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Immune thrombotic thrombocytopenic purpura (iTTP) is primarily caused by immunoglobulin G (IgG)-type autoantibodies that bind and inhibit plasma ADAMTS13 activity and/or accelerate its clearance from circulation. Approximately 50% of patients with iTTP who achieve initial clinical response to therapy experience recurrence (ie, exacerbation and/or relapse); however, a reliable biomarker that predicts such an event is currently lacking. The present study determines the role of longitudinal assessments of plasma ADAMTS13 biomarkers in predicting iTTP exacerbation/recurrence. Eighty-three unique iTTP patients with 97 episodes from the University of Alabama at Birmingham Medical Center between April 2006 and June 2019 were enrolled. Plasma levels of ADAMTS13 activity, antigen, and anti-ADAMTS13 IgG on admission showed no significant value in predicting iTTP exacerbation or recurrence. However, persistently low plasma ADAMTS13 activity (<10 U/dL; hazard ratio [HR], 4.4; 95% confidence interval [CI], 1.6-12.5; P = .005) or high anti-ADAMTS13 IgG (HR, 3.1; 95% CI, 1.2-7.8; P = .016) 3 to 7 days after the initiation of therapeutic plasma exchange was associated with an increased risk for exacerbation or recurrence. Furthermore, low plasma ADAMTS13 activity (<10 IU/dL; HR, 4.8; 95% CI, 1.8-12.8; P = .002) and low ADAMTS13 antigen (<25th percentile; HR, 3.3; 95% CI, 1.3-8.2; P = .01) or high anti-ADAMTS13 IgG (>75th percentile; HR, 2.6; 95% CI, 1.0-6.5; P = .047) at clinical response or remission was also predictive of exacerbation or recurrence. Our results suggest the potential need for a more aggressive approach to achieve biochemical remission (ie, normalization of plasma ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG) in patients with iTTP to prevent the disease recurrence., (© 2019 by The American Society of Hematology.)

Objective- ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves VWF (von Willebrand factor). This process is essential for hemostasis. Severe deficiency of plasma ADAMTS13 activity, most commonly resulting from autoantibodies against ADAMTS13, causes thrombotic thrombocytopenic purpura. Therapeutic plasma exchange is the standard of care to date, which removes autoantibodies and replenishes ADAMTS13. However, such a therapy is often ineffective to raise plasma ADAMTS13 activity, and in-hospital mortality rate remains as high as 20%. Approach and Results- To overcome the inhibition by autoantibodies, we developed a novel approach by delivering rADAMTS13 (recombinant ADAMTS13 ) using platelets as vehicles. We show that both human and murine platelets can uptake rADAMTS13 ex vivo. The endocytosed rADAMTS13 within platelets remains intact, active, and is stored in α-granules. Under arterial shear (100 dyne/cm 2 ), the rADAMTS13 in platelets is released and effectively inhibits platelet adhesion and aggregation on a collagen-coated surface in a concentration-dependent manner. Transfusion of rADAMTS13-loaded platelets into Adamts13 -/- mice dramatically reduces the rate of thrombus formation in the mesenteric arterioles after FeCl 3 injury. An ex vivo transfusion of rADAMTS13-loaded platelets to a reconstituted whole blood containing plasma from a patient with immune-mediated thrombotic thrombocytopenic purpura and the cellular components (eg, erythrocytes and leukocytes) from a healthy individual, as well as a fresh whole blood obtained from a patient with congenital or immune-mediated thrombotic thrombocytopenic purpura also dramatically reduces the rate of thrombus formation under arterial flow. Conclusions- Our results demonstrate that transfusion of rADAMTS13-loaded platelets may be a novel and potentially effective therapeutic approach for arterial thrombosis, associated with congenital and immune-mediated thrombotic thrombocytopenic purpura.