Blood Vessels, Thrombosis & Hemostasis最新文献

{"title":"Procoagulant off-target effect of the direct oral anticoagulant reversal agent Andexanet alfa","authors":"Ischa M. S. Hoornstra ,&nbsp;Junxiong Zhao ,&nbsp;Harmen Middelveld ,&nbsp;Siyu Sun ,&nbsp;Claudia Schönichen ,&nbsp;Johan W. M. Heemskerk ,&nbsp;Hendrik Stragier ,&nbsp;René Heylen ,&nbsp;Bas de Laat ,&nbsp;Mark Roest","doi":"10.1016/j.bvth.2025.100100","DOIUrl":"10.1016/j.bvth.2025.100100","url":null,"abstract":"<div><h3>Abstract</h3><div>Patients with hemorrhage after treatment with direct oral anticoagulants (DOACs) are saved from hematoma expansion by administration of Andexanet alfa, a modified factor Xa analog. A recent clinical trial points to incidental prothrombotic effects after Andexanet alfa treatment. We investigated mechanisms explaining the thrombogenic side effect. Calibrated automated thrombin generation was employed to assess the effect of Andexanet alfa on the coagulant potential of DOAC-treated plasma and whole blood. The study examined anticoagulant inhibition pathways involving tissue factor pathway inhibitor (TFPI), antithrombin, and endothelial cell components. Treatment of control plasmas with rivaroxaban, apixaban, or edoxaban resulted in an impaired thrombin generation, exemplified by a prolonged lag time and reduced thrombin peak height. Andexanet alfa over-converted this anticoagulant activity into a procoagulant effect. Plasma treatment with Andexanet alfa similarly increased thrombin generation in the absence of DOACs, even at 8 nM far below the therapeutic dose. The enhancement was abrogated in the absence or by blocking of TFPI. The Andexanet alfa effect was enhanced in the presence of heparin, thereby reversing the antithrombin protection. In the presence of endothelial cells, Andexanet alfa stimulated coagulation via TFPI and heparin inhibition. Andexanet alfa overconverts the anticoagulant effect of rivaroxaban, apixaban, and edoxaban to achieve a hypercoagulable plasma state. The action mechanism involves TFPI inhibition and neutralization of antithrombin-heparin complexes. This may account for the incidence of thrombosis observed in patients treated with Andexanet alfa.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 4","pages":"Article 100100"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogen reduction diminishes the protective effects of platelets on endothelial barrier permeability in vitro","authors":"Alison B. Nair ,&nbsp;Byron Miyazawa ,&nbsp;Alpa Trivedi ,&nbsp;Lindsay Vivona ,&nbsp;Alexander Fields ,&nbsp;Kimberly Herrera ,&nbsp;Lucy Z. Kornblith ,&nbsp;Joseph Cuschieri ,&nbsp;Shibani Pati","doi":"10.1016/j.bvth.2025.100058","DOIUrl":"10.1016/j.bvth.2025.100058","url":null,"abstract":"<div><h3>Abstract</h3><div>Platelet transfusion not only attenuates bleeding and promotes hemostasis but also plays a critical role in vascular stability and endothelial barrier integrity. Under amotosalen-UVA pathogen reduction of platelets, pathogen nucleic acids undergo adduction, which prevents their replication and greatly reduces the risk of transfusion-transmitted infections. Although pathogen-reduced (PR) platelets are increasing in clinical use, the physiologic effects of pathogen reduction on platelets, particularly its impact on platelet-endothelial interactions, have yet to be described. This study compared PR platelets with nonpathogen-reduced (NPR) platelets in measures of effect on endothelial permeability in vitro. We hypothesized that PR platelets would be similar to NPR platelets. However, in endothelial cell immunohistochemistry and impedance assays, PR platelets demonstrated a significantly diminished capacity to attenuate endothelial barrier permeability at early storage time points. This small but significant difference requires further mechanistic and clinical study to understand its implications, particularly in patients with bleeding with vascular fragility.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100058"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iMer, a naturally occurring MERTK splice variant, binds to GAS6 to decrease platelet activation and thrombus formation","authors":"Stephanie Springborn ,&nbsp;Samantha Judd ,&nbsp;Patricia Morateck ,&nbsp;David VanderZee ,&nbsp;Adam Kidwell ,&nbsp;Christine Brzezinski ,&nbsp;Allaura Cox ,&nbsp;Susan Sather ,&nbsp;Keith B. Neeves ,&nbsp;Deborah DeRyckere ,&nbsp;Jorge Di Paola ,&nbsp;Douglas K. Graham ,&nbsp;Brian R. Branchford","doi":"10.1016/j.bvth.2025.100078","DOIUrl":"10.1016/j.bvth.2025.100078","url":null,"abstract":"<div><h3>Abstract</h3><div>Unopposed platelet activation can be associated with pathologic thrombosis. An intact growth arrest–specific gene 6 (GAS6)/Mer receptor tyrosine kinase (MERTK) signaling pathway contributes importantly to potentiating platelet activation triggered by molecular agonists ex vivo and thrombus stabilization in vivo. We describe, herein, the inhibition of platelet function and stable thrombus formation conferred by iMer, a naturally occurring MERTK splice variant, that acts as a GAS6 decoy receptor and decreases phosphorylation of MERTK. Human and murine platelets incubated with this truncated protein demonstrate reduced activation in ex vivo assays including aggregometry (similar to treatment with anti-GAS6 antibody), expression of P-selectin, spreading on collagen, and accumulation on collagen at a venous shear rate. Wild-type C57BL/6 mice treated with iMer had improved survival in a collagen/epinephrine-induced pulmonary embolism model, without increase in tail bleeding time on preliminary analysis. Taken together, these findings confirm previous data suggesting the importance of GAS6-MERTK signaling in platelet activation and thrombus formation and highlighting the potential therapeutic implications of targeting this pathway as a means of treating or preventing thrombosis.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100078"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiencies in care for adults with vascular anomalies","authors":"Bryan A. Sisk ,&nbsp;Anna M. Kerr ,&nbsp;Sally Cohen-Cutler ,&nbsp;Kristen Sanfilippo","doi":"10.1016/j.bvth.2025.100083","DOIUrl":"10.1016/j.bvth.2025.100083","url":null,"abstract":"","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100083"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet protease-activated receptor 4 genotype and response to aspirin in pregnancy","authors":"Rupsa C. Boelig ,&nbsp;James V. Michael ,&nbsp;Antonios Tawk ,&nbsp;Tingting Zhan ,&nbsp;Joanna S. Y. Chan ,&nbsp;Walter K. Kraft ,&nbsp;Steven E. McKenzie","doi":"10.1016/j.bvth.2025.100085","DOIUrl":"10.1016/j.bvth.2025.100085","url":null,"abstract":"<div><h3>Abstract</h3><div>The platelet protease-activated receptor 4 (PAR4) threonine 120 (Thr120) allele is an activating allele associated with reduced aspirin response in vitro. Aspirin is recommended in high-risk pregnancies to prevent preeclampsia and preterm birth. We evaluated the impact of PAR4 genotype on aspirin response in pregnancy, as measured by platelet function assay 100 (PFA-100) epinephrine closure time, and perinatal outcomes. We conducted a prospective cohort study of high-risk pregnant patients who took 81-mg aspirin daily. PFA-100 was assessed at baseline, 2 to 4 weeks after aspirin initiation (follow-up 1), and 28 to 32 weeks’ gestation (follow-up 2). Primary outcome was difference in PFA-100 by genotype. Exposure was defined as PAR4-Thr120 homozygous vs not. Of the 122 participants were included, 24 (19.6%) were PAR4-Thr120 homozygous, and 106 completed follow-up 1 with &gt;75% adherence. Participants homozygous for PAR4-Thr120 had a significantly higher rate of prior preterm birth (50.0% vs 16.1%; <em>P</em> = .004). Genotype was not significantly associated with PFA-100 response in multivariable regression. In the subset with urinary thromboxane data available (n = 18), thromboxane levels were higher in those who were homozygous vs not (geometric mean ratio, 208 [95% confidence interval, 1.66-2.61]; <em>P</em> &lt; .001) in multivariable regression. There was a higher rate of placental intervillous thrombosis, although not statistically significant (16.7% vs 3.9%; <em>P</em> = .08). Patients homozygous for PAR4-Thr120 had a higher incidence of prior preterm birth, a risk factor for poor perinatal outcome. Aspirin response, measured by PFA-100, was similar across genotypes, although Thr120 homozygosity may be associated with reduced thromboxane suppression and a higher rate of placental vasculopathy even with 81-mg aspirin daily.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100085"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory pathways in transfusion-associated circulatory overload","authors":"RoseAnn E. Vik ∗ ,&nbsp;Esther B. Bulle ∗ ,&nbsp;Wilmore C. Webley ,&nbsp;Paul Visintainer ,&nbsp;Samantha Ramirez ,&nbsp;Peter St. Marie ,&nbsp;Theresa Stec ,&nbsp;Lynne O’Hearn ,&nbsp;Chester Andrzejewski Jr. † ,&nbsp;Alexander P. J. Vlaar †","doi":"10.1016/j.bvth.2025.100080","DOIUrl":"10.1016/j.bvth.2025.100080","url":null,"abstract":"<div><h3>Abstract</h3><div>Transfusion-associated circulatory overload (TACO) is a leading cause of transfusion-associated mortality. TACO is thought to result from hydrostatic forces in the vascular space, leading to transudative pulmonary edema. Recent studies suggest that TACO is not solely a volume overload phenomenon, but may involve inflammatory processes. This study aimed to further explore the presence of inflammation in patients with TACO. We conducted a retrospective study with 3 cohorts receiving red blood cell transfusion: (1) patients having TACO as defined by a national hemovigilance case surveillance classification (conventional TACO [cTACO], n = 33); (2) patients having symptoms consistent with TACO but not completely meeting reporting criteria (institutional TACO [iTACO], n = 33); and (3) a patient cohort who experienced uncomplicated transfusions (n = 6). Samples from before transfusion, after transfusion, and 8 to 36 hours after transfusion were examined. Samples were analyzed for levels of tumor necrosis factor α, interleukin-1α (IL-1α), IL-6, IL-8, IL-10, C-reactive protein, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1, atrial natriuretic peptide, cardiac troponin, and N-terminal pro–B-type natriuretic peptide. Patients with cTACO and iTACO had an elevated body temperature, higher heart rate, and lower oxygen saturation after transfusion, whereas only patients with cTACO had higher blood pressures. Levels of key proinflammatory cytokines, IL-6, and IL-8 were elevated in patients with cTACO and iTACO after transfusion, whereas ICAM-1 was elevated only in patients with iTACO after transfusion. Our results suggest that inflammatory pathways may be invoked in patients with TACO. Patients with iTACO showed a more distinctive inflammatory profile, suggesting a gray area between transfusion-related acute lung injury and TACO.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100080"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nasal RADA16 hydrogel application decreases epistaxis severity scores in adults with hereditary hemorrhagic telangiectasia","authors":"Avraham Adelman ,&nbsp;Eunice Im ,&nbsp;Lindsey Jackson ,&nbsp;Anil Patel ,&nbsp;Nikita Chapurin ,&nbsp;Christina Eagan ,&nbsp;Ali Ataya ,&nbsp;Marc Zumberg ,&nbsp;Jennifer K. Mulligan ,&nbsp;Carl Atkinson ,&nbsp;Brian C. Lobo ,&nbsp;Jeb M. Justice","doi":"10.1016/j.bvth.2025.100098","DOIUrl":"10.1016/j.bvth.2025.100098","url":null,"abstract":"<div><h3>Abstract</h3><div>More than 90% of adults with hereditary hemorrhagic telangiectasia (HHT) experience epistaxis, which can be recurrent and cause significant morbidity. RADA16 is a self-assembling peptide hydrogel approved by the US Food and Drug Administration for hemostasis and wound healing. In this cohort study, we assessed the effectiveness of nasal RADA16 application in controlling HHT-related epistaxis. A retrospective chart review was performed on a cohort of adult patients who received nasal RADA16 without any other changes in treatment. Pre- and post-Epistaxis Severity Scores (ESS), hemoglobin, and hematocrit were collected to assess treatment response. Of the included patients (n = 22), there were 26 applications of RADA16. The cohort was 54.5% male and 86.4% White, had a mean age of 55.5 years, and had a predominantly <em>ACVRL1</em> genotype (40.9%). Baseline mean ESS was 5.0 and decreased by an average of 2.0 at an average of 46.9 days after treatment, which is 2.8 times more than the minimal clinically important difference for ESS in HHT (0.71). The mean baseline hemoglobin (n = 13) and hematocrit (n = 10), were 11.3 g/dL and 37.5%, respectively, and did not exhibit significant changes after RADA16 application. No bleeding, pain, or allergic reactions occurred due to the application. Several patients reported mild nasal congestion. Our experience demonstrates that RADA16 can be considered as a safe epistaxis treatment modality for HHT that is easy to apply and does not require the operating suite.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 4","pages":"Article 100098"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Bleeding Disorders Research Collaborative","authors":"Leonard A. Valentino ,&nbsp;Maria E. Santaella ,&nbsp;Michelle L. Witkop ,&nbsp;Raymond W. Stanhope ,&nbsp;Sammie Valadez ,&nbsp;Samantha A. Carlson ,&nbsp;Halli Benasutti ,&nbsp;Donna DiMichele ,&nbsp;Michael Recht","doi":"10.1016/j.bvth.2025.100099","DOIUrl":"10.1016/j.bvth.2025.100099","url":null,"abstract":"<div><h3>Abstract</h3><div>The Bleeding Disorders Research Collaborative (BDRC) aims to advance an accessible standard of care and quality of life for all people living with inheritable bleeding disorders. This goal will be achieved through collaborative and meaningful scientific inquiry, coordinated by an efficient research infrastructure, and undertaken by a diverse, capacitated workforce in partnership with an engaged community. The BDRC is supported by facilitative research policy and grounded in the principles of health equity, diversity, inclusion, accessibility, and belonging, striving for dignity, safety, well-being, and opportunities, leading to health justice. Importantly, the initiative is fully informed by lived experience experts, people affected by inheritable bleeding disorders, who are key members in the research development, implementation, and dissemination team.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 4","pages":"Article 100099"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction–induced hemolysis: a precursor to vascular leakage and pulmonary hypertension","authors":"Joel James ∗ ,&nbsp;Maki Niihori ∗ ,&nbsp;Mathews V. Varghese ,&nbsp;Nolan McClain ,&nbsp;Olga Rafikova ,&nbsp;Ruslan Rafikov","doi":"10.1016/j.bvth.2025.100097","DOIUrl":"10.1016/j.bvth.2025.100097","url":null,"abstract":"","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 4","pages":"Article 100097"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M1 protein from group A Streptococcus affects fibrin clot formation, structure, and fibrinolytic potential","authors":"Sophie Cherrington ,&nbsp;Lewis J. Hardy ,&nbsp;Azhar Maqbool ,&nbsp;Helen Philippou ,&nbsp;Craig Thelwell","doi":"10.1016/j.bvth.2025.100094","DOIUrl":"10.1016/j.bvth.2025.100094","url":null,"abstract":"<div><h3>Abstract</h3><div>M1 protein is a major virulence determinant of group A <em>Streptococcus</em> (GAS). During infection, M1 is cleaved from the cell surface by host and bacterial proteases resulting in soluble M1 at the site of infection. M1 forms a supramolecular complex with host fibrinogen. We hypothesize that this supramolecular complex affects the formation of fibrin clots. Fibrin formation is an essential part of innate immunity, sealing off infections to limit bacteria spreading. The effects of recombinant M1 (rM1) were assessed in fibrin clots made from whole blood, plasma, or purified fibrinogen incubated in thrombin by a semiautomated coagulation analyzer, permeation studies, confocal microscopy, and scanning electron microscopy. Clotting and lysis profiles (with plasminogen activators and plasminogen) were investigated using microtiter plate assays and kinetically with rotational thromboelastography. Factor XIII crosslinking was quantified using commercial kits and sodium dodecyl sulfate–polyacrylamide gel electrophoresis densitometry analysis. This study demonstrated that rM1-bound (0.47-60 μg/mL) fibrinogen produced clots with remarkably different structures and properties compared with clots without rM1. Inclusion of rM1 formed heterogeneous clots with irregular fiber bundles and compacted fibrin. Formation of the protective fibrin film was disrupted by rM1. Furthermore, mechanical strength of fibrin clots was reduced, and the fibrin networks were more porous with increased fluid permeability. Fibrin clots formed using whole blood incorporating rM1 were more susceptible to lysis by plasmin. GAS strains of M1 type are often associated with invasive infections; the impact of M1 on fibrin structure could contribute to the severity of GAS infection by compromising the fibrin barrier that limits bacterial proliferation and migration.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 4","pages":"Article 100094"},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}