Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis

Abstract

Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate–labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure.

Platelet dysfunction after trauma: From mechanisms to targeted treatment

“…80 ADAMTS13 is, in general, decreased in concentration and activity after trauma. 76,81,82 However, increased ADAMTS13 activity can also exist in severely injured patients. 76 Under normal circumstances, ADAMTS13 circulates in an inactive form (its cleavage site is protected by CUB-domains), and becomes activated upon binding to unfolded VWF, underlining its specificity to VWF.…”

“…109 VWF multimers are continuously released, and ADAMTS13 is decreased, associated with microthrombi formation and organ dysfunction. 76,78 Moreover, histones and HMGB1 remain significantly elevated for multiple days following injury. 94,97 Furthermore, platelet TLR4 expression stimulates formation of platelet-leukocyte aggregates.…”

“…113 Firstly, the endothelial glycocalyx can be protected by plasma transfusion, the benefits of which are shown in severely injured trauma patients and in animal trauma models. 76,181,182 Secondly, VWF release can be targeted by administration of recombinant ADAMTS13, associated with reduced endothelial permeability and organ failure. 76,79 Furthermore, the VWF-targeting thrombolytic agent Microlyse has been shown to reduce microvascular thrombosis, which may be beneficial after trauma.…”

“…76,181,182 Secondly, VWF release can be targeted by administration of recombinant ADAMTS13, associated with reduced endothelial permeability and organ failure. 76,79 Furthermore, the VWF-targeting thrombolytic agent Microlyse has been shown to reduce microvascular thrombosis, which may be beneficial after trauma. 183 Thirdly, prostaglandin receptor agonists (e.g., iloprost) can reduce endothelial activation, glycocalyx shedding, and platelet aggregation.…”

“…VWF is regulated by its cleaving enzyme a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), but possibly also by plasmin 80 . ADAMTS13 is, in general, decreased in concentration and activity after trauma 76,81,82 . However, increased ADAMTS13 activity can also exist in severely injured patients 76 .…”