Transfusion of Platelets Loaded With Recombinant ADAMTS13 (A Disintegrin and Metalloprotease With Thrombospondin Type 1 Repeats-13) Is Efficacious for Inhibiting Arterial Thrombosis Associated With Thrombotic Thrombocytopenic Purpura

Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2731-2743. doi: 10.1161/ATVBAHA.118.311407.

Abstract

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/cm2), 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 FeCl3 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.

Keywords: disintegrin; platelet transfusion; thrombosis; thrombospondins; von Willebrand factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS13 Protein / blood*
  • ADAMTS13 Protein / deficiency
  • ADAMTS13 Protein / genetics
  • ADAMTS13 Protein / immunology
  • Animals
  • Arterial Occlusive Diseases / blood
  • Arterial Occlusive Diseases / enzymology
  • Arterial Occlusive Diseases / genetics
  • Arterial Occlusive Diseases / prevention & control*
  • Autoantibodies / blood
  • Blood Platelets / enzymology*
  • Disease Models, Animal
  • Endocytosis
  • Humans
  • Mice, Knockout
  • Platelet Adhesiveness
  • Platelet Aggregation
  • Platelet Transfusion*
  • Purpura, Thrombotic Thrombocytopenic / blood
  • Purpura, Thrombotic Thrombocytopenic / enzymology
  • Purpura, Thrombotic Thrombocytopenic / genetics
  • Purpura, Thrombotic Thrombocytopenic / therapy*
  • Thrombosis / blood
  • Thrombosis / enzymology
  • Thrombosis / genetics
  • Thrombosis / prevention & control*
  • Vascular System Injuries / blood
  • Vascular System Injuries / enzymology
  • Vascular System Injuries / genetics
  • Vascular System Injuries / therapy*

Substances

  • Autoantibodies
  • ADAMTS13 protein, mouse
  • ADAMTS13 Protein
  • ADAMTS13 protein, human