Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102443
Miguel A.D. Neves , Tiffany T. Ni , Daniel T. Mackeigan , Aron A. Shoara , Xi Lei , Sladjana Slavkovic , Si-Yang Yu , Tyler W. Stratton , Reid C. Gallant , Dan Zhang , Xiaohong Ruby Xu , Cheryl Fernandes , Guangheng Zhu , Xudong Hu , Noa Chazot , Logan W. Donaldson , Philip E. Johnson , Kim Connelly , Margaret Rand , Yiming Wang , Heyu Ni
Background
Salvianolic acid B (SAB) is a major component of Salvia miltiorrhiza root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated.
Objective
To delineate the antithrombotic mechanisms of SAB.
Methods
We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular in silico docking models to predict the interactions of SAB with thrombin.
Results
SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site.
Conclusion
Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis.
背景丹参酚酸 B(SAB)是丹参(Salvianolic acid B)的主要成分,数百年来在东亚/东南亚被广泛用于治疗心血管疾病。中国已批准使用丹参去势盐治疗慢性心绞痛,其中 85% 的成分为 SAB。尽管临床观察表明丹参提取物可抑制动脉和静脉血栓形成,但其确切机制尚未得到充分阐明。通过凝血酶酶解试验、本征荧光分光光度法和等温滴定量热法测量了 SAB 的抑制动力学和与凝血酶的结合亲和力。结果SAB能剂量依赖性地抑制凝血酶诱导的血小板活化和聚集。SAB 还能降低二磷酸腺苷和胶原诱导的血小板聚集。通过改变纤维蛋白网络结构,SAB 可减轻血液凝固,并显著减少小鼠嵴状动脉血管和灌注室中血栓的形成。酶测定法、本征荧光分光光度法和等温滴定量热法证实了 SAB 与凝血酶的直接相互作用。有趣的是,SAB 与三取代苯并咪唑类凝血酶抑制剂(如达比加群)具有关键的结构相似性。分子对接模型预测了 SAB 与凝血酶活性位点的结合。结论我们的数据证实 SAB 是第一种直接从草药中提取的凝血酶催化位点抑制剂,可通过依赖凝血酶和不依赖凝血酶的途径抑制血栓形成。纯化的 SAB 可能是治疗动脉和深静脉血栓的一种经济有效的药物。
{"title":"Salvianolic acid B inhibits thrombosis and directly blocks the thrombin catalytic site","authors":"Miguel A.D. Neves , Tiffany T. Ni , Daniel T. Mackeigan , Aron A. Shoara , Xi Lei , Sladjana Slavkovic , Si-Yang Yu , Tyler W. Stratton , Reid C. Gallant , Dan Zhang , Xiaohong Ruby Xu , Cheryl Fernandes , Guangheng Zhu , Xudong Hu , Noa Chazot , Logan W. Donaldson , Philip E. Johnson , Kim Connelly , Margaret Rand , Yiming Wang , Heyu Ni","doi":"10.1016/j.rpth.2024.102443","DOIUrl":"10.1016/j.rpth.2024.102443","url":null,"abstract":"<div><h3>Background</h3><p>Salvianolic acid B (SAB) is a major component of <em>Salvia miltiorrhiza</em> root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated.</p></div><div><h3>Objective</h3><p>To delineate the antithrombotic mechanisms of SAB.</p></div><div><h3>Methods</h3><p>We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular <em>in silico</em> docking models to predict the interactions of SAB with thrombin.</p></div><div><h3>Results</h3><p>SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site.</p></div><div><h3>Conclusion</h3><p>Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001328/pdfft?md5=5390bc8f4ac0f011cf1d709097844134&pid=1-s2.0-S2475037924001328-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141031143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102427
Leticia Lemos Jardim , Mariana Brandão Franco , Neimy Ramos de Oliveira , Beatriz Nogueira de Carvalho , Fernando Basques , Daniel Dias Ribeiro , Ton Lisman , Leonardo Soares Pereira , Suely Meireles Rezende
Background
Severe yellow fever infection (YFI) may be complicated by a hemorrhagic diathesis. However, the hemostasis profile of YFI has rarely been reported.
Objectives
The aim of this study was to characterize the hemostatic features of YFI by using a rotational thromboelastometry (ROTEM).
Methods
We evaluated clinical, laboratory, and ROTEM parameters in adults with severe YFI and their correlation with hemostatic variables according to bleeding and death.
Results
A total of 35 patients were included (median age, 49 years). ROTEM was performed in 22 patients, of whom 21 (96%) presented bleeding and 4 (18%) died. All patients who died had major bleeding. Patients who died presented prolonged clotting time (CT; median, 2326 seconds; IQR, 1898-2986 seconds) and reduced alpha angle (median, 12°; IQR, 12°-15°) in comparison with patients who had minor (median CT, 644 seconds; IQR, 552-845 seconds and alpha angle, 47°; IQR, 28°-65°) and major (median CT, 719 seconds; IQR, 368-1114 seconds and alpha angle, 43°; IQR, 32°-64°) bleeding who survived. In patients who had bleeding, CT showed a strong negative correlation with factor (F)V (r = −.68), FIX (r = −.84), and FX (r = −.63) as well as alpha angle showed a strong negative correlation with FIX (r = −.92). In patients who died, the correlations were even stronger. A total of 19/21 (90%) patients presented hypocoagulability assessed by ROTEM.
Conclusion
Hypocoagulabitity is the hallmark of the bleeding diathesis of severe YFI. Abnormal CT and alpha angle associated with death and could be used as potential predictors of adverse outcome in severe YFI.
{"title":"Hypocoagulability in severe yellow fever infection is associated with bleeding: results from a cohort study","authors":"Leticia Lemos Jardim , Mariana Brandão Franco , Neimy Ramos de Oliveira , Beatriz Nogueira de Carvalho , Fernando Basques , Daniel Dias Ribeiro , Ton Lisman , Leonardo Soares Pereira , Suely Meireles Rezende","doi":"10.1016/j.rpth.2024.102427","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102427","url":null,"abstract":"<div><h3>Background</h3><p>Severe yellow fever infection (YFI) may be complicated by a hemorrhagic diathesis. However, the hemostasis profile of YFI has rarely been reported.</p></div><div><h3>Objectives</h3><p>The aim of this study was to characterize the hemostatic features of YFI by using a rotational thromboelastometry (ROTEM).</p></div><div><h3>Methods</h3><p>We evaluated clinical, laboratory, and ROTEM parameters in adults with severe YFI and their correlation with hemostatic variables according to bleeding and death.</p></div><div><h3>Results</h3><p>A total of 35 patients were included (median age, 49 years). ROTEM was performed in 22 patients, of whom 21 (96%) presented bleeding and 4 (18%) died. All patients who died had major bleeding. Patients who died presented prolonged clotting time (CT; median, 2326 seconds; IQR, 1898-2986 seconds) and reduced alpha angle (median, 12°; IQR, 12°-15°) in comparison with patients who had minor (median CT, 644 seconds; IQR, 552-845 seconds and alpha angle, 47°; IQR, 28°-65°) and major (median CT, 719 seconds; IQR, 368-1114 seconds and alpha angle, 43°; IQR, 32°-64°) bleeding who survived. In patients who had bleeding, CT showed a strong negative correlation with factor (F)V (<em>r</em> = −.68), FIX (<em>r</em> = −.84), and FX (<em>r</em> = −.63) as well as alpha angle showed a strong negative correlation with FIX (<em>r</em> = −.92). In patients who died, the correlations were even stronger. A total of 19/21 (90%) patients presented hypocoagulability assessed by ROTEM.</p></div><div><h3>Conclusion</h3><p>Hypocoagulabitity is the hallmark of the bleeding diathesis of severe YFI. Abnormal CT and alpha angle associated with death and could be used as potential predictors of adverse outcome in severe YFI.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S247503792400116X/pdfft?md5=7da2120cfa6f393a29d4c38fbf53e8b8&pid=1-s2.0-S247503792400116X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102467
Samuel R. Taylor , Jean M. Connors , Vinayak Venkataraman
Background
Coagulopathies are frequently observed in alveolar rhabdomyosarcoma (ARMS), with disseminated intravascular coagulation (DIC) being the most common presentation. However, hyperfibrinolysis represents a distinct but often overlapping and potentially life-threatening subset of coagulation disorders that requires specific diagnostic and management approaches.
Key Clinical Question
How can clinicians identify hyperfibrinolysis and what are the implications for management?
Clinical Approach
This case report describes a 25-year-old man with metastatic ARMS arising from the prostate who developed persistent gross hematuria one week after initiating chemotherapy. A comprehensive coagulation workup was performed, including assessment of platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, and fibrin degradation products. Management included repletion of fibrinogen and the use of anti-fibrinolytic agents.
Conclusion
Recognizing hyperfibrinolysis in ARMS patients is crucial for appropriate management. Clinicians should maintain a high index of suspicion for hyperfibrinolysis in ARMS patients presenting with severe coagulation abnormalities, particularly those with prostatic involvement or undergoing chemotherapy. In cases of primary hyperfibrinolysis, antifibrinolytic agents may be considered, whereas they are generally contraindicated in DIC.
{"title":"Hyperfibrinolysis during the treatment of rhabdomyosarcoma","authors":"Samuel R. Taylor , Jean M. Connors , Vinayak Venkataraman","doi":"10.1016/j.rpth.2024.102467","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102467","url":null,"abstract":"<div><h3>Background</h3><p>Coagulopathies are frequently observed in alveolar rhabdomyosarcoma (ARMS), with disseminated intravascular coagulation (DIC) being the most common presentation. However, hyperfibrinolysis represents a distinct but often overlapping and potentially life-threatening subset of coagulation disorders that requires specific diagnostic and management approaches.</p></div><div><h3>Key Clinical Question</h3><p>How can clinicians identify hyperfibrinolysis and what are the implications for management?</p></div><div><h3>Clinical Approach</h3><p>This case report describes a 25-year-old man with metastatic ARMS arising from the prostate who developed persistent gross hematuria one week after initiating chemotherapy. A comprehensive coagulation workup was performed, including assessment of platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, and fibrin degradation products. Management included repletion of fibrinogen and the use of anti-fibrinolytic agents.</p></div><div><h3>Conclusion</h3><p>Recognizing hyperfibrinolysis in ARMS patients is crucial for appropriate management. Clinicians should maintain a high index of suspicion for hyperfibrinolysis in ARMS patients presenting with severe coagulation abnormalities, particularly those with prostatic involvement or undergoing chemotherapy. In cases of primary hyperfibrinolysis, antifibrinolytic agents may be considered, whereas they are generally contraindicated in DIC.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001560/pdfft?md5=2b51d5aa1a5749c603e9b78a475131ee&pid=1-s2.0-S2475037924001560-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141485825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102437
S.F.B. van der Horst , Y. de Jong , N. van Rein , J.W. Jukema , M. Palmen , E. Janssen , E.F. Bonneville , F.A. Klok , M.V. Huisman , L.F. Tops , P.L. den Exter
Background
Implantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern.
Objectives
We evaluated current risk scores’ predictive accuracy for MB in LVAD recipients.
Methods
We conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS).
Results
One hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk.
Conclusion
Current bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.
{"title":"Performance of risk scores in predicting major bleeding in left ventricular assist device recipients: a comparative external validation","authors":"S.F.B. van der Horst , Y. de Jong , N. van Rein , J.W. Jukema , M. Palmen , E. Janssen , E.F. Bonneville , F.A. Klok , M.V. Huisman , L.F. Tops , P.L. den Exter","doi":"10.1016/j.rpth.2024.102437","DOIUrl":"10.1016/j.rpth.2024.102437","url":null,"abstract":"<div><h3>Background</h3><p>Implantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern.</p></div><div><h3>Objectives</h3><p>We evaluated current risk scores’ predictive accuracy for MB in LVAD recipients.</p></div><div><h3>Methods</h3><p>We conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS).</p></div><div><h3>Results</h3><p>One hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk.</p></div><div><h3>Conclusion</h3><p>Current bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001262/pdfft?md5=a3e07daf5bc02130d36104aeac7bd1e3&pid=1-s2.0-S2475037924001262-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141043227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The management of hemophilia, von Willebrand disease (VWD), and rare coagulation disorders traditionally relied on replacement therapies, such as factor concentrates, to address clotting factor deficiencies. However, in recent years, the emergence of nonreplacement therapies has shown promise as an adjunctive approach, especially in hemophilia, and also for patients with VWD and rare bleeding disorders.
This review article offers an overview of nonreplacement therapies, such as FVIII-mimicking agents and drugs aimed at rebalancing hemostasis by inhibiting natural anticoagulants, particularly in the management of hemophilia. The utilization of nonreplacement therapies in VWD and rare bleeding disorders has recently attracted attention, as evidenced by presentations at the International Society on Thrombosis and Haemostasis 2023 Congress. Nonreplacement therapies provide alternative methods for preventing bleeding episodes and enhancing patients’ quality of life, as many of them are administered subcutaneously and allow longer infusion intervals, resulting in improved quality of life and comfort for patients.
{"title":"Exploring nonreplacement therapies’ impact on hemophilia and other rare bleeding disorders","authors":"Flora Peyvandi , Omid Seidizadeh , Samin Mohsenian , Isabella Garagiola","doi":"10.1016/j.rpth.2024.102434","DOIUrl":"10.1016/j.rpth.2024.102434","url":null,"abstract":"<div><p>The management of hemophilia, von Willebrand disease (VWD), and rare coagulation disorders traditionally relied on replacement therapies, such as factor concentrates, to address clotting factor deficiencies. However, in recent years, the emergence of nonreplacement therapies has shown promise as an adjunctive approach, especially in hemophilia, and also for patients with VWD and rare bleeding disorders.</p><p>This review article offers an overview of nonreplacement therapies, such as FVIII-mimicking agents and drugs aimed at rebalancing hemostasis by inhibiting natural anticoagulants, particularly in the management of hemophilia. The utilization of nonreplacement therapies in VWD and rare bleeding disorders has recently attracted attention, as evidenced by presentations at the International Society on Thrombosis and Haemostasis 2023 Congress. Nonreplacement therapies provide alternative methods for preventing bleeding episodes and enhancing patients’ quality of life, as many of them are administered subcutaneously and allow longer infusion intervals, resulting in improved quality of life and comfort for patients.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001237/pdfft?md5=b04cb155e98eafa1af60877c506e07ca&pid=1-s2.0-S2475037924001237-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141041925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR.
Objectives
To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics.
Methods
Moderate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed.
Results
At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%).
Conclusion
Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.
{"title":"Mitral regurgitation is associated with similar loss of von Willebrand factor large multimers but lower frequency of anemia compared with aortic stenosis","authors":"Hiroshi Takiguchi , Mizuki Miura , Shin-ichi Shirai , Yoshimitsu Soga , Michiya Hanyu , Genichi Sakaguchi , Yoshiharu Soga , Yoshio Arai , Shin Watanabe , Takeshi Kimura , Hiroyuki Takahama , Satoshi Yasuda , Takaharu Nakayoshi , Yoshihiro Fukumoto , Nobuhiro Yaoita , Hiroaki Shimokawa , Ko Sakatsume , Yoshikatsu Saiki , Koichi Kaikita , Kenichi Tsujita , Hisanori Horiuchi","doi":"10.1016/j.rpth.2024.102431","DOIUrl":"10.1016/j.rpth.2024.102431","url":null,"abstract":"<div><h3>Background</h3><p>Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR.</p></div><div><h3>Objectives</h3><p>To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics.</p></div><div><h3>Methods</h3><p>Moderate or severe MR patients (<em>n</em> = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed.</p></div><div><h3>Results</h3><p>At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%).</p></div><div><h3>Conclusion</h3><p>Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001201/pdfft?md5=2b6a0d020c6646b9f72afbe3d9943654&pid=1-s2.0-S2475037924001201-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141047234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102464
Daniel Steiner , Stephan Nopp , Georg Heinze , Daniel Kraemmer , Oliver Schlager , Stefano Barco , Frederikus A. Klok , Ingrid Pabinger , Benedikt Weber , Cihan Ay
Background
Venous thromboembolism (VTE) is associated with various long-term complications.
Objectives
We aimed to investigate the association of clinical characteristics at VTE diagnosis with functional limitations 3 and 12 months afterward.
Methods
We conducted a prospective cohort study of VTE patients, excluding patients with cancer, pregnancy, and postpartum period. Functional limitations were assessed with the post-VTE functional status (PVFS) scale (range, 0-4) within 21 days of diagnosis, after 3 and 12 months (prospectively), and 1 month before diagnosis (retrospectively). Twelve-month follow-up was only performed in patients on anticoagulation. We fitted 2 proportional odds logistic regression models for the 3- and 12-month follow-ups and computed odds ratios (ORs) with 95% bootstrap percentile confidence intervals (CIs).
Results
We included 307 patients (42% female, median age 55.6 years) with a median (IQR) PVFS scale grade of 2 (2-3) at study inclusion and 0 (0-0) before diagnosis. After 3 months, PVFS scale grade in 269 patients was 1 (0-2). Female sex (OR, 2.15; 95% CI, 1.26-4.14), body mass index (OR per 1 kg/m2 increase, 1.05; 95% CI, 1.00-1.10), functional limitations at baseline, and older age were associated with functional limitations. After 12 months, PVFS scale grade in 124 patients was 1 (0-2). Female sex (OR, 4.47; 95% CI, 2.11-16.00), history of cardiovascular/pulmonary disease (OR, 2.36; 95% CI, 1.01-6.89), and functional limitations at baseline were associated with functional limitations.
Conclusion
Functional limitations in VTE patients improved 3 and 12 months after diagnosis but did not return to pre-VTE values. We identified clinical characteristics that could help identify patients at risk of persisting functional limitations after VTE.
{"title":"Functional limitations 3 and 12 months after venous thromboembolism: a cohort study","authors":"Daniel Steiner , Stephan Nopp , Georg Heinze , Daniel Kraemmer , Oliver Schlager , Stefano Barco , Frederikus A. Klok , Ingrid Pabinger , Benedikt Weber , Cihan Ay","doi":"10.1016/j.rpth.2024.102464","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102464","url":null,"abstract":"<div><h3>Background</h3><p>Venous thromboembolism (VTE) is associated with various long-term complications.</p></div><div><h3>Objectives</h3><p>We aimed to investigate the association of clinical characteristics at VTE diagnosis with functional limitations 3 and 12 months afterward.</p></div><div><h3>Methods</h3><p>We conducted a prospective cohort study of VTE patients, excluding patients with cancer, pregnancy, and postpartum period. Functional limitations were assessed with the post-VTE functional status (PVFS) scale (range, 0-4) within 21 days of diagnosis, after 3 and 12 months (prospectively), and 1 month before diagnosis (retrospectively). Twelve-month follow-up was only performed in patients on anticoagulation. We fitted 2 proportional odds logistic regression models for the 3- and 12-month follow-ups and computed odds ratios (ORs) with 95% bootstrap percentile confidence intervals (CIs).</p></div><div><h3>Results</h3><p>We included 307 patients (42% female, median age 55.6 years) with a median (IQR) PVFS scale grade of 2 (2-3) at study inclusion and 0 (0-0) before diagnosis. After 3 months, PVFS scale grade in 269 patients was 1 (0-2). Female sex (OR, 2.15; 95% CI, 1.26-4.14), body mass index (OR per 1 kg/m<sup>2</sup> increase, 1.05; 95% CI, 1.00-1.10), functional limitations at baseline, and older age were associated with functional limitations. After 12 months, PVFS scale grade in 124 patients was 1 (0-2). Female sex (OR, 4.47; 95% CI, 2.11-16.00), history of cardiovascular/pulmonary disease (OR, 2.36; 95% CI, 1.01-6.89), and functional limitations at baseline were associated with functional limitations.</p></div><div><h3>Conclusion</h3><p>Functional limitations in VTE patients improved 3 and 12 months after diagnosis but did not return to pre-VTE values. We identified clinical characteristics that could help identify patients at risk of persisting functional limitations after VTE.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001535/pdfft?md5=327f2a5fc43c10e2fa2b466818adb948&pid=1-s2.0-S2475037924001535-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102479
Background
Venous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events.
Objectives
To investigate APC and AT resistance in factor (F)VIII–deficient (FVIIIdef) plasma in the presence of emicizumab and APCC.
Methods
In pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor–triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined.
Results
The AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation.
Conclusion
FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.
{"title":"Activated protein C resistance in the copresence of emicizumab and activated prothrombin complex concentrates","authors":"","doi":"10.1016/j.rpth.2024.102479","DOIUrl":"10.1016/j.rpth.2024.102479","url":null,"abstract":"<div><h3>Background</h3><p>Venous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events.</p></div><div><h3>Objectives</h3><p>To investigate APC and AT resistance in factor (F)VIII–deficient (FVIIIdef) plasma in the presence of emicizumab and APCC.</p></div><div><h3>Methods</h3><p>In pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor–triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined.</p></div><div><h3>Results</h3><p>The AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation.</p></div><div><h3>Conclusion</h3><p>FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001687/pdfft?md5=b6beebf353210e86bdb8def7c863b102&pid=1-s2.0-S2475037924001687-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141623234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102446
Annabel K. Frank , Bethany Samuelson Bannow
The topic of this review is venous thromboembolism (VTE) during pregnancy and postpartum. The following topics will be addressed: epidemiology and pathophysiology of VTE in pregnancy and postpartum, diagnostic considerations for VTE in pregnancy, indications for prophylactic and therapeutic anticoagulation in pregnancy and postpartum, choice of anticoagulation in pregnancy and breastfeeding, anticoagulation management during labor and delivery, and anticoagulation considerations for assisted reproductive technology.
{"title":"Venous thromboembolism in pregnancy and postpartum: an illustrated review","authors":"Annabel K. Frank , Bethany Samuelson Bannow","doi":"10.1016/j.rpth.2024.102446","DOIUrl":"10.1016/j.rpth.2024.102446","url":null,"abstract":"<div><p>The topic of this review is venous thromboembolism (VTE) during pregnancy and postpartum. The following topics will be addressed: epidemiology and pathophysiology of VTE in pregnancy and postpartum, diagnostic considerations for VTE in pregnancy, indications for prophylactic and therapeutic anticoagulation in pregnancy and postpartum, choice of anticoagulation in pregnancy and breastfeeding, anticoagulation management during labor and delivery, and anticoagulation considerations for assisted reproductive technology.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001353/pdfft?md5=4862a6ff7d1fc904170be0e04889f361&pid=1-s2.0-S2475037924001353-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141398775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.rpth.2024.102465
Sergio Bevilacqua , Pierluigi Stefàno , Martina Berteotti , Stefano Del Pace , Matteo Pieri , Raffaele Mandarano , Angela Rogolino , Francesca Cesari , Anna Maria Gori , Betti Giusti , Rossella Marcucci
Background
Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting.
Objectives
To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity.
Methods
A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center.
Results
HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause.
Conclusion
Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.
背景心脏手术是肝素诱导血小板减少症(HIT)的高风险环境。然而,在这种情况下,其发病率、血栓并发症发生率和死亡率存在很大差异。目的 描述我们的队列中 HIT 患者的发病率、预后和管理情况,并与出现血小板因子 4/肝素抗体但无血小板激活能力的患者进行比较。0.22%的患者被诊断为HIT,0.04%的病例伴有血栓栓塞并发症。30天内有2例死亡病例,均为伴有血栓形成的患者。4T 评分的阴性预测值为 99.9%。免疫球蛋白G特异性化学发光试验阳性率对HIT有很高的预测性。华法林通常在术后早期开始使用,虽然在确诊 HIT 时很少停药,但随后并未出现新的血栓栓塞并发症。无论病因如何,血小板减少似乎都是预后不良的征兆。结论HIT虽然罕见,但在这种情况下死亡率很高,尤其是发生血栓并发症时。应开展大型多中心研究或国际登记,以加强 HIT 诊断和管理方面的科学证据。
{"title":"Heparin-induced thrombocytopenia after cardiac surgery. A single-center, retrospective cohort study","authors":"Sergio Bevilacqua , Pierluigi Stefàno , Martina Berteotti , Stefano Del Pace , Matteo Pieri , Raffaele Mandarano , Angela Rogolino , Francesca Cesari , Anna Maria Gori , Betti Giusti , Rossella Marcucci","doi":"10.1016/j.rpth.2024.102465","DOIUrl":"10.1016/j.rpth.2024.102465","url":null,"abstract":"<div><h3>Background</h3><p>Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting.</p></div><div><h3>Objectives</h3><p>To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity.</p></div><div><h3>Methods</h3><p>A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center.</p></div><div><h3>Results</h3><p>HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause.</p></div><div><h3>Conclusion</h3><p>Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001547/pdfft?md5=d83db14062b5fb26765151ad231cec30&pid=1-s2.0-S2475037924001547-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141404411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}