Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation
Open Access
- 7 April 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (7), 1340-1349
- https://doi.org/10.1182/bloodadvances.2020001500
Abstract
Systemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein moderates DIC. We used confocal microscopy to analyze the fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine fibrin polymerization, and a murine model for LPS-induced DIC and introduced a loss-of-function mutation into the A2 protein for fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for fibrin, possibly mapping a novel region containing a putative binding site for fibrin. The A2 protein increased the initial rate of change of fibrin polymerization, intercalated into the fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with endotoxemia treated with the A2 protein revealed an increased rate of fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2 protein improved survival and reduced fibrin deposition and microvascular thrombosis in mice with endotoxemia-induced DIC. Importantly, in vivo and in vitro studies indicated that the A2 protein did not affect experimental thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic inflammation-induced coagulopathy/DIC via targeting fibrin formation, without an increased risk for bleeding.This publication has 46 references indexed in Scilit:
- Discrepant Fibrinolytic Response in Plasma and Whole Blood during Experimental Endotoxemia in Healthy VolunteersPLOS ONE, 2013
- Shear stress–induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 regionBlood, 2011
- Molecular Mechanisms Affecting Fibrin Structure and StabilityArteriosclerosis, Thrombosis, and Vascular Biology, 2011
- Destabilization of the A1 Domain in von Willebrand Factor Dissociates the A1A2A3 Tri-domain and Provokes Spontaneous Binding to Glycoprotein Ibα and Platelet Activation under Shear StressOnline Journal of Public Health Informatics, 2010
- Polymicrobial sepsis and endotoxemia promote microvascular thrombosis via distinct mechanismsJournal of Thrombosis and Haemostasis, 2010
- Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factorProceedings of the National Academy of Sciences of the United States of America, 2009
- Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytesThrombosis and Haemostasis, 2009
- N-linked glycosylation of VWF modulates its interaction with ADAMTS13Blood, 2008
- Using peptide arrays to define nuclear carrier binding sites on nucleoporinsMethods, 2006
- Evaluation of ADAMTS-13 activity in plasma using recombinant von Willebrand Factor A2 domain polypeptide as substrateThrombosis and Haemostasis, 2003