Blood Vessels, Thrombosis & Hemostasis最新文献

英文中文

A nonactivating ITGB3 mutation in the β3 cytoplasmic region causes macrothrombocytopenia with an impaired αIIbβ3/RhoA pathway

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100036

Keiichi Nakata , Keigo Akuta , Takaya Endo , Midori Koike , Daisuke Motooka , Daisuke Okuzaki , Hisashi Kato , Yoshiaki Tomiyama , Naoki Hosen , Hirokazu Kashiwagi

Abstract

Almost all mutations of ITGA2B or ITGB3 identified in congenital macrothrombocytopenia induce constitutive activation of αIIbβ3. However, whether concomitant αIIbβ3 activation is essential for macrothrombocytopenia development remains unknown. Recently, we identified the β3(R760C) mutation that does not induce αIIbβ3 activation in a patient with macrothrombocytopenia. The family study showed that macrothrombocytopenia with reduced expression of αIIbβ3 and glycoprotein IV (GPVI) appeared to be associated with patients heterozygous for β3(R760C). We generated β3(R760C) knockin (KI) mice and investigated the effects of the mutation on platelet/megakaryote biology. Macrothrombocytopenia was decreased to 76% and 40% of platelet counts in heterozygous (Hetero) and homozygous (Homo) KI mice, respectively, when compared with the wild-type mice. Platelet αIIbβ3 and GPVI expression were decreased in KI mice, and αIIbβ3 activation was not detected in nonstimulated KI platelets. Thus, the hetero KI mice reproduced the phenotype of the human participant, indicating that the β3(R760C) mutation is responsible for the macrothrombocytopenia. Platelet aggregation, agonist-induced JON/A binding, and P-selectin expression were impaired in KI mice. Platelet spreading on fibrinogen was also impaired in Homo mice with adenosine 5′-diphosphate or thrombin stimulation. Filopodia and lamellipodia formation was impaired in fibrinogen-adhered megakaryocytes of Homo mice with significantly impaired RhoA activation. Proplatelet formation in Homo mice was impaired with abnormal morphology. In addition, platelet life span was shortened in Homo mice. These data indicate that the β3(R760C) mutation impairs the inside-out and outside-in signaling of αIIbβ3, and abnormal actin rearrangement and impaired RhoA activation may play major roles in macrothrombocytopenia.

{"title":"A nonactivating ITGB3 mutation in the β3 cytoplasmic region causes macrothrombocytopenia with an impaired αIIbβ3/RhoA pathway","authors":"Keiichi Nakata , Keigo Akuta , Takaya Endo , Midori Koike , Daisuke Motooka , Daisuke Okuzaki , Hisashi Kato , Yoshiaki Tomiyama , Naoki Hosen , Hirokazu Kashiwagi","doi":"10.1016/j.bvth.2024.100036","DOIUrl":"10.1016/j.bvth.2024.100036","url":null,"abstract":"<div><h3>Abstract</h3><div>Almost all mutations of <em>ITGA2B</em> or <em>ITGB3</em> identified in congenital macrothrombocytopenia induce constitutive activation of αIIbβ3. However, whether concomitant αIIbβ3 activation is essential for macrothrombocytopenia development remains unknown. Recently, we identified the β3(R760C) mutation that does not induce αIIbβ3 activation in a patient with macrothrombocytopenia. The family study showed that macrothrombocytopenia with reduced expression of αIIbβ3 and glycoprotein IV (GPVI) appeared to be associated with patients heterozygous for β3(R760C). We generated β3(R760C) knockin (KI) mice and investigated the effects of the mutation on platelet/megakaryote biology. Macrothrombocytopenia was decreased to 76% and 40% of platelet counts in heterozygous (Hetero) and homozygous (Homo) KI mice, respectively, when compared with the wild-type mice. Platelet αIIbβ3 and GPVI expression were decreased in KI mice, and αIIbβ3 activation was not detected in nonstimulated KI platelets. Thus, the hetero KI mice reproduced the phenotype of the human participant, indicating that the β3(R760C) mutation is responsible for the macrothrombocytopenia. Platelet aggregation, agonist-induced JON/A binding, and P-selectin expression were impaired in KI mice. Platelet spreading on fibrinogen was also impaired in Homo mice with adenosine 5′-diphosphate or thrombin stimulation. Filopodia and lamellipodia formation was impaired in fibrinogen-adhered megakaryocytes of Homo mice with significantly impaired RhoA activation. Proplatelet formation in Homo mice was impaired with abnormal morphology. In addition, platelet life span was shortened in Homo mice. These data indicate that the β3(R760C) mutation impairs the inside-out and outside-in signaling of αIIbβ3, and abnormal actin rearrangement and impaired RhoA activation may play major roles in macrothrombocytopenia.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100036"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Podoplanin and microthrombi in lung injury

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100034

Jahnavi Gollamudi , Ricardo Gonzalez Delgado , Min Soon Cho , Brianne Wharton , Hani Lee , Animesh Vadaparti , Swapan K. Dasgupta , Miguel A. Cruz , Perumal Thiagarajan , Vahid Afshar-Kharghan

引用次数: 0

Association of high γ′ fibrinogen levels with adverse events in patients with COVID-19

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2025.100048

Queen Revollido , Lydia Buzzard , David X. Lee , Matthew Strnad , Scott McLoud , Akram Khan , William B. Messer , David H. Farrell

引用次数: 0

Altered shear stress of blood flow causes plasma membrane damage in endothelial cells

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100040

Nikita Raj , Chang Pan , Ann Marleen Starke , Anna L. L. Matos , Oliver Soehnlein , Volker Gerke

Abstract

The endothelial lining of blood vessels faces many mechanical challenges, including the shear stress (SS) of blood flow, which render it prone to cell membrane ruptures. Such ruptures must be repaired efficiently to maintain cellular integrity and proper vascular function. However, whether SS of blood flow can indeed affect plasma membrane integrity of endothelial cells and whether any ruptures occurring are repaired is not understood. Here, we show that alterations in the SS of fluid flow induce membrane damage in human endothelial cells, and membrane ruptures increase with increasing shear alterations. Furthermore, we show that inherent SS disturbances at aortic branches in mice are associated with endothelial membrane wounds, which are not observed in regions of laminar flow. We also show that endothelial membrane damages inflicted by shear stress alterations are repaired by a Ca²⁺-dependent process that involves early endosome exocytosis to provide membrane material for wound closure, suggesting conserved and robust membrane repair responses to endothelial damage in vitro and in vivo. Thus, shear stress alterations, which frequently occur at sites of endothelial dysfunction and before associated pathophysiology, cause membrane wounds in the endothelium, which are repaired efficiently to maintain a functional vasculature.

{"title":"Altered shear stress of blood flow causes plasma membrane damage in endothelial cells","authors":"Nikita Raj , Chang Pan , Ann Marleen Starke , Anna L. L. Matos , Oliver Soehnlein , Volker Gerke","doi":"10.1016/j.bvth.2024.100040","DOIUrl":"10.1016/j.bvth.2024.100040","url":null,"abstract":"<div><h3>Abstract</h3><div>The endothelial lining of blood vessels faces many mechanical challenges, including the shear stress (SS) of blood flow, which render it prone to cell membrane ruptures. Such ruptures must be repaired efficiently to maintain cellular integrity and proper vascular function. However, whether SS of blood flow can indeed affect plasma membrane integrity of endothelial cells and whether any ruptures occurring are repaired is not understood. Here, we show that alterations in the SS of fluid flow induce membrane damage in human endothelial cells, and membrane ruptures increase with increasing shear alterations. Furthermore, we show that inherent SS disturbances at aortic branches in mice are associated with endothelial membrane wounds, which are not observed in regions of laminar flow. We also show that endothelial membrane damages inflicted by shear stress alterations are repaired by a Ca<sup>2+</sup>-dependent process that involves early endosome exocytosis to provide membrane material for wound closure, suggesting conserved and robust membrane repair responses to endothelial damage in vitro and in vivo. Thus, shear stress alterations, which frequently occur at sites of endothelial dysfunction and before associated pathophysiology, cause membrane wounds in the endothelium, which are repaired efficiently to maintain a functional vasculature.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100040"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Large language models for chart review: how machine learning can accelerate hematology research

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2025.100052

Barbara D. Lam , Peiqi Wang , Shengling Ma , Omid Jafari , Iuliia Kovalenko , Ang Li

引用次数: 0

Antithrombin regulates neutrophil activities through the stimulation of C-type lectin family 1A

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100032

Yohei Takahashi , Soe Soe Htwe , Dengli Wang , Hidenori Wake , Mariko Yata , Nahoko Tomonobu , Rie Kinoshita , Masakiyo Sakaguchi , Masahiro Nishibori

Abstract

It has been suggested that a serine proteinase inhibitor, antithrombin (AT), exerts anti-inflammatory effects on different types of cells, independent of thrombin inhibition. In this study, we aimed to identify a specific receptor for AT by a screening method using a transmembrane–tethered AT ligand expressed on HEK293T cells together with the coexpression of candidate receptors, followed by the immunoprecipitation of a complex of AT ligand with a receptor. We identified C-type lectin family 1A (CLEC1A) as a receptor for AT. We confirmed the binding of AT to the extracellular domain of CLEC1A using surface plasmon resonance. Recombinant as well as native AT concentration-dependently induced the rounding of purified human neutrophils in shape, associated with the suppression of spontaneous reactive oxygen species production in vitro, but argatroban did not, indicating the independence of AT effects on thrombin inhibition. Native AT maintained the passage of neutrophils through the artificial microcapillaries. Both AT enhanced the phagocytosis of pHrodo-labeled Escherichia coli and prolonged the viability of the neutrophils. The cellular effects of AT were similar to those of histidine-rich glycoprotein, which has the same CLEC1A as a receptor, and were partially inhibited by the addition of anti-CLEC1A antibody to the incubation media. These results suggested that CLEC1A is a novel receptor for AT, and the stimulation of CLEC1A by AT at least in part mediates the important functional changes of human neutrophils.

{"title":"Antithrombin regulates neutrophil activities through the stimulation of C-type lectin family 1A","authors":"Yohei Takahashi , Soe Soe Htwe , Dengli Wang , Hidenori Wake , Mariko Yata , Nahoko Tomonobu , Rie Kinoshita , Masakiyo Sakaguchi , Masahiro Nishibori","doi":"10.1016/j.bvth.2024.100032","DOIUrl":"10.1016/j.bvth.2024.100032","url":null,"abstract":"<div><h3>Abstract</h3><div>It has been suggested that a serine proteinase inhibitor, antithrombin (AT), exerts anti-inflammatory effects on different types of cells, independent of thrombin inhibition. In this study, we aimed to identify a specific receptor for AT by a screening method using a transmembrane–tethered AT ligand expressed on HEK293T cells together with the coexpression of candidate receptors, followed by the immunoprecipitation of a complex of AT ligand with a receptor. We identified C-type lectin family 1A (CLEC1A) as a receptor for AT. We confirmed the binding of AT to the extracellular domain of CLEC1A using surface plasmon resonance. Recombinant as well as native AT concentration-dependently induced the rounding of purified human neutrophils in shape, associated with the suppression of spontaneous reactive oxygen species production in vitro, but argatroban did not, indicating the independence of AT effects on thrombin inhibition. Native AT maintained the passage of neutrophils through the artificial microcapillaries. Both AT enhanced the phagocytosis of pHrodo-labeled <em>Escherichia coli</em> and prolonged the viability of the neutrophils. The cellular effects of AT were similar to those of histidine-rich glycoprotein, which has the same CLEC1A as a receptor, and were partially inhibited by the addition of anti-CLEC1A antibody to the incubation media. These results suggested that CLEC1A is a novel receptor for AT, and the stimulation of CLEC1A by AT at least in part mediates the important functional changes of human neutrophils.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100032"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellular and enzymatic features of thrombi in humans are vascular bed dependent

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100029

Matthew T. Bender ∗ , Anu Aggarwal ∗ , Matthew Godwin , Suman Guntupalli , Aravinda Nanjundappa , Leben Tefera , Ihab Haddadin , Michael Tong , William M. Baldwin III , Robert L. Fairchild , Marcelo Gomes , Joseph Campbell , David Schumick , Pulkit Chaudhury , Doran Mix , Scott J. Cameron

Abstract

Mechanisms behind vascular remodeling following thrombosis are unclear. Although acute arterial thrombosis in the cerebrovascular circulation has devastating consequences and requires immediate attention, the management of venous thromboembolism (VTE) varies significantly. Our goal was to determine the molecular signatures and cellular content of thrombus extracted using a catheter to gain insight into vascular remodeling. Twenty-five patients underwent catheter-directed thrombectomy (CDT); 13 for cerebrovascular accident (CVA), 8 for pulmonary embolism, and 4 for deep vein thrombosis. Protein and RNA were extracted from thrombi to enable immunoblotting, RNA sequencing, and quantification of gene expression. The time from symptom onset to thrombus extraction was 7.7 ± 1.9 hours for CVA and 109 ± 55 hours for VTE. Protein concentration, white blood cell content (monocytes), and red blood cell content were greater in venous thrombus than in arterial thrombus, whereas the platelet content was similar. Both venous and arterial thrombi contained several zinc endopeptidases belonging to the matrix metalloproteinase (MMP) family. MMP9 activity in venous thrombus was greater than arterial thrombus (61 ± 9 ng/mL per μg protein vs 25 ± 6 ng/mL per μg protein; P = .005). Arterial and venous thrombi displayed surprisingly different phenotypes, with biologically active enzymes promoting blood vessel remodeling and enzymatic activity proportional to thrombus age extracted from the veins. These mechanistic data may support the role of early CDT in venous circulation to avoid irreversible vascular remodeling.

{"title":"Cellular and enzymatic features of thrombi in humans are vascular bed dependent","authors":"Matthew T. Bender ∗ , Anu Aggarwal ∗ , Matthew Godwin , Suman Guntupalli , Aravinda Nanjundappa , Leben Tefera , Ihab Haddadin , Michael Tong , William M. Baldwin III , Robert L. Fairchild , Marcelo Gomes , Joseph Campbell , David Schumick , Pulkit Chaudhury , Doran Mix , Scott J. Cameron","doi":"10.1016/j.bvth.2024.100029","DOIUrl":"10.1016/j.bvth.2024.100029","url":null,"abstract":"<div><h3>Abstract</h3><div>Mechanisms behind vascular remodeling following thrombosis are unclear. Although acute arterial thrombosis in the cerebrovascular circulation has devastating consequences and requires immediate attention, the management of venous thromboembolism (VTE) varies significantly. Our goal was to determine the molecular signatures and cellular content of thrombus extracted using a catheter to gain insight into vascular remodeling. Twenty-five patients underwent catheter-directed thrombectomy (CDT); 13 for cerebrovascular accident (CVA), 8 for pulmonary embolism, and 4 for deep vein thrombosis. Protein and RNA were extracted from thrombi to enable immunoblotting, RNA sequencing, and quantification of gene expression. The time from symptom onset to thrombus extraction was 7.7 ± 1.9 hours for CVA and 109 ± 55 hours for VTE. Protein concentration, white blood cell content (monocytes), and red blood cell content were greater in venous thrombus than in arterial thrombus, whereas the platelet content was similar. Both venous and arterial thrombi contained several zinc endopeptidases belonging to the matrix metalloproteinase (MMP) family. MMP9 activity in venous thrombus was greater than arterial thrombus (61 ± 9 ng/mL per μg protein vs 25 ± 6 ng/mL per μg protein; <em>P</em> = .005). Arterial and venous thrombi displayed surprisingly different phenotypes, with biologically active enzymes promoting blood vessel remodeling and enzymatic activity proportional to thrombus age extracted from the veins. These mechanistic data may support the role of early CDT in venous circulation to avoid irreversible vascular remodeling.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100029"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of azathioprine in the management of ITP in the TPO-RA era: a single-center retrospective study

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100035

Alexandre Le-Nguyen , Shamim Mortuza , Cyrus C. Hsia

Abstract

Access to modern therapeutics for immune thrombocytopenia (ITP), such as thrombopoietin-receptor agonists (TPO-RAs), remains a challenge, limiting clinicians’ options. We investigated azathioprine in relapsed/refractory ITP to determine its efficacy and safety, focusing on evaluating its utility in post–TPO-RA patients. We retrospectively reviewed all adult patients, aged ≥18 years, who were worked up for thrombocytopenia between 2009 and 2022 at a tertiary care center in Ontario, Canada. Only patients with ITP treated with azathioprine were included. We identified 92 patients with ITP who received azathioprine, with a mean age of 55.6 ± 22.3 years; 53 were females and 39 males, with 64 having primary ITP. The overall response rate (ORR) was 47.8% (44/92), with a sustained response rate of 77.3% (34/44) at 6 months. The median time to response was 6 weeks. Fourteen patients (31.8%) relapsed, with a median duration of response of 10 weeks. Most patients (73.9%) had documented side effects, with nausea/vomiting, infections, and myelosuppression being the most common. The majority of patients received azathioprine as third-line therapy; 6 patients after TPO-RA and 27 after splenectomy. ORR was 50.0% (3/6) and 40.7% (11/27) in each group, respectively. This is the largest retrospective study, to our knowledge, demonstrating benefit with azathioprine in relapsed/refractory ITP. Its efficacy remains consistent both after TPO-RA (P = .948) and after splenectomy (P = .259), offering clinicians a comparable drug response irrespective of prior TPO-RA exposure or splenectomy. We propose that azathioprine remains a viable option for relapsed/refractory ITP in the TPO-RA era.

{"title":"Role of azathioprine in the management of ITP in the TPO-RA era: a single-center retrospective study","authors":"Alexandre Le-Nguyen , Shamim Mortuza , Cyrus C. Hsia","doi":"10.1016/j.bvth.2024.100035","DOIUrl":"10.1016/j.bvth.2024.100035","url":null,"abstract":"<div><h3>Abstract</h3><div>Access to modern therapeutics for immune thrombocytopenia (ITP), such as thrombopoietin-receptor agonists (TPO-RAs), remains a challenge, limiting clinicians’ options. We investigated azathioprine in relapsed/refractory ITP to determine its efficacy and safety, focusing on evaluating its utility in post–TPO-RA patients. We retrospectively reviewed all adult patients, aged ≥18 years, who were worked up for thrombocytopenia between 2009 and 2022 at a tertiary care center in Ontario, Canada. Only patients with ITP treated with azathioprine were included. We identified 92 patients with ITP who received azathioprine, with a mean age of 55.6 ± 22.3 years; 53 were females and 39 males, with 64 having primary ITP. The overall response rate (ORR) was 47.8% (44/92), with a sustained response rate of 77.3% (34/44) at 6 months. The median time to response was 6 weeks. Fourteen patients (31.8%) relapsed, with a median duration of response of 10 weeks. Most patients (73.9%) had documented side effects, with nausea/vomiting, infections, and myelosuppression being the most common. The majority of patients received azathioprine as third-line therapy; 6 patients after TPO-RA and 27 after splenectomy. ORR was 50.0% (3/6) and 40.7% (11/27) in each group, respectively. This is the largest retrospective study, to our knowledge, demonstrating benefit with azathioprine in relapsed/refractory ITP. Its efficacy remains consistent both after TPO-RA (<em>P</em> = .948) and after splenectomy (<em>P</em> = .259), offering clinicians a comparable drug response irrespective of prior TPO-RA exposure or splenectomy. We propose that azathioprine remains a viable option for relapsed/refractory ITP in the TPO-RA era.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100035"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunothrombosis and plasma fibrinolytic function for pediatric COVID-19: a secondary analysis from the COVAC-TP trial

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100038

Anthony A. Sochet , Austin R. Sellers , Marisol Betensky , John M. Morrison , Dina Ashour , Jamie L. Fierstein , Ernest K. Amankwah , Steven Bruzek , Vera Ignjatovic , Neil A. Goldenberg , COVID-19 Anticoagulation in Children–Thromboprophylaxis Trial Investigators

Abstract

The relationship between fibrinolysis, inflammation, and prothrombotic risk among children hospitalized for coronavirus disease 2019 (COVID-19)–related illness is ill defined. To investigate the association between plasma fibrinolytic capacity and proinflammatory cytokine concentrations among children hospitalized for primary COVID-19 infection and multisystem inflammatory syndrome in children (MIS-C), we hypothesized that cytokine concentrations differ by clinical phenotype and are associated with hypofibrinolysis. We analyzed banked plasma specimens serially collected from children aged <18 years admitted for primary COVID-19 or MIS-C and enrolled in the COVID-19 Anticoagulation in Children–Thromboprophylaxis multicenter trial, an open-label, multicenter, phase 2 clinical trial conducted between July 2020 and May 2021. Plasma coagulative and fibrinolytic function were measured via the clot formation and lysis (CloFAL) assay and modified mini-euglobulin clot lysis assay (ECLA). Interleukin-1β (IL-1β), IL-6, and IL-8, and tumor necrosis factor α were measured by the Meso Scale Discovery assay. Correlations were evaluated using Spearman rank testing. A total of 132 banked plasma specimens from 38 participants (COVID-19: n = 18; MIS-C: n = 20) were analyzed. Overall, increased coagulative function (ie, elevated CloFAL area under the curve) and impaired fibrinolytic function (ie, reduced CloFAL fibrinolytic index [FI] and elevated modified mini-ECLA clot lysis time ratio [CLTR]) were observed but most notably among those with MIS-C. Plasma cytokine concentrations correlated with assay indices of hypofibrinolysis (ie, modified mini-ECLA CLTR and CloFAL FI). In summary, among children hospitalized for COVID-19–related illness, hypercoagulability and hypofibrinolysis are mediated, in part, by inflammation that may contribute to prothrombotic risk. This trial was registered at www.ClinicalTrials.gov as #NCT04354155.

{"title":"Immunothrombosis and plasma fibrinolytic function for pediatric COVID-19: a secondary analysis from the COVAC-TP trial","authors":"Anthony A. Sochet , Austin R. Sellers , Marisol Betensky , John M. Morrison , Dina Ashour , Jamie L. Fierstein , Ernest K. Amankwah , Steven Bruzek , Vera Ignjatovic , Neil A. Goldenberg , COVID-19 Anticoagulation in Children–Thromboprophylaxis Trial Investigators","doi":"10.1016/j.bvth.2024.100038","DOIUrl":"10.1016/j.bvth.2024.100038","url":null,"abstract":"<div><h3>Abstract</h3><div>The relationship between fibrinolysis, inflammation, and prothrombotic risk among children hospitalized for coronavirus disease 2019 (COVID-19)–related illness is ill defined. To investigate the association between plasma fibrinolytic capacity and proinflammatory cytokine concentrations among children hospitalized for primary COVID-19 infection and multisystem inflammatory syndrome in children (MIS-C), we hypothesized that cytokine concentrations differ by clinical phenotype and are associated with hypofibrinolysis. We analyzed banked plasma specimens serially collected from children aged <18 years admitted for primary COVID-19 or MIS-C and enrolled in the COVID-19 Anticoagulation in Children–Thromboprophylaxis multicenter trial, an open-label, multicenter, phase 2 clinical trial conducted between July 2020 and May 2021. Plasma coagulative and fibrinolytic function were measured via the clot formation and lysis (CloFAL) assay and modified mini-euglobulin clot lysis assay (ECLA). Interleukin-1β (IL-1β), IL-6, and IL-8, and tumor necrosis factor α were measured by the Meso Scale Discovery assay. Correlations were evaluated using Spearman rank testing. A total of 132 banked plasma specimens from 38 participants (COVID-19: n = 18; MIS-C: n = 20) were analyzed. Overall, increased coagulative function (ie, elevated CloFAL area under the curve) and impaired fibrinolytic function (ie, reduced CloFAL fibrinolytic index [FI] and elevated modified mini-ECLA clot lysis time ratio [CLTR]) were observed but most notably among those with MIS-C. Plasma cytokine concentrations correlated with assay indices of hypofibrinolysis (ie, modified mini-ECLA CLTR and CloFAL FI). In summary, among children hospitalized for COVID-19–related illness, hypercoagulability and hypofibrinolysis are mediated, in part, by inflammation that may contribute to prothrombotic risk. This trial was registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT04354155.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100038"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unfolded von Willebrand factor binds protein S and reduces anticoagulant activity

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-02-01 DOI: 10.1016/j.bvth.2024.100030

Martha M. S. Sim , Molly Y. Mollica , Hammodah R. Alfar , Melissa Hollifield , Dominic W. Chung , Xiaoyun Fu , Siva Gandhapudi , Daniëlle M. Coenen , Kanakanagavalli Shravani Prakhya , Dlovan F. D Mahmood , Meenakshi Banerjee , Chi Peng , Xian Li , Alice C. Thornton , James Z. Porterfield , Jamie L. Sturgill , Gail A. Sievert , Marietta Barton-Baxter , Ze Zheng , Kenneth S. Campbell , Jeremy P. Wood

Abstract

The critical plasma anticoagulant protein S (PS) circulates in 2 functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP; anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we used biochemical approaches and human patient plasma samples to identify an interaction between PS and von Willebrand factor (VWF), which causes free PS deficiency and reduced PS anticoagulant activity. We first identified a shear-dependent interaction between PS and VWF by mass spectrometry. Consistently, PS and VWF could be crosslinked together in plasma, and plasma PS and VWF comigrated in gel electrophoresis. The PS/VWF interaction was blocked by and tissue factor pathway inhibitor but not activated protein C, suggesting an interaction with the sex hormone binding globulin region of PS. Microfluidic systems demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation–based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in patients with COVID-19 correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data indicate that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. Because many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.

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