A novel von Willebrand factor multimer ratio as marker of disease activity in thrombotic thrombocytopenic purpura

Immune-mediated thrombotic thrombocytopenic purpura (iTTP), an autoantibody-mediated severe ADAMTS13 deficiency, is caused by insufficient proteolytic processing of von Willebrand factor (VWF) multimers and microvascular thrombi. Recurrence of acute iTTP is associated with persistence or reappearance of ADAMTS13 deficiency. Some patients remain in remission despite recurring/persisting severe ADAMTS13 deficiency. In a prospective 2-year observational study, we investigated VWF multimer patterns and ADAMTS13 in iTTP patients in remission and at acute episodes. From 83 iTTP patients, 16 suffered 22 acute episodes whereas 67 remained in clinical remission during follow-up, including 13 with ADAMTS13 <10% and 54 with ADAMTS13 ≥10%. High-molecular- weight to low-molecular-weight VWF multimer ratio (VWF MM ratio) based on SDS-agarose gel electrophoresis was compared to ADAMTS13 activity. VWF MM ratio was significantly higher in remission patients with <10% compared to ≥10% ADAMTS13 activity. 14 samples obtained 13-50 days (IQR, median 39) before acute iTTP onset (ADAMTS13 <10% in 9, 10-26% in 5) showed VWF MM ratios significantly higher than those from 13 patients remaining in remission with ADAMTS13 <10%. At acute iTTP onset, VWF MM ratio decreased significantly and was low in all patients despite <10% ADAMTS13. The VWF MM ratio does not depend exclusively on ADAMTS13 activity. The disappearance of high-molecular weight VWF multimers resulting in low VWF MM ratio at iTTP onset may be explained by consumption of larger VWF multimers in the microcirculation. The very high VWF MM ratio preceding acute iTTP recurrence suggests that VWF processing is hampered more than in patients remaining in remission.