Pub Date : 2024-09-17DOI: 10.1016/j.jtha.2024.08.021
Julie Hahn, Gerard Temprano-Sagrera, Natalie R Hasbani, Symen Ligthart, Abbas Dehghan, Alisa S Wolberg, Nicholas L Smith, Maria Sabater-Lleal, Alanna C Morrison, Paul S de Vries
Background: Fibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP.
Objectives: To identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS.
Methods: We performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data.
Results: We identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS.
Conclusion: Bivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.
{"title":"Bivariate genome-wide association study of circulating fibrinogen and C-reactive protein levels.","authors":"Julie Hahn, Gerard Temprano-Sagrera, Natalie R Hasbani, Symen Ligthart, Abbas Dehghan, Alisa S Wolberg, Nicholas L Smith, Maria Sabater-Lleal, Alanna C Morrison, Paul S de Vries","doi":"10.1016/j.jtha.2024.08.021","DOIUrl":"10.1016/j.jtha.2024.08.021","url":null,"abstract":"<p><strong>Background: </strong>Fibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP.</p><p><strong>Objectives: </strong>To identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS.</p><p><strong>Methods: </strong>We performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data.</p><p><strong>Results: </strong>We identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS.</p><p><strong>Conclusion: </strong>Bivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289960","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}
Background: The ONCO DVT study (Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis) revealed superiority of 12-month relative to 3-month edoxaban treatment for the thrombotic risk in cancer-associated isolated distal deep vein thrombosis. However, it is unknown whether the superiority could be common in different modified Ottawa score subgroups.
Objectives: To identify more preferable candidates for extended anticoagulation in patients with cancer-associated isolated distal deep vein thrombosis using the modified Ottawa score.
Methods: In this post-hoc subgroup analysis of the ONCO DVT study, we stratified 601 patients into the low (≤-1, N = 126), intermediate (0, N = 323), and high (≥1, N = 152) modified Ottawa score subgroups and compared clinical outcomes between the 12-month and 3-month edoxaban treatment groups.
Results: The cumulative incidence of symptomatic recurrent venous thromboembolism or venous thromboembolism-related death was not different between the 12-month and 3-month edoxaban treatment groups in the low score subgroup (0.0% vs 2.2%), whereas it was lower in the 12-month than in the 3-month edoxaban treatment group in the intermediate (0.8% vs 7.6%) and high (3.1% vs 15.6%) score subgroups. There were no significant differences in the cumulative incidences of the major bleeding between the 12-month and 3-month edoxaban treatment groups in the low (10.1% vs 7.6%), intermediate (8.8% vs 5.0%), and high (13.9% vs 12.6%) score subgroups.
Conclusion: A 12-month compared with 3-month edoxaban treatment showed a lower risk of thrombotic events in patients with cancer-associated isolated distal deep vein thrombosis in the intermediate and high modified Ottawa score subgroups but not in the low score subgroup, suggesting a limited benefit of extended anticoagulation therapy beyond 3 months in patients with low modified Ottawa score.
研究背景ONCO DVT研究显示,在癌症相关孤立远端深静脉血栓(DVT)的血栓风险方面,12个月的依多沙班治疗优于3个月的依多沙班治疗。然而,这种优越性在不同的改良渥太华评分亚组中是否具有共性尚不得而知:在这项 ONCO DVT 研究的事后亚组分析中,我们将 601 例患者分为低(≤-1,N=126)、中(0,N=323)和高(≥1,N=152)改良渥太华评分亚组,并比较了 12 个月和 3 个月依多沙班治疗组的临床结果:在低分亚组中,12个月和3个月依多沙班治疗组的无症状复发性静脉血栓栓塞症(VTE)或VTE相关死亡的累积发生率没有差异(0.0% vs. 2.2%),而在中分(0.8% vs. 7.6%)和高分(3.1% vs. 15.6%)亚组中,12个月依多沙班治疗组的发生率低于3个月依多沙班治疗组。在低分(10.1% vs. 7.6%)、中分(8.8% vs. 5.0%)和高分(13.9% vs. 12.6%)亚组中,埃多沙班治疗12个月组和3个月组的大出血累计发生率无明显差异:为期12个月的依多沙班治疗与为期3个月的依多沙班治疗相比,在中度和高度修改后渥太华评分亚组中,癌症相关孤立性远端深静脉血栓患者发生血栓事件的风险较低,但在低评分亚组中风险不高,这表明在低修改后渥太华评分患者中,延长抗凝治疗3个月以上的获益有限。
{"title":"Utility of the modified Ottawa score for identification of more preferable candidates of extended anticoagulation therapy in cancer-associated isolated distal deep vein thrombosis: insight from the ONCO DVT Study.","authors":"Wei Xiong, Yugo Yamashita, Takeshi Morimoto, Nao Muraoka, Michihisa Umetsu, Yuji Nishimoto, Takuma Takada, Yoshito Ogihara, Tatsuya Nishikawa, Nobutaka Ikeda, Kazunori Otsui, Daisuke Sueta, Yukari Tsubata, Masaaki Shoji, Ayumi Shikama, Yutaka Hosoi, Yasuhiro Tanabe, Ryuki Chatani, Kengo Tsukahara, Naohiko Nakanishi, Kitae Kim, Satoshi Ikeda, Koh Ono, Takeshi Kimura","doi":"10.1016/j.jtha.2024.09.003","DOIUrl":"10.1016/j.jtha.2024.09.003","url":null,"abstract":"<p><strong>Background: </strong>The ONCO DVT study (Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis) revealed superiority of 12-month relative to 3-month edoxaban treatment for the thrombotic risk in cancer-associated isolated distal deep vein thrombosis. However, it is unknown whether the superiority could be common in different modified Ottawa score subgroups.</p><p><strong>Objectives: </strong>To identify more preferable candidates for extended anticoagulation in patients with cancer-associated isolated distal deep vein thrombosis using the modified Ottawa score.</p><p><strong>Methods: </strong>In this post-hoc subgroup analysis of the ONCO DVT study, we stratified 601 patients into the low (≤-1, N = 126), intermediate (0, N = 323), and high (≥1, N = 152) modified Ottawa score subgroups and compared clinical outcomes between the 12-month and 3-month edoxaban treatment groups.</p><p><strong>Results: </strong>The cumulative incidence of symptomatic recurrent venous thromboembolism or venous thromboembolism-related death was not different between the 12-month and 3-month edoxaban treatment groups in the low score subgroup (0.0% vs 2.2%), whereas it was lower in the 12-month than in the 3-month edoxaban treatment group in the intermediate (0.8% vs 7.6%) and high (3.1% vs 15.6%) score subgroups. There were no significant differences in the cumulative incidences of the major bleeding between the 12-month and 3-month edoxaban treatment groups in the low (10.1% vs 7.6%), intermediate (8.8% vs 5.0%), and high (13.9% vs 12.6%) score subgroups.</p><p><strong>Conclusion: </strong>A 12-month compared with 3-month edoxaban treatment showed a lower risk of thrombotic events in patients with cancer-associated isolated distal deep vein thrombosis in the intermediate and high modified Ottawa score subgroups but not in the low score subgroup, suggesting a limited benefit of extended anticoagulation therapy beyond 3 months in patients with low modified Ottawa score.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289966","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}
Pub Date : 2024-09-13DOI: 10.1016/j.jtha.2024.08.019
Hendy Kristyanto, Leen Slaets, Esmée Braams, Ilse Scheys, Roy Heesbeen, Vicky Cárdenas, Georgi Shukarev, Gert Scheper, Jerald Sadoff, Kerstin Lühn, Hanneke Schuitemaker, Frank Struyf, Jenny Hendriks
Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event identified following vaccination with some adenovirus-vectored COVID-19 vaccines, including Ad26.COV2.S. VITT is characterized by the presence of antibodies against platelet factor 4 (PF4).
Objectives: To evaluate whether PF4 antibodies were generally induced following vaccination with adenovirus type 26 (Ad26)-vectored vaccines.
Methods: The study included 913 and 991 healthy participants without thromboembolic (TE) events in Ad26.COV2.S and non-COVID-19 Ad26-vectored vaccine clinical studies, respectively, and 1 participant with VITT following Ad26.COV2.S vaccination. PF4 antibody levels were measured in prevaccination and postvaccination sera. PF4 antibody positivity rates were assessed in a case-control setting in participants who developed TE events during participation in Ad26-vectored vaccine clinical studies.
Results: In the 1 VITT patient, PF4 antibodies were negative before vaccination. Seroconversion for platelet-activating PF4 antibodies was observed upon Ad26.COV2.S vaccination. In participants without TE events, the PF4 antibody levels and positivity rates were similar before and after Ad26 vaccination. Ad26 vaccination did not increase PF4 antibody levels in participants who were PF4 antibody-positive at baseline (n = 47). Lastly, 1 out of 28 TE cases and 2 out of 156 non-TE controls seroconverted after Ad26.COV2.S vaccination. None of the 15 TE cases and 3 of the 77 non-TE controls seroconverted following non-COVID-19 Ad26 vaccination.
Conclusion: Ad26.COV2.S and the other Ad26-vectored vaccines studied did not generally induce PF4 antibodies or increase preexisting PF4 antibody levels. Moreover, unlike VITT, TE events that occurred at any time following Ad26 vaccination were not associated with PF4 antibodies.
{"title":"Assessment of antibodies against platelet factor 4 following vaccination with adenovirus type 26-vectored vaccines.","authors":"Hendy Kristyanto, Leen Slaets, Esmée Braams, Ilse Scheys, Roy Heesbeen, Vicky Cárdenas, Georgi Shukarev, Gert Scheper, Jerald Sadoff, Kerstin Lühn, Hanneke Schuitemaker, Frank Struyf, Jenny Hendriks","doi":"10.1016/j.jtha.2024.08.019","DOIUrl":"10.1016/j.jtha.2024.08.019","url":null,"abstract":"<p><strong>Background: </strong>Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event identified following vaccination with some adenovirus-vectored COVID-19 vaccines, including Ad26.COV2.S. VITT is characterized by the presence of antibodies against platelet factor 4 (PF4).</p><p><strong>Objectives: </strong>To evaluate whether PF4 antibodies were generally induced following vaccination with adenovirus type 26 (Ad26)-vectored vaccines.</p><p><strong>Methods: </strong>The study included 913 and 991 healthy participants without thromboembolic (TE) events in Ad26.COV2.S and non-COVID-19 Ad26-vectored vaccine clinical studies, respectively, and 1 participant with VITT following Ad26.COV2.S vaccination. PF4 antibody levels were measured in prevaccination and postvaccination sera. PF4 antibody positivity rates were assessed in a case-control setting in participants who developed TE events during participation in Ad26-vectored vaccine clinical studies.</p><p><strong>Results: </strong>In the 1 VITT patient, PF4 antibodies were negative before vaccination. Seroconversion for platelet-activating PF4 antibodies was observed upon Ad26.COV2.S vaccination. In participants without TE events, the PF4 antibody levels and positivity rates were similar before and after Ad26 vaccination. Ad26 vaccination did not increase PF4 antibody levels in participants who were PF4 antibody-positive at baseline (n = 47). Lastly, 1 out of 28 TE cases and 2 out of 156 non-TE controls seroconverted after Ad26.COV2.S vaccination. None of the 15 TE cases and 3 of the 77 non-TE controls seroconverted following non-COVID-19 Ad26 vaccination.</p><p><strong>Conclusion: </strong>Ad26.COV2.S and the other Ad26-vectored vaccines studied did not generally induce PF4 antibodies or increase preexisting PF4 antibody levels. Moreover, unlike VITT, TE events that occurred at any time following Ad26 vaccination were not associated with PF4 antibodies.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289959","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}
Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.
Objectives
We determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes.
Methods
Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2V617F expression compared with wild-type (WT) mice (Jak2WT) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (JAK2V617F mutation, n = 50; CALR mutations, n = 9) compared with 28 healthy controls.
Results
In whole blood from Jak2V617F mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2WT (95 ± 22 vs 147 ± 39 AU/min; P < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min−1; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2V617F mice compared with Jak2WT mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in JAK2V617F and CALR patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared with controls.
Conclusion
Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.
背景骨髓增殖性肿瘤(MPN)的特点是血栓并发症发生率高,导致死亡率增加。与 MPN 相关的血栓形成被认为是多因素的,涉及促凝血和促炎症过程。纤溶功能受损是否也参与了 MPN 促血栓形成表型的形成,这一问题尚未得到深入研究。患者与野生型小鼠(Jak2WT)相比,我们使用(1)光环凝块裂解法、(2)前端裂解法和(3)血浆蛋白酶生成测定法,对造血受限的 Jak2V617F 表达小鼠的全血(WB)和血浆中组织纤溶酶原激活剂(tPA)介导的纤溶进行了评估。结果在Jak2V617F小鼠的WB中,我们观察到纤维蛋白溶解减少,其特征是与Jak2WT相比,晕凝块溶解率显著降低(95±22 vs 147±39 UA/min,p<0.05)。在血浆中也观察到类似的结果(晕凝块溶解率:130±27 vs 186±29 UA/min):130±27 vs 186±29 UA/min;正面裂解率:2.8±1.6 vs 6.1±1.2 μm.min-1,p<0.05)。与 Jak2WT 小鼠相比,Jak2V617F 小鼠血浆凝块和标准化纤维蛋白凝块中产生的凝血酶明显减少。在骨髓增生性疾病患者中,JAK2V617F 和 CALR 患者的 tPA 相关纤溶功能受损,血块溶解时间延长。与对照组相比,JAK2V617F 患者血浆中的纤溶酶原激活物抑制剂-1 和α-2-抗蛋白酶显著增加。
{"title":"Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms","authors":"Marie-Charlotte Bourrienne , Stéphane Loyau , Dorothée Faille , Juliette Gay , Séléna Akhenak , Carine Farkh , Véronique Ollivier , Mialitiana Solonomenjanahary , Sébastien Dupont , Christine Choqueux , Jean-Luc Villeval , Isabelle Plo , Valérie Edmond , Benoît Ho-Tin-Noé , Nadine Ajzenberg , Mikaël Mazighi","doi":"10.1016/j.jtha.2024.07.031","DOIUrl":"10.1016/j.jtha.2024.07.031","url":null,"abstract":"<div><h3>Background</h3><div>Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.</div></div><div><h3>Objectives</h3><div>We determined whether MPN, particularly <em>JAK2</em>V617F-positive MPN, is associated with fibrinolytic changes.</div></div><div><h3>Methods</h3><div>Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2<sup>V617F</sup> expression compared with wild-type (WT) mice (Jak2<sup>WT</sup>) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (<em>JAK2</em>V617F mutation, <em>n</em> = 50; <em>CALR</em> mutations, <em>n</em> = 9) compared with 28 healthy controls.</div></div><div><h3>Results</h3><div>In whole blood from Jak2<sup>V617F</sup> mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2<sup>WT</sup> (95 ± 22 vs 147 ± 39 AU/min; <em>P</em> < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min<sup>−1</sup>; <em>P</em> < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2<sup>V617F</sup> mice compared with Jak2<sup>WT</sup> mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in <em>JAK2</em>V617F and <em>CALR</em> patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from <em>JAK2</em>V617F patients compared with controls.</div></div><div><h3>Conclusion</h3><div>Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182687","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}
Pub Date : 2024-09-12DOI: 10.1016/j.jtha.2024.08.014
Edward Louis George Pryzdial, John Ruggles Perrier, Mahamud-Ur Rashid, Henry Euan West, Michael Ross Sutherland
Many virus types affect the blood clotting system with correlations to pathology that range widely from thrombosis to hemorrhage linking to inflammation. Here we overview the intricate crosstalk induced by infection between proteins on the virus encoded by either the host or virus genomes, coagulation proteins, platelets, leukocytes, and endothelial cells. For blood-borne viruses with an outer covering acquired from the host cell, the envelope, a key player may be the cell-derived trigger of coagulation on the virus surface, tissue factor (TF). TF is a multifunctional transmembrane cofactor that accelerates factor (F)VIIa-dependent activation of FX to FXa, leading to clot formation. However, the nascent TF/FVIIa/FXa complex also facilitates G protein-coupled modulation of cells via protease-activated receptor 2. As a viral envelope constituent, TF can bypass the physiological modes of regulation, thereby initiating the activation of neighboring platelets, leukocytes, and endothelial cells. A thromboinflammatory environment is predicted due to feedback amplification in response to cellular release of cytokines, procoagulant proteins, neutrophil extracellular traps, and stimulus-induced accessibility of adhesive receptors, resulting in cellular aggregates. The pathobiological effects of thromboinflammation ultimately contribute to innate and adaptive immunity for viral clearance. In contrast, the preceding stages of viral infection may be enhanced via the TF-protease axis.
许多病毒类型都会影响凝血系统,并与从血栓形成到大出血再到炎症等各种病理现象相关联。在此,我们将概述由宿主或病毒基因组编码的病毒蛋白质、凝血蛋白、血小板、白细胞和内皮细胞之间因感染而产生的错综复杂的相互影响。对于从宿主细胞获得外壳(包膜)的血源性病毒来说,病毒表面源自细胞的凝血触发因子--组织因子(TF)可能是一个关键角色。TF 是一种多功能跨膜辅助因子,可加速因子(F)VIIa 依赖性活化 FX 为 FXa,从而形成血凝块。不过,新生的 TF/FVIIa/FXa 复合物还能通过蛋白酶激活受体-2 促进 G 蛋白耦合调节细胞。作为一种病毒包膜成分,TF 可以绕过生理调节模式,从而激活邻近的血小板、白细胞和内皮细胞。细胞因子、促凝血蛋白和中性粒细胞胞外捕获物的细胞释放,以及刺激引起的粘附受体的可及性导致细胞聚集,由此产生的反馈放大作用预示着血栓性炎症环境的形成。血栓栓塞性炎症的病理生物学效应最终会促进先天性和适应性免疫,从而清除病毒。相反,病毒感染的前几个阶段可能会通过 TF 蛋白酶轴得到加强。
{"title":"Viral coagulation: pushing the envelope.","authors":"Edward Louis George Pryzdial, John Ruggles Perrier, Mahamud-Ur Rashid, Henry Euan West, Michael Ross Sutherland","doi":"10.1016/j.jtha.2024.08.014","DOIUrl":"10.1016/j.jtha.2024.08.014","url":null,"abstract":"<p><p>Many virus types affect the blood clotting system with correlations to pathology that range widely from thrombosis to hemorrhage linking to inflammation. Here we overview the intricate crosstalk induced by infection between proteins on the virus encoded by either the host or virus genomes, coagulation proteins, platelets, leukocytes, and endothelial cells. For blood-borne viruses with an outer covering acquired from the host cell, the envelope, a key player may be the cell-derived trigger of coagulation on the virus surface, tissue factor (TF). TF is a multifunctional transmembrane cofactor that accelerates factor (F)VIIa-dependent activation of FX to FXa, leading to clot formation. However, the nascent TF/FVIIa/FXa complex also facilitates G protein-coupled modulation of cells via protease-activated receptor 2. As a viral envelope constituent, TF can bypass the physiological modes of regulation, thereby initiating the activation of neighboring platelets, leukocytes, and endothelial cells. A thromboinflammatory environment is predicted due to feedback amplification in response to cellular release of cytokines, procoagulant proteins, neutrophil extracellular traps, and stimulus-induced accessibility of adhesive receptors, resulting in cellular aggregates. The pathobiological effects of thromboinflammation ultimately contribute to innate and adaptive immunity for viral clearance. In contrast, the preceding stages of viral infection may be enhanced via the TF-protease axis.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289967","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}
Pub Date : 2024-09-11DOI: 10.1016/j.jtha.2024.09.002
Margaret L Rand,Nicholas Blanchette,Manuel D Carcao
{"title":"Professor Victor S. Blanchette, MA, MB, Bchir (Cantab), FRCP(C), FRCP (1945-2024).","authors":"Margaret L Rand,Nicholas Blanchette,Manuel D Carcao","doi":"10.1016/j.jtha.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.002","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251214","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}
Pub Date : 2024-09-11DOI: 10.1016/j.jtha.2024.08.017
Natasha Lalos,Zachary Vesoulis,Carly Maucione,Charles Eby,Dennis J Dietzen,Stephen Roper,Nicholas C Spies
BACKGROUNDInterpretation of coagulation testing in neonates currently relies on reference intervals (RIs) defined from older patient cohorts. Direct RI studies are difficult, but indirect estimation may allow us to infer normative neonatal distributions from routinely collected clinical data.METHODSWe analyzed first-in-life coagulation testing results from all patients admitted to a level IV neonatal intensive care unit between 1/1/2018-1/1/2024. Results obtained after transfusion of any blood product were excluded. Indirect RIs were estimated across gestational age groups using refineR and compared to currently reported intervals for patients less than one year of age.RESULTSProthrombin times (PT) and international normalized ratios (INR) were available for 1,128 neonates, while activated partial thromboplastin times (aPTT) were available for 790 neonates. The indirect RI was 10-25s in preterm, 10-22s in term, and 10-24s in all neonates for PT, 0.7-2.1 in preterm, 0.8-1.8 in term, and 0.8-1.9 in all neonates for INR, and 25-68s in preterm, 25-58s in term, and 25-62s in all neonates for aPTT. Compared to our current intervals, the indirect RIs would flag 58% fewer PT, 43% fewer INR, and 17% fewer aPTT results as abnormal.CONCLUSIONSIndirectly estimated RIs in neonates admitted to intensive care show substantial divergence from current, first-year-of-life RIs, leading to an abundance of abnormal flags. The associations between these flags and provider behavior, transfusion practice, or clinical outcomes is an area of future exploration.
背景目前,对新生儿凝血检测结果的解释主要依赖于根据年龄较大的患者队列确定的参考区间(RI)。我们分析了 2018 年 1 月 1 日至 2024 年 1 月 1 日期间入住 IV 级新生儿重症监护病房的所有患者的首次生命凝血检测结果。不包括输注任何血液制品后获得的结果。结果1128名新生儿的凝血酶原时间(PT)和国际正常化比率(INR)可用,790名新生儿的活化部分凝血活酶时间(aPTT)可用。早产儿的 PT 间接 RI 为 10-25,足月儿为 10-22,所有新生儿为 10-24;早产儿的 INR 为 0.7-2.1,足月儿为 0.8-1.8,所有新生儿为 0.8-1.9;早产儿的 aPTT 为 25-68,足月儿为 25-58,所有新生儿为 25-62。结论重症监护室收治的新生儿中,间接估计的 RI 与当前的新生儿第一年 RI 有很大差异,导致了大量异常标记。这些标记与医疗服务提供者的行为、输血实践或临床结果之间的关联是未来需要探索的领域。
{"title":"Estimation of Gestational Age-Specific Reference Intervals for Coagulation Assays in a Neonatal Intensive Care Unit Using Real-World Data.","authors":"Natasha Lalos,Zachary Vesoulis,Carly Maucione,Charles Eby,Dennis J Dietzen,Stephen Roper,Nicholas C Spies","doi":"10.1016/j.jtha.2024.08.017","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.017","url":null,"abstract":"BACKGROUNDInterpretation of coagulation testing in neonates currently relies on reference intervals (RIs) defined from older patient cohorts. Direct RI studies are difficult, but indirect estimation may allow us to infer normative neonatal distributions from routinely collected clinical data.METHODSWe analyzed first-in-life coagulation testing results from all patients admitted to a level IV neonatal intensive care unit between 1/1/2018-1/1/2024. Results obtained after transfusion of any blood product were excluded. Indirect RIs were estimated across gestational age groups using refineR and compared to currently reported intervals for patients less than one year of age.RESULTSProthrombin times (PT) and international normalized ratios (INR) were available for 1,128 neonates, while activated partial thromboplastin times (aPTT) were available for 790 neonates. The indirect RI was 10-25s in preterm, 10-22s in term, and 10-24s in all neonates for PT, 0.7-2.1 in preterm, 0.8-1.8 in term, and 0.8-1.9 in all neonates for INR, and 25-68s in preterm, 25-58s in term, and 25-62s in all neonates for aPTT. Compared to our current intervals, the indirect RIs would flag 58% fewer PT, 43% fewer INR, and 17% fewer aPTT results as abnormal.CONCLUSIONSIndirectly estimated RIs in neonates admitted to intensive care show substantial divergence from current, first-year-of-life RIs, leading to an abundance of abnormal flags. The associations between these flags and provider behavior, transfusion practice, or clinical outcomes is an area of future exploration.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251213","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}
Pub Date : 2024-09-11DOI: 10.1016/j.jtha.2024.08.018
Vincenzo LA Mura,Massimo Colombo,Graham R Foster,Paolo Angeli,Wolfgang Miesbach,Robert Klamroth,Glenn F Pierce,Brian O'Mahony,Ming Y Lim,Virginia Hernandez-Gea,Michael Makris,Flora Peyvandi
People with bleeding disorders (PWBD) have been exposed to the risk of developing chronic viral hepatitis and cirrhosis after replacement therapy. At today, the advent of new pharmacological strategies for the control of hemostasis and the efficacious antiviral therapies against HCV and HBV have significantly reduced this risk. However, the real success for liver health in this clinical setting is based on other risk factors, among them, the severity of liver disease at time of HBV/HCV antiviral therapy and the exposure to highly prevalent factors of chronic liver damage (e.g.; metabolic dysfunction and/or alcohol) that can cause a residual risk of complications such as hepatocellular carcinoma, portal hypertension, liver insufficiency. With this background, a group of experts selected among hepatologists, PWBD treaters and patient representatives, produced this practical multisociety guidance for the protection of liver health and the prevention and management of liver complications in PWBD based on the most updated protocols of care.
{"title":"The management of liver disease in people with congenital bleeding disorders: guidance from EAHAD, EHC, ISTH, WFH.","authors":"Vincenzo LA Mura,Massimo Colombo,Graham R Foster,Paolo Angeli,Wolfgang Miesbach,Robert Klamroth,Glenn F Pierce,Brian O'Mahony,Ming Y Lim,Virginia Hernandez-Gea,Michael Makris,Flora Peyvandi","doi":"10.1016/j.jtha.2024.08.018","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.018","url":null,"abstract":"People with bleeding disorders (PWBD) have been exposed to the risk of developing chronic viral hepatitis and cirrhosis after replacement therapy. At today, the advent of new pharmacological strategies for the control of hemostasis and the efficacious antiviral therapies against HCV and HBV have significantly reduced this risk. However, the real success for liver health in this clinical setting is based on other risk factors, among them, the severity of liver disease at time of HBV/HCV antiviral therapy and the exposure to highly prevalent factors of chronic liver damage (e.g.; metabolic dysfunction and/or alcohol) that can cause a residual risk of complications such as hepatocellular carcinoma, portal hypertension, liver insufficiency. With this background, a group of experts selected among hepatologists, PWBD treaters and patient representatives, produced this practical multisociety guidance for the protection of liver health and the prevention and management of liver complications in PWBD based on the most updated protocols of care.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268552","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}
Pub Date : 2024-09-10DOI: 10.1016/j.jtha.2024.08.015
James S O'Donnell,Ross I Baker,Ferdows Atiq
The 2021 ASH ISTH NHF WFH guidelines recommendation that patients with VWF levels of 30-50 IU/dL and an increased bleeding phenotype be categorized as type 1 VWD rather than Low VWF has proved controversial. However, in support of that decision, recent data have demonstrated that individuals with partial quantitative VWF deficiency exhibit an age-dependent evolving phenotype and confirmed that Low VWF represents a sub-group within heterogeneous type 1 VWD. Nonetheless, type 1 VWD heterogeneity continues to pose significant diagnostic challenges. In this Forum Article, we address outstanding issues critical to preventing the inappropriate overdiagnosis of type 1 VWD, while maximizing access to healthcare and minimizing diagnostic delays. In addition, we propose an algorithm for type 1 VWD diagnosis. This algorithm pays special attention to individuals with plasma VWF levels in the 30-50 IU/dL range who have no or minimal bleeding history and have not yet been exposed to significant hemostatic challenges.
{"title":"Low VWF - unravelling an enigma wrapped in a conundrum.","authors":"James S O'Donnell,Ross I Baker,Ferdows Atiq","doi":"10.1016/j.jtha.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.015","url":null,"abstract":"The 2021 ASH ISTH NHF WFH guidelines recommendation that patients with VWF levels of 30-50 IU/dL and an increased bleeding phenotype be categorized as type 1 VWD rather than Low VWF has proved controversial. However, in support of that decision, recent data have demonstrated that individuals with partial quantitative VWF deficiency exhibit an age-dependent evolving phenotype and confirmed that Low VWF represents a sub-group within heterogeneous type 1 VWD. Nonetheless, type 1 VWD heterogeneity continues to pose significant diagnostic challenges. In this Forum Article, we address outstanding issues critical to preventing the inappropriate overdiagnosis of type 1 VWD, while maximizing access to healthcare and minimizing diagnostic delays. In addition, we propose an algorithm for type 1 VWD diagnosis. This algorithm pays special attention to individuals with plasma VWF levels in the 30-50 IU/dL range who have no or minimal bleeding history and have not yet been exposed to significant hemostatic challenges.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251215","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}
Pub Date : 2024-09-09DOI: 10.1016/j.jtha.2024.08.012
Caroline Dix,Beverley J Hunt
Cerebral venous sinus thrombosis (CVST) is an uncommon site of venous thromboembolism. CVST more commonly affects younger people and women, in stark contrast to other forms of venous thrombosis where incidence increases with age and overall affects men. Traditional risk factors for the development of CVST include endogenous and exogenous estrogen (combined oral contraceptives and pregnancy and the puerperium), thrombophilias and rare haematologic disorders. New and emerging risk factors include obesity, polycystic ovary syndrome, COVID-19 infection, and vaccine-induced thrombocytopenia and thrombosis (VITT) and VITT-like disorders. Management centres around anticoagulation, managing the underlying cause, and consideration of invasive measures including endovascular thrombolysis and/or thrombectomy and craniectomy for severe cases. This review discusses the emerging risk factors and their identification, evidence for treatment including the use of direct oral anticoagulants, and the role of invasive management options.
{"title":"The changing face of cerebral venous sinus thrombosis - emerging new causes and treatments.","authors":"Caroline Dix,Beverley J Hunt","doi":"10.1016/j.jtha.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.012","url":null,"abstract":"Cerebral venous sinus thrombosis (CVST) is an uncommon site of venous thromboembolism. CVST more commonly affects younger people and women, in stark contrast to other forms of venous thrombosis where incidence increases with age and overall affects men. Traditional risk factors for the development of CVST include endogenous and exogenous estrogen (combined oral contraceptives and pregnancy and the puerperium), thrombophilias and rare haematologic disorders. New and emerging risk factors include obesity, polycystic ovary syndrome, COVID-19 infection, and vaccine-induced thrombocytopenia and thrombosis (VITT) and VITT-like disorders. Management centres around anticoagulation, managing the underlying cause, and consideration of invasive measures including endovascular thrombolysis and/or thrombectomy and craniectomy for severe cases. This review discusses the emerging risk factors and their identification, evidence for treatment including the use of direct oral anticoagulants, and the role of invasive management options.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182690","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}