Journal of Thrombosis and Haemostasis最新文献

{"title":"Lack of factor VIII detection in humans and dogs with an intron 22 inversion challenges hypothesis regarding inhibitor risk.","authors":"Pooja Vir, Devi Gunasekera, Batsukh Dorjbal, Dennis McDaniel, Atul Agrawal, Elizabeth P Merricks, Margaret V Ragni, Cindy A Leissinger, Allen I Stering, Kenneth Lieuw, Timothy C Nichols, Kathleen P Pratt","doi":"10.1016/j.jtha.2024.08.007","DOIUrl":"10.1016/j.jtha.2024.08.007","url":null,"abstract":"<p><strong>Background: </strong>Almost half of severe hemophilia A (HA) cases are caused by an intron 22 inversion (Int22Inv) mutation, which truncates the 26-exon F8 messenger RNA (mRNA) after exon 22. Another F8 transcript, F8_B, is initiated from within F8-intron-22. F8_B mRNA consists of a short exon spliced to exons 23 to 26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial factor (F)VIII proteins expressed from these 2 transcripts. FVIII is expressed in endothelial cells, primarily in the liver and lungs. Several studies have reported FVIII expression in other cell types, although this has been controversial.</p><p><strong>Objectives: </strong>To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8_B mRNA and if FVIII is expressed in nonendothelial cells.</p><p><strong>Methods: </strong>A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues and for immunoprecipitation followed by western blots and mass spectrometry proteomics analysis.</p><p><strong>Results: </strong>Immunofluorescent staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIII_B was detected in human peripheral blood mononuclear cells, B cell or T cell lines, or cell lines expanded from peripheral blood mononuclear cells, whereas FVIII antigen and activity were readily detected in primary nonhemophilic liver sinusoidal endothelial cells.</p><p><strong>Conclusion: </strong>If FVIII is expressed in nonendothelial cells or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of direct oral anticoagulants in the secondary prevention of venous thromboembolism in patients with severe thrombophilia: communication from the ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia","authors":"Mirjana Kovac ,&nbsp;Vera Ignjatovic ,&nbsp;Christelle Orlando ,&nbsp;Zsuzsanna Bereczky ,&nbsp;Beverley J. Hunt","doi":"10.1016/j.jtha.2024.08.006","DOIUrl":"10.1016/j.jtha.2024.08.006","url":null,"abstract":"<div><div>Direct oral anticoagulants (DOACs) are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. In this communication, we focus on the utility of DOACs in the secondary prevention of VTE in patients with severe thrombophilia. Current evidence is based only on cohort or single-center studies, and poor data are available on compliance of the patients in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs warfarin, ranging from 0.3 to 0.75. We wish to highlight that treatment failure is greater in those with severe forms of protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. In summary, the current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists. We recommend caution in using low-dose DOACs due to lack of evidence. Ideally, large randomized multicenter studies are required to develop a reliable treatment algorithm.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3322-3329"},"PeriodicalIF":5.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study","authors":"Simon Kraler ,&nbsp;Luca Liberale ,&nbsp;Stephan Nopp ,&nbsp;Cornelia Englisch ,&nbsp;Ella Grilz ,&nbsp;Tetiana Lapikova-Bryhinska ,&nbsp;Alexander Akhmedov ,&nbsp;Federico Carbone ,&nbsp;Davide Ramoni ,&nbsp;Amedeo Tirandi ,&nbsp;Alessandro Scuricini ,&nbsp;Simone Isoppo ,&nbsp;Curzia Tortorella ,&nbsp;Federica La Rosa ,&nbsp;Cristina Michelauz ,&nbsp;Federica Frè ,&nbsp;Aurora Gavoci ,&nbsp;Anna Lisa ,&nbsp;Thomas M. Suter ,&nbsp;Arnold von Eckardstein ,&nbsp;Florian Moik","doi":"10.1016/j.jtha.2024.07.019","DOIUrl":"10.1016/j.jtha.2024.07.019","url":null,"abstract":"<div><h3>Background</h3><div>Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable.</div></div><div><h3>Objectives</h3><div>To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients.</div></div><div><h3>Methods</h3><div>In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed.</div></div><div><h3>Results</h3><div>Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age of ≥60 years and +2 points for atherosclerotic disease, yielding a bootstrapped <em>C</em>-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a <em>C</em>-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death.</div></div><div><h3>Conclusion</h3><div>Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this <em>first-of-its-kind</em> risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3125-3136"},"PeriodicalIF":5.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology, natural history, diagnosis, and management of ovarian vein thrombosis: a scoping review","authors":"Margaux Monnet ,&nbsp;Virginie Dufrost ,&nbsp;Denis Wahl ,&nbsp;Olivier Morel ,&nbsp;Mikaël Agopiantz ,&nbsp;Stéphane Zuily","doi":"10.1016/j.jtha.2024.07.033","DOIUrl":"10.1016/j.jtha.2024.07.033","url":null,"abstract":"<div><div>Ovarian vein thrombosis (OVT) is a rare but potentially serious condition. We conducted a scoping review of published data to provide a better understanding of OVT management. MEDLINE and Cochrane databases were searched. The eligibility criterion was original articles including women with OVT until May 2024. Quantitative data were pooled via Comprehensive Meta-Analysis software (Biostat, Inc). Quality of the primary studies was assessed via the Newcastle‒Ottawa Scale. Out of 1007 identified records, 19 primary studies including 1128 patients were selected. Mean age at OVT diagnosis was 37 years old. Frequency of OVT depended on the clinical situation: cancer (37%) and postpartum (0.06%), including cesarean (0.19%), or persistent fever despite antibiotics (23%). Magnetic resonance imaging was associated with the best diagnostic performance, followed by computed tomography. Pulmonary embolism and extension to the iliac vein, inferior vena cava, or left renal vein occurred in 6.5%, 5.9%, 10.3%, and 9.6% of patients, respectively. Among anticoagulants, low-molecular-height heparin with/without oral anticoagulant was preferred for 3 to 6 months. Among the women tested, thrombophilia was present in 18% of the patients. Recanalization, recurrent thrombosis, or major bleeding occurred in 70%, 8%, and 2% of patients, respectively. The majority of studies had poor evidence. This scoping review provides a comprehensive evaluation of available data. Frequency of OVT depends on the clinical setting. Physicians should be aware of OVT in postpartum women with persistent fever despite the use of antibiotics. OVT belongs to the spectrum of venous thromboembolism and should be considered both in puerperal settings and in cancer patients.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 2991-3003"},"PeriodicalIF":5.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrinolysis is impaired in patients with primary immune thrombocytopenia","authors":"Theresa Schramm ,&nbsp;Jasmin Rast ,&nbsp;Dino Mehic ,&nbsp;Stéphanie E. Reitsma ,&nbsp;Claire de Moreuil ,&nbsp;Michael Fillitz ,&nbsp;Peter Quehenberger ,&nbsp;Bas de Laat ,&nbsp;Alisa S. Wolberg ,&nbsp;Cihan Ay ,&nbsp;Ingrid Pabinger ,&nbsp;Johanna Gebhart","doi":"10.1016/j.jtha.2024.07.034","DOIUrl":"10.1016/j.jtha.2024.07.034","url":null,"abstract":"<div><h3>Background</h3><div>Patients with primary immune thrombocytopenia (ITP) have an increased risk of thrombosis, which may be due to altered fibrinolysis.</div></div><div><h3>Objectives</h3><div>To elucidate the clinical impact of delayed fibrinolysis in ITP patients.</div></div><div><h3>Methods</h3><div>A turbidimetric clot formation and lysis assay and a fluorometric plasmin generation (PG) assay were performed, and levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), tPA-PAI-1 complexes, α2-antiplasmin, thrombin activatable fibrinolysis inhibitor, and D-dimer were assessed in 86 adult primary ITP patients and 78 healthy controls (HCs).</div></div><div><h3>Results</h3><div>ITP patients showed significantly delayed clot formation, increased clot density, and prolonged clot lysis time (CLT) compared with HCs, with a median (IQR) CLT of 28.0 (13.7-34.7) minutes in patients and 17.3 (12.0-28.0) minutes in HCs, while in the PG assay, only the lag time was prolonged. In ITP patients compared with controls, PAI-1 was higher (1.2 [0.8-2.6] vs 1.1 [0.6-2.1] U/mL) and tPA antigen and activity were lower (tPA antigen: 2.6 [1.1-4.4] vs 3.7 [3.2-4.7] ng/mL; tPA activity ≤ 0 U/mL: 26% vs 7%). TPA-PAI-1 complex levels were positively associated with CLT in multiple linear regression analysis (β = 0.241; <em>P</em> = .019), whereas PG parameters were not associated with CLT. Six patients who developed thrombosis during follow-up had higher levels of tPA-PAI-1 complexes.</div></div><div><h3>Conclusion</h3><div>Prolonged CLT and delayed onset of PG may indicate a hypofibrinolytic tendency in ITP patients, as also indicated by high PAI-1 and low tPA levels. No association was found between fibrinolytic potential and the bleeding phenotype, whereas higher tPA-PAI-1 complex levels were associated with prolonged CLT and increased in patients with future thrombosis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3209-3220"},"PeriodicalIF":5.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RUNX1 isoforms regulate RUNX1 and target genes differentially in platelets-megakaryocytes: association with clinical cardiovascular events.","authors":"Liying Guan, Deepak Voora, Rachel Myers, Fabiola Del Carpio-Cano, A Koneti Rao","doi":"10.1016/j.jtha.2024.07.032","DOIUrl":"10.1016/j.jtha.2024.07.032","url":null,"abstract":"<p><strong>Background: </strong>Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoters to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream gene regulation in megakaryocytes and platelets are unknown.</p><p><strong>Objectives: </strong>To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms.</p><p><strong>Methods: </strong>We performed studies on RUNX1 isoforms in megakaryocytic human erythroleukemia (HEL) cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD).</p><p><strong>Results: </strong>In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells, RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A, and others) differentially in HEL cells. In platelets, RUNX1B transcripts (by RNA sequencing) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events.</p><p><strong>Conclusion: </strong>RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner, and this is associated with acute events in CVD.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy for people with hemophilia B: a proposed care delivery model in Italy","authors":"Giancarlo Castaman ,&nbsp;Giovanni Di Minno ,&nbsp;Paolo Simioni ,&nbsp;Angelo Claudio Molinari ,&nbsp;Sergio Siragusa ,&nbsp;Erminia Baldacci ,&nbsp;Vincenzo La Mura ,&nbsp;Angelo Lupi ,&nbsp;Enrico Ferri Grazzi ,&nbsp;Flora Peyvandi","doi":"10.1016/j.jtha.2024.07.029","DOIUrl":"10.1016/j.jtha.2024.07.029","url":null,"abstract":"<div><h3>Background</h3><div>Gene therapy is designed to provide people with hemophilia B with a steady and elevated factor (F)IX activity, thereby strengthening protection and relieving the burden of frequent replacement therapy infusions. The European Medicines Agency has approved gene therapy for the severe and moderately severe forms of hemophilia B that uses the FIX-Padua variant (etranacogene dezaparvovec).</div></div><div><h3>Objectives</h3><div>The aim was to provide a document dedicated to hemophilia B gene therapy and give a comprehensive overview of the topic.</div></div><div><h3>Methods</h3><div>An Italian group of experts in hemophilia carried out a narrative review of the literature and discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organizational model, the role of the multidisciplinary team, the laboratory surveillance, and the patient’s journey, from the follow-up to the identification of safety issues and outcome measures.</div></div><div><h3>Results</h3><div>This article highlights the need to follow the Hub and Spoke organizational model and sheds light on the role of each professional figure within the multidisciplinary teams to favor patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian hemophilia centers have been considered to ensure an efficient implementation of the care delivery model.</div></div><div><h3>Conclusion</h3><div>It is crucial to ensure that centers are appropriately organized, equipped, and trained to adequately select patients, deliver the gene therapy, and perform follow-up.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3084-3096"},"PeriodicalIF":5.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet HMGB1 steers intravascular immunity and thrombosis.","authors":"Norma Maugeri, Angelo A Manfredi","doi":"10.1016/j.jtha.2024.07.030","DOIUrl":"10.1016/j.jtha.2024.07.030","url":null,"abstract":"<p><p>Platelets navigate the fine balance between homeostasis and injury. They regulate vascular homeostasis and drive repair after injury amidst leukocyte extravasation. Crucially, platelets initiate extracellular traps generation and promote immunothrombosis. In chronic human diseases, platelet action often extends beyond its normative role, sparking sustained reciprocal activation of leukocytes and mural cells, culminating in adverse vascular remodeling. Studies in the last decade have spotlighted a novel key player in platelet activation, the high mobility group box 1 (HMGB1) protein. Despite its initial characterization as a chromatin molecule, anucleated platelets express abundant HMGB1, which has emerged as a linchpin in thromboinflammatory risks and microvascular remodeling. We propose that a comprehensive assessment of platelet HMGB1, spanning quantification of content, membrane localization, and accumulation of HMGB1-expressing vesicles in biological fluids should be integral to dissecting and quantifying platelet activation. This review provides evidence supporting this claim and underscores the significance of platelet HMGB1 as a biomarker in conditions associated with heightened thrombotic risks and systemic microvascular involvement, spanning cardiovascular, autoimmune, and infectious diseases.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Production of physiological amounts of hemostatic proteins by human donor livers during ex situ long-term normothermic machine perfusion for up to 7 days","authors":"Bianca Lascaris ,&nbsp;Silke B. Bodewes ,&nbsp;Jelle Adelmeijer ,&nbsp;Maarten W.N. Nijsten ,&nbsp;Robert J. Porte ,&nbsp;Vincent E. de Meijer ,&nbsp;Ton Lisman","doi":"10.1016/j.jtha.2024.08.004","DOIUrl":"10.1016/j.jtha.2024.08.004","url":null,"abstract":"<div><h3>Background</h3><div>Normothermic machine perfusion (NMP) is used for preservation and assessment of human donor livers prior to transplantation. During NMP, the liver is metabolically active, which allows detailed studies on the physiology of human livers.</div></div><div><h3>Objectives</h3><div>To study the production of hemostatic proteins in human donor livers during NMP for up to 7 days.</div></div><div><h3>Methods</h3><div>In this observational study, 9 livers underwent NMP for up to 7 days with a heparinized perfusate based on red blood cells and colloids using a modified Liver Assist device (XVIVO). Perfusate samples were collected before NMP and daily thereafter for measurement of antigen and activity levels of a comprehensive panel of hemostatic proteins after heparin neutralization.</div></div><div><h3>Results</h3><div>Within 1 day, perfusate samples displayed the potential for coagulation activation as evidenced by international normalized ratio and activated partial thromboplastin assays. This was accompanied by detection of substantial quantities of functionally active coagulation proteins and inhibitors, although the specific activity of many proteins was decreased, compared with that in normal plasma. Perfusate levels of hemostatic proteins increased in the first days, reaching a stable level after 3 to 4 days of perfusion.</div></div><div><h3>Conclusion</h3><div>During long-term NMP of human livers, functionally active hemostatic proteins are released into the perfusate in substantial quantities, but some proteins appear to have decreased functional properties compared with proteins in normal human plasma. We propose that NMP may be used as a platform to test efficacy of drugs that stimulate or inhibit the production of coagulation factors or to test liver-mediated clearance of prohemostatic protein therapeutics.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3097-3106"},"PeriodicalIF":5.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early thrombus formation is required for eccentric and heterogeneous neointimal hyperplasia under disturbed flow.","authors":"Hualong Bai, Zhuo Li, Weichang Zhang, Carly Thaxton, Yuichi Ohashi, Luis Gonzalez, Masaki Kano, Bogdan Yatsula, John Hwa, Alan Dardik","doi":"10.1016/j.jtha.2024.07.028","DOIUrl":"10.1016/j.jtha.2024.07.028","url":null,"abstract":"<p><strong>Background: </strong>Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared with laminar flow in the arterial inflow and the venous outflow.</p><p><strong>Objectives: </strong>We hypothesized that early thrombus formation is required for eccentric and heterogeneous NIH in the presence of disturbed flow.</p><p><strong>Methods: </strong>Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-Cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were second-stage basilic vein transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry, and en face staining.</p><p><strong>Results: </strong>In the presence of disturbed flow, both mouse and human AVF showed eccentric and heterogeneous NIH. Maladapted vein wall was characterized by eccentric and heterogeneous neointima that was composed of a different abundance of thrombus and smooth muscle cells. PF4-cre × mT/mG reporter mice AVF showed that green fluorescent protein-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cell loss and continue to accumulate in the presence of disturbed flow. Neither disturbed flow with limited endothelial cell loss nor nondisturbed flow induced heterogeneous neointima in different animal models.</p><p><strong>Conclusion: </strong>Early thrombus contributes to late heterogeneous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss, and thrombus formation are critical to form eccentric and heterogeneous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogeneous NIH.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}