The role of ADAMTS‐13 in the coagulopathy of sepsis

Abstract

The interaction between platelets and the vessel wall is mediated by various receptors and adhesive proteins, of which von Willebrand factor (VWF) is the most prominent. The multimeric size of VWF is an important determinant of a more intense platelet-vessel wall interaction, and is regulated by the VWF-cleaving protease ADAMTS-13. A deficiency in ADAMTS-13 leads to higher concentrations of ultralarge VWF multimers and pathological platelet-vessel wall interactions, in its most typical and extreme form leading to thrombocytopenic thrombotic purpura, a thrombotic microangiopathy characterized by thrombocytopenia, non-immune hemolysis, and organ dysfunction. Thrombotic microangiopathy associated with low levels of ADAMTS-13 may be a component of the coagulopathy observed in patients with sepsis. Here, we review the potential role of ADAMTS-13 deficiency and ultralarge VWF multimers in sepsis, and their relationship with sepsis severity and prognosis. In addition, we discuss the possible benefit of restoring ADAMTS-13 levels or reducing the effect of ultralarge VWF as an adjunctive treatment in patients with sepsis.

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

“…In traumatic injury with hemorrhage, hemostatic resuscitation with agents containing coagulation factors, including vWF, can mitigate bleeding . Similarly, other diseases that result in excessive endothelial injury and inflammation, such as severe sepsis or burns may interfere with the normal release and processing of vWF, causing microvascular thromboses and altering the hemostatic response . In this section, blood products that impact vWF concentrations or metabolism in various conditions with altered vWF profiles will be reviewed.…”

Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis

“…The potential role of ADAMTS13 repletion in ameliorating outcome, as shown for stroke and myocardial ischemia, and in our experiments with ADAMTS13‐deficient mice, should be tested in more detail in sepsis models. We and others hypothesize that the cleavage of the highly adhesive ultra large VWF on endothelium by ADAMTS13, could reduce recruitment of platelets, neutrophils, and bacteria, and microthrombosis in end organs during sepsis . ADAMTS‐13 could be delivered as injection of the recombinant protein, or via adeno‐associated viral expression .…”

“…We and others hypothesize that the cleavage of the highly adhesive ultra large VWF on endothelium by ADAMTS13, could reduce recruitment of platelets, neutrophils, and bacteria, and microthrombosis in end organs during sepsis . ADAMTS‐13 could be delivered as injection of the recombinant protein, or via adeno‐associated viral expression . Alternatively, rather than cleaving the ultra large VWF, one could inhibit its interactions with platelets, by blocking the platelet GPIb‐binding site on VWF with the nanobody caplacizumab .…”

“…30 ADAMTS-13 could be delivered as injection of the recombinant protein, or via adeno-associated viral expression. 30 Alternatively, rather than cleaving the ultra large VWF, one could inhibit its interactions with platelets, by blocking the platelet GPIb-binding site on VWF with the nanobody caplacizumab. 63 The further study of ADAMTS13 and other molecules that reduce the adhesive and prothrombotic phenotype of an activated endothelial cell layer in sepsis, is…”

“…This imbalance between VWF and ADAMTS13 was hypothesized to contribute to the development of microvascular thrombosis and multiorgan failure in sepsis . However, animal studies using models for Gram‐negative or polymicrobial sepsis, such as cecal ligation and puncture or lipopolysaccharide injection, have yielded conflicting results on the contribution of VWF and ADAMTS13 to the course of sepsis…”