent cysteine protease (calpa in) in patients with TTP, A type of TTP, sometimes called secondary TTP, ha s been associated with bone marrow transplantation (BMT), However, unlike p rimary adult TTP, BMT-TTP has important differences and often does not resp ond well to plasma exchange. We describe the measurement of calpain activit y in a group of BMT patients (with and without the clinical syndrome of tra nsplant-associated TTP), Calpain was measured using a functional assay (C-1 4-serotonin platelet release with inhibition by the cysteine protease inhib itor, leupeptin) in the sera of patients following autologous (auto) or all ogeneic (allo) BMT, We also independently diagnosed and graded the BMT-TTP on the day of blood sampling using a scale that related to the percentage s chistocytes and lactic dehydrogenase level, Calpain activity was detected i n 1/8 (13%) grade 0-1 (6 auto, 2 allo); 6/16 (38%) grade 2 (3 auto, 13 allo ) 9/16 (56%) grade 3 (2 auto, 14 allo) and 8/8 (100%) grade 4 BMT-TTP, Pre- BMT samples were tested in 10 allo-BMT patients who had positive calpain re sults post-BMT, One patient gave positive results before the transplant. Th is patient developed grade 4 BMT-TTP (day 24 post-BMT) and died despite aph eresis, Positive calpain results were highly associated with neurologic sym ptoms, P < 0.001. Nineteen of 24 (79%) patients with positive results had n eurologic symptoms compared to three of 21 (14%) patients with negative res ults. In conclusion, calpain was detected in half of the BMT patients with mild to moderate BMT-TTP (grades 2-3) and was uniformly found in those with severe (grade 4) BMT-TTP, Typically the calpain activity develops as TTP c omplicates the transplant process, It is unknown whether calpain contribute s to the pathogenesis of this disorder, or is a secondary event.