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Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation
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| Zeitschriftentitel: | Blood Advances |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , |
| In: | Blood Advances, 4, 2020, 7, S. 1340-1349 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. |
|---|---|
| author |
Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. |
| spellingShingle |
Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. Blood Advances Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation Hematology |
| author_sort |
valladolid, christian |
| spelling |
Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. 2473-9529 2473-9537 American Society of Hematology Hematology http://dx.doi.org/10.1182/bloodadvances.2020001500 <jats:title>Abstract</jats:title><jats:p>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.</jats:p> Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation Blood Advances |
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American Society of Hematology, 2020 |
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American Society of Hematology, 2020 |
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2020 |
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| title |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_unstemmed |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_full |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_fullStr |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_full_unstemmed |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_short |
Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_sort |
modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| topic |
Hematology |
| url |
http://dx.doi.org/10.1182/bloodadvances.2020001500 |
| publishDate |
2020 |
| physical |
1340-1349 |
| description |
<jats:title>Abstract</jats:title><jats:p>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.</jats:p> |
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| author | Valladolid, Christian, Martinez-Vargas, Marina, Sekhar, Nitin, Lam, Fong, Brown, Cameron, Palzkill, Timothy, Tischer, Alexander, Auton, Mathew, Vijayan, K. Vinod, Rumbaut, Rolando E., Nguyen, Trung C., Cruz, Miguel A. |
| author_facet | Valladolid, Christian, Martinez-Vargas, Marina, Sekhar, Nitin, Lam, Fong, Brown, Cameron, Palzkill, Timothy, Tischer, Alexander, Auton, Mathew, Vijayan, K. Vinod, Rumbaut, Rolando E., Nguyen, Trung C., Cruz, Miguel A., Valladolid, Christian, Martinez-Vargas, Marina, Sekhar, Nitin, Lam, Fong, Brown, Cameron, Palzkill, Timothy, Tischer, Alexander, Auton, Mathew, Vijayan, K. Vinod, Rumbaut, Rolando E., Nguyen, Trung C., Cruz, Miguel A. |
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| description | <jats:title>Abstract</jats:title><jats:p>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.</jats:p> |
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| imprint | American Society of Hematology, 2020 |
| imprint_str_mv | American Society of Hematology, 2020 |
| institution | DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4 |
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| spelling | Valladolid, Christian Martinez-Vargas, Marina Sekhar, Nitin Lam, Fong Brown, Cameron Palzkill, Timothy Tischer, Alexander Auton, Mathew Vijayan, K. Vinod Rumbaut, Rolando E. Nguyen, Trung C. Cruz, Miguel A. 2473-9529 2473-9537 American Society of Hematology Hematology http://dx.doi.org/10.1182/bloodadvances.2020001500 <jats:title>Abstract</jats:title><jats:p>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.</jats:p> Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation Blood Advances |
| spellingShingle | Valladolid, Christian, Martinez-Vargas, Marina, Sekhar, Nitin, Lam, Fong, Brown, Cameron, Palzkill, Timothy, Tischer, Alexander, Auton, Mathew, Vijayan, K. Vinod, Rumbaut, Rolando E., Nguyen, Trung C., Cruz, Miguel A., Blood Advances, Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation, Hematology |
| title | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_full | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_fullStr | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_full_unstemmed | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_short | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_sort | modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| title_unstemmed | Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation |
| topic | Hematology |
| url | http://dx.doi.org/10.1182/bloodadvances.2020001500 |