Pub Date : 2024-06-03DOI: 10.1016/j.thromres.2024.109057
Cameron Brown , Lauren Tokessy , Aurélien Delluc , Marc Carrier
Background
Post-thrombotic syndrome (PTS) is common in patients with deep vein thrombosis (DVT). It is unclear if different types of anticoagulant therapies (e.g. vitamin K antagonists (VKA), direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH)) are associated with different risks of PTS. We sought to assess the incidence rates of PTS development following a proximal DVT of the lower extremity managed with different types of anticoagulation regimens.
Methods
A systematic search of MEDLINE, EMBASE and PubMed, from inception to June 2023 was performed. The primary outcome was development of PTS. The secondary outcomes included severe PTS, venous ulcers, and major bleeding. Incidence rates were pooled using the random effects model and expressed as event per 100 patient-years with its associated 95 % confidence intervals (CI) using R software.
Results
A total of 21 (4342 patients) articles were included in the analysis. The adjusted pooled incidence of PTS was 15.1 (95 % CI: 8.7 to 26.1), 18.2 (95 % CI: 9.4 to 35.1) and 24.6 (95 % CI: 9.2 to 65.5) per 100 patient-years patients managed with VKA, DOAC and LMWH, respectively. The adjusted pooled incidence of severe PTS was 5.1 (95 % CI: 2.6 to 10.0) and 0.2 (95 % CI: 0.01 to 2.7) per 100 patient-years for VKAs and DOACs, respectively.
Conclusions
The development of PTS is common in patients with proximal lower extremity DVT. The incidence rates of PTS seem to be similar across the different anticoagulation regimens, but severe PTS may be lower among patients receiving a DOAC.
{"title":"Risk of developing post thrombotic syndrome after deep vein thrombosis with different anticoagulant regimens: A systematic review and pooled analysis","authors":"Cameron Brown , Lauren Tokessy , Aurélien Delluc , Marc Carrier","doi":"10.1016/j.thromres.2024.109057","DOIUrl":"10.1016/j.thromres.2024.109057","url":null,"abstract":"<div><h3>Background</h3><p>Post-thrombotic syndrome (PTS) is common in patients with deep vein thrombosis (DVT). It is unclear if different types of anticoagulant therapies (e.g. vitamin K antagonists (VKA), direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH)) are associated with different risks of PTS. We sought to assess the incidence rates of PTS development following a proximal DVT of the lower extremity managed with different types of anticoagulation regimens.</p></div><div><h3>Methods</h3><p>A systematic search of MEDLINE, EMBASE and PubMed, from inception to June 2023 was performed. The primary outcome was development of PTS. The secondary outcomes included severe PTS, venous ulcers, and major bleeding. Incidence rates were pooled using the random effects model and expressed as event per 100 patient-years with its associated 95 % confidence intervals (CI) using R software.</p></div><div><h3>Results</h3><p>A total of 21 (4342 patients) articles were included in the analysis. The adjusted pooled incidence of PTS was 15.1 (95 % CI: 8.7 to 26.1), 18.2 (95 % CI: 9.4 to 35.1) and 24.6 (95 % CI: 9.2 to 65.5) per 100 patient-years patients managed with VKA, DOAC and LMWH, respectively. The adjusted pooled incidence of severe PTS was 5.1 (95 % CI: 2.6 to 10.0) and 0.2 (95 % CI: 0.01 to 2.7) per 100 patient-years for VKAs and DOACs, respectively.</p></div><div><h3>Conclusions</h3><p>The development of PTS is common in patients with proximal lower extremity DVT. The incidence rates of PTS seem to be similar across the different anticoagulation regimens, but severe PTS may be lower among patients receiving a DOAC.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141274212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-02DOI: 10.1016/j.thromres.2024.109058
Se-Ge Ma , Yi Yang , Yan Huang
Aims
This meta-analysis was conducted to evaluate the validity of the Caprini venous thromboembolism (VTE) risk assessment scale in predicting the risk of VTE in inpatients with cancer.
Methods
Studies relating to the Caprini VTE risk assessment scale were systematically retrieved from the MEDLINE, EMBASE, Web of Science, Cochrane Library, BIOSIS Previews, EBSCOhost, and China National Knowledge Infrastructure (CNKI) databases up to May 1, 2022. Two reviewers independently conducted data extraction and quality evaluation. MetaDisc 1.4 and Stata 15.0 software were used for data analysis.
Results
We included 10 studies with 23,644 subjects in our analyses. The results showed that the pooled sensitivity (SEN) and specificity (SPE) were 0.59 (95 % CI: 0.55 to 0.63) and 0.57 (95 % CI:0.57 to 0.58), respectively; the pooled diagnostic odds ratio (DOR) was 6.05 (95 % CI: 2.70 to 13.58); and the area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.76. Subgroup analysis was performed according to ethnicity (Chinese or non-Chinese), study design (prospective/retrospective), Caprini RAM version (2005/2009), and cut-off (≤7 or > 7).
Conclusion
The Caprini VTE risk assessment scale has a moderate ability to predict VTE in surgical inpatients with cancer, as well as in Western populations; Caprini 2009 has a stronger predictive ability than 2005, and its predictive power is better if the cut-off value is >7. Future studies in clinical practice and specific specialties are needed to explore the optimal cut-off value of different cancers. This will improve our accuracy in understanding the risk of VTE in inpatients and help promote timely and targeted prevention. In turn, this will reduce the incidence of VTE and improve the quality of life of inpatients with cancer.
{"title":"Venous thromboembolism risk assessment scale for prediction of venous thromboembolism in inpatients with cancer: A meta-analysis","authors":"Se-Ge Ma , Yi Yang , Yan Huang","doi":"10.1016/j.thromres.2024.109058","DOIUrl":"10.1016/j.thromres.2024.109058","url":null,"abstract":"<div><h3>Aims</h3><p>This meta-analysis was conducted to evaluate the validity of the Caprini venous thromboembolism (VTE) risk assessment scale in predicting the risk of VTE in inpatients with cancer.</p></div><div><h3>Methods</h3><p>Studies relating to the Caprini VTE risk assessment scale were systematically retrieved from the MEDLINE, EMBASE, Web of Science, Cochrane Library, BIOSIS Previews, EBSCOhost, and China National Knowledge Infrastructure (CNKI) databases up to May 1, 2022. Two reviewers independently conducted data extraction and quality evaluation. MetaDisc 1.4 and Stata 15.0 software were used for data analysis.</p></div><div><h3>Results</h3><p>We included 10 studies with 23,644 subjects in our analyses. The results showed that the pooled sensitivity (SEN) and specificity (SPE) were 0.59 (95 % CI: 0.55 to 0.63) and 0.57 (95 % CI:0.57 to 0.58), respectively; the pooled diagnostic odds ratio (DOR) was 6.05 (95 % CI: 2.70 to 13.58); and the area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.76. Subgroup analysis was performed according to ethnicity (Chinese or non-Chinese), study design (prospective/retrospective), Caprini RAM version (2005/2009), and cut-off (≤7 or > 7).</p></div><div><h3>Conclusion</h3><p>The Caprini VTE risk assessment scale has a moderate ability to predict VTE in surgical inpatients with cancer, as well as in Western populations; Caprini 2009 has a stronger predictive ability than 2005, and its predictive power is better if the cut-off value is >7. Future studies in clinical practice and specific specialties are needed to explore the optimal cut-off value of different cancers. This will improve our accuracy in understanding the risk of VTE in inpatients and help promote timely and targeted prevention. In turn, this will reduce the incidence of VTE and improve the quality of life of inpatients with cancer.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141279779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-31DOI: 10.1016/j.thromres.2024.109056
Shaoheng Chen , Jia Han , Huimin Deng , Yuanshan Lu , Zhicheng Wang , Qi Zhang , Rong Xia
Platelet apoptosis is irreversible under current storage conditions in blood banks. Studies have shown that programmed cell death ligand 1 (PD-L1) in tumour cells is required for neoplastic progression, tumour recurrence and metastasis by regulating apoptosis. However, whether PD-L1 is involved in storage-induced apoptosis in platelets remains poorly understood. In this study, we explored whether PD-L1 on platelets participated in the regulation of storage-induced apoptosis under blood bank conditions, as well as the underlying mechanism. Several apoptotic events in platelets from humans and PD-L1-knockout mice during storage under blood bank conditions were measured. The mechanism by which storage-induced apoptosis was regulated by platelet-intrinsic PD-L1 signalling was further investigated. Our results showed that PD-L1 in platelets progressively decreased. There was a strong negative correlation between platelet PD-L1 expression and the phosphatidylserine (PS) externalization rate and cleaved caspase-3 level and a positive correlation with anti-apoptosis protein Bcl-xl. Ex vivo, PD-L1−/− platelets stored at 22 °C showed rapid apoptosis via an intrinsic mitochondria-dependent pathway over time. Likewise, inhibiting PD-L1 signalling with BMS-1166 accelerated apoptosis by intrinsic mitochondria-dependent pathway. Coimmunoprecipitation analysis revealed that PD-L1 could bind AKT in platelets, and the binding capacity of both showed a progressive decrease with time. Finally, the decrease in PD-L1 expression levels during storage could be attributed to a complex process of progressive secretion. Therefore, platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway, which is expected to become a target for alleviating platelet storage lesions (PSLs) under current blood bank conditions.
{"title":"Platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway","authors":"Shaoheng Chen , Jia Han , Huimin Deng , Yuanshan Lu , Zhicheng Wang , Qi Zhang , Rong Xia","doi":"10.1016/j.thromres.2024.109056","DOIUrl":"https://doi.org/10.1016/j.thromres.2024.109056","url":null,"abstract":"<div><p>Platelet apoptosis is irreversible under current storage conditions in blood banks. Studies have shown that programmed cell death ligand 1 (PD-L1) in tumour cells is required for neoplastic progression, tumour recurrence and metastasis by regulating apoptosis. However, whether PD-L1 is involved in storage-induced apoptosis in platelets remains poorly understood. In this study, we explored whether PD-L1 on platelets participated in the regulation of storage-induced apoptosis under blood bank conditions, as well as the underlying mechanism. Several apoptotic events in platelets from humans and PD-L1-knockout mice during storage under blood bank conditions were measured. The mechanism by which storage-induced apoptosis was regulated by platelet-intrinsic PD-L1 signalling was further investigated. Our results showed that PD-L1 in platelets progressively decreased. There was a strong negative correlation between platelet PD-L1 expression and the phosphatidylserine (PS) externalization rate and cleaved caspase-3 level and a positive correlation with anti-apoptosis protein Bcl-xl. Ex vivo, PD-L1−/− platelets stored at 22 °C showed rapid apoptosis via an intrinsic mitochondria-dependent pathway over time. Likewise, inhibiting PD-L1 signalling with BMS-1166 accelerated apoptosis by intrinsic mitochondria-dependent pathway. Coimmunoprecipitation analysis revealed that PD-L1 could bind AKT in platelets, and the binding capacity of both showed a progressive decrease with time. Finally, the decrease in PD-L1 expression levels during storage could be attributed to a complex process of progressive secretion. Therefore, platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway, which is expected to become a target for alleviating platelet storage lesions (PSLs) under current blood bank conditions.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141325325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1016/j.thromres.2024.109044
Zhe Lai , Jiaming Li , Shijie Zhou , Xi Wu , Junwei Yuan , Fang Li , Wenman Wu , Qiulan Ding , Jing Dai , Xuefeng Wang , Yeling Lu , Xiaohong Cai
Protein C (PC), a vitamin K–dependent serine protease zymogen in plasma, can be activated by thrombin-thrombomodulin(TM) complex, resulting in the formation of activated protein C (APC). APC functions to downregulate thrombin generation by inactivating active coagulation factors V(FVa) and VIII(FVIIIa). Deficiency in PC increases the risk of venous thromboembolism (VTE). We have identified two unrelated VTE patients with the same heterozygous mutation (c.1384 T > C, p.Ter462GlnextTer17) in PROC. To comprehend the role of this mutation in VTE development, we expressed recombinant PC-Ter462GlnextTer17 in mammalian cells and evaluated its characteristics using established coagulation assay systems. Functional studies revealed a significant impairment in the activation of the mutant by thrombin or thrombin-TM complex. Furthermore, APC-Ter462GlnextTer17 demonstrated diminished hydrolytic activity towards the chromogenic substrate S2366. APTT and FVa degradation assays showed that both the anticoagulant activity of the mutant protein was markedly impaired, regardless of whether protein S was present or absent. These results were further supported by a thrombin generation assay conducted using purified and plasma-based systems. In conclusion, the Ter462GlnextTer17 mutation introduces a novel tail at the C-terminus of PC, leading to impaired activity in both PC zymogen activation and APC's anticoagulant function. This impairment contributes to thrombosis in individuals carrying this heterozygous mutation and represents a genetic risk factor for VTE.
蛋白 C(PC)是血浆中一种依赖维生素 K 的丝氨酸蛋白酶酶原,可被凝血酶-血栓调节蛋白(TM)复合物激活,形成活化蛋白 C(APC)。活化蛋白 C 的功能是通过灭活活性凝血因子 V(FVa)和 VIII(FVIIIa)来降低凝血酶的生成。缺乏 PC 会增加静脉血栓栓塞症(VTE)的风险。我们在 PROC 中发现了两名无亲属关系的 VTE 患者,他们具有相同的杂合突变(c.1384 T > C, p.Ter462GlnextTer17)。为了解该突变在 VTE 发生中的作用,我们在哺乳动物细胞中表达了重组 PC-Ter462GlnextTer17,并使用已建立的凝血检测系统评估了其特性。功能研究显示,凝血酶或凝血酶-TM 复合物对突变体的激活作用明显减弱。此外,APC-Ter462GlnextTer17 对染色底物 S2366 的水解活性也有所降低。APTT 和 FVa 降解试验表明,无论蛋白 S 存在与否,突变体蛋白的抗凝活性都明显受损。使用纯化和血浆系统进行的凝血酶生成试验进一步证实了这些结果。总之,Ter462GlnextTer17 突变在 PC 的 C 端引入了一个新的尾部,导致 PC 酶原激活活性和 APC 抗凝功能受损。这种损伤导致携带这种杂合突变的个体出现血栓形成,并成为 VTE 的遗传风险因素。
{"title":"Mutation Ter462GlnextTer17 introduces a tail to C-terminus of protein C and causes venous thrombosis","authors":"Zhe Lai , Jiaming Li , Shijie Zhou , Xi Wu , Junwei Yuan , Fang Li , Wenman Wu , Qiulan Ding , Jing Dai , Xuefeng Wang , Yeling Lu , Xiaohong Cai","doi":"10.1016/j.thromres.2024.109044","DOIUrl":"10.1016/j.thromres.2024.109044","url":null,"abstract":"<div><p>Protein C (PC), a vitamin K–dependent serine protease zymogen in plasma, can be activated by thrombin-thrombomodulin(TM) complex, resulting in the formation of activated protein C (APC). APC functions to downregulate thrombin generation by inactivating active coagulation factors V(FVa) and VIII(FVIIIa). Deficiency in PC increases the risk of venous thromboembolism (VTE). We have identified two unrelated VTE patients with the same heterozygous mutation (c.1384 T > C, p.Ter462GlnextTer17) in <em>PROC.</em> To comprehend the role of this mutation in VTE development, we expressed recombinant PC-Ter462GlnextTer17 in mammalian cells and evaluated its characteristics using established coagulation assay systems. Functional studies revealed a significant impairment in the activation of the mutant by thrombin or thrombin-TM complex. Furthermore, APC-Ter462GlnextTer17 demonstrated diminished hydrolytic activity towards the chromogenic substrate S2366. APTT and FVa degradation assays showed that both the anticoagulant activity of the mutant protein was markedly impaired, regardless of whether protein S was present or absent. These results were further supported by a thrombin generation assay conducted using purified and plasma-based systems. In conclusion, the Ter462GlnextTer17 mutation introduces a novel tail at the C-terminus of PC, leading to impaired activity in both PC zymogen activation and APC's anticoagulant function. This impairment contributes to thrombosis in individuals carrying this heterozygous mutation and represents a genetic risk factor for VTE.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1016/j.thromres.2024.109043
Xinjie Wang , Hui Ma , Xiaowei Zhao
{"title":"Letter to the editor regarding the article “Platelet activity, coagulation, and fibrinolysis in long-term users of anabolic-androgenic steroids compared to strength-trained athletes”","authors":"Xinjie Wang , Hui Ma , Xiaowei Zhao","doi":"10.1016/j.thromres.2024.109043","DOIUrl":"https://doi.org/10.1016/j.thromres.2024.109043","url":null,"abstract":"","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141313099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1016/j.thromres.2024.109045
Bauke Haisma , Saskia E.M. Schols , René G.M. van Oerle , Kitty Verbeek-Knobbe , Dave Hellenbrand , Evelien J. Verwoerd , Floor C.J.I. Heubel-Moenen , An K. Stroobants , Danielle Meijer , Sanna R. Rijpma , Yvonne M.C. Henskens
Introduction
Thrombin generation assays (TGAs) assess the overall functionality of the hemostatic system and thereby provide a reflection of the hemostatic capacity of patients with disorders in this system. Currently, four (semi-)automated TGA platforms are available: the Calibrated Automated Thrombogram, Nijmegen Hemostasis Assay, ST Genesia and Ceveron s100. In this study, we compared their performance for detecting patients with congenital single coagulation factor deficiencies.
Materials and methods
Pooled patient samples, healthy control samples and normal pooled plasma were tested on all four platforms, using the available reagents that vary in tissue factor and phospholipid concentrations. The TGA parameters selected for analysis were peak height and thrombin potential. Results were normalized by using the calculated mean of healthy controls and a correction for between-run variation. Outcomes were presented as relative values, with the mean of healthy controls standardized to 100 %.
Results
Across all platforms and reagents used, thrombin potentials and peak heights of samples with coagulation factor deficiencies were lower than those of healthy controls. Reagents designed for bleeding tendencies yielded the lowest values on all platforms (relative median peak height 19–32 %, relative median thrombin potential 19–45 %). Samples representing more severe coagulation factor deficiencies generally exhibited lower relative peak heights and thrombin potentials.
Conclusions
Thrombin generation assays prove effective in differentiating single coagulation factor deficient samples from healthy controls, with modest discrepancies observed between the platforms. Reagents designed for assessing bleeding tendencies, featuring the lowest tissue factor and phospholipid concentrations, emerged as the most suitable option for detecting coagulation factor deficiencies.
{"title":"Comparative analysis of thrombin generation platforms for patients with coagulation factor deficiencies: A comprehensive assessment","authors":"Bauke Haisma , Saskia E.M. Schols , René G.M. van Oerle , Kitty Verbeek-Knobbe , Dave Hellenbrand , Evelien J. Verwoerd , Floor C.J.I. Heubel-Moenen , An K. Stroobants , Danielle Meijer , Sanna R. Rijpma , Yvonne M.C. Henskens","doi":"10.1016/j.thromres.2024.109045","DOIUrl":"https://doi.org/10.1016/j.thromres.2024.109045","url":null,"abstract":"<div><h3>Introduction</h3><p>Thrombin generation assays (TGAs) assess the overall functionality of the hemostatic system and thereby provide a reflection of the hemostatic capacity of patients with disorders in this system. Currently, four (semi-)automated TGA platforms are available: the Calibrated Automated Thrombogram, Nijmegen Hemostasis Assay, ST Genesia and Ceveron s100. In this study, we compared their performance for detecting patients with congenital single coagulation factor deficiencies.</p></div><div><h3>Materials and methods</h3><p>Pooled patient samples, healthy control samples and normal pooled plasma were tested on all four platforms, using the available reagents that vary in tissue factor and phospholipid concentrations. The TGA parameters selected for analysis were peak height and thrombin potential. Results were normalized by using the calculated mean of healthy controls and a correction for between-run variation. Outcomes were presented as relative values, with the mean of healthy controls standardized to 100 %.</p></div><div><h3>Results</h3><p>Across all platforms and reagents used, thrombin potentials and peak heights of samples with coagulation factor deficiencies were lower than those of healthy controls. Reagents designed for bleeding tendencies yielded the lowest values on all platforms (relative median peak height 19–32 %, relative median thrombin potential 19–45 %). Samples representing more severe coagulation factor deficiencies generally exhibited lower relative peak heights and thrombin potentials.</p></div><div><h3>Conclusions</h3><p>Thrombin generation assays prove effective in differentiating single coagulation factor deficient samples from healthy controls, with modest discrepancies observed between the platforms. Reagents designed for assessing bleeding tendencies, featuring the lowest tissue factor and phospholipid concentrations, emerged as the most suitable option for detecting coagulation factor deficiencies.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0049384824001774/pdfft?md5=46b630b9e983683e2db1852d6ebc5210&pid=1-s2.0-S0049384824001774-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141244292","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 : 2024-05-24DOI: 10.1016/j.thromres.2024.109042
Ghada Araji , Ahmad Mustafa , Muhammad Niazi , Chapman Wei , Rubal Sharma , Saif Abu-Baker , Georges Khattar , Suzanne El-Sayegh , Marcel Odaimi
Background
Disseminated intravascular coagulation (DIC) is a common complication of all leukemia subtypes, but it is an especially prominent feature of Acute Myeloid Leukemias (AML). DIC complicating AML can lead to a variety of complications, however, its association with acute cardiovascular complications has not been reported before.
Methods
National Inpatient Sample Database was used to procure individuals with AML, and baseline demographics and comorbidities were collected using ICD-10-DM codes. Patients were stratified into those with and without DIC. Greedy propensity matching using R was performed to match the two cohorts in 1:1 ratio on age, gender, and fifteen other baseline comorbidities. Univariate analysis pre and post-match along with binary logistic regression analysis post-match were used to analyze outcomes.
Results
Out of a total of 37,344 patients with AML, 996 had DIC. DIC patients were younger, predominantly males, and had lower prevalence of baseline cardiovascular comorbidities. DIC patients had statistically significant higher mortality (30.2 % vs 7.8 %), acute myocardial infarction (5.1 % vs 1.8 %), acute pulmonary edema (2.3 % vs 0.7 %), cardiac arrest (6.4 % vs 0.9 %), and acute DVT/PE (6.6 % vs 2.7 %). Logistic regression model after matching showed similar outcomes along with significantly higher rates of acute heart failure in DIC patients.
Conclusion
These findings highlight the importance of close cardiovascular monitoring and prompt recognition of complications in AML patients with DIC. The underlying mechanisms involve a complex interplay of procoagulant factors, cytokine release, and endothelial dysfunction. Further studies are needed to develop targeted interventions for prevention and management of these complications.
背景弥散性血管内凝血(DIC)是所有白血病亚型的常见并发症,但在急性髓性白血病(AML)中尤为突出。方法利用全国住院病人抽样数据库收集急性髓细胞白血病患者,并使用 ICD-10-DM 编码收集基线人口统计学资料和合并症。将患者分为有 DIC 和无 DIC 两类。使用 R 进行贪婪倾向匹配,以 1:1 的比例匹配年龄、性别和其他 15 项基线合并症。结果 在总共 37,344 名 AML 患者中,996 人患有 DIC。DIC患者更年轻,以男性为主,基线心血管合并症发生率较低。据统计,DIC 患者的死亡率(30.2% vs 7.8%)、急性心肌梗死(5.1% vs 1.8%)、急性肺水肿(2.3% vs 0.7%)、心脏骤停(6.4% vs 0.9%)和急性深静脉血栓/脑栓塞(6.6% vs 2.7%)均显著高于其他患者。匹配后的逻辑回归模型显示,DIC 患者的结果相似,但急性心力衰竭的发生率明显更高。其潜在机制涉及促凝血因子、细胞因子释放和内皮功能障碍的复杂相互作用。还需要进一步研究,以制定有针对性的干预措施,预防和处理这些并发症。
{"title":"Acute cardiovascular complications of disseminated intravascular coagulation in acute myeloid leukemia","authors":"Ghada Araji , Ahmad Mustafa , Muhammad Niazi , Chapman Wei , Rubal Sharma , Saif Abu-Baker , Georges Khattar , Suzanne El-Sayegh , Marcel Odaimi","doi":"10.1016/j.thromres.2024.109042","DOIUrl":"https://doi.org/10.1016/j.thromres.2024.109042","url":null,"abstract":"<div><h3>Background</h3><p>Disseminated intravascular coagulation (DIC) is a common complication of all leukemia subtypes, but it is an especially prominent feature of Acute Myeloid Leukemias (AML). DIC complicating AML can lead to a variety of complications, however, its association with acute cardiovascular complications has not been reported before.</p></div><div><h3>Methods</h3><p>National Inpatient Sample Database was used to procure individuals with AML, and baseline demographics and comorbidities were collected using ICD-10-DM codes. Patients were stratified into those with and without DIC. Greedy propensity matching using R was performed to match the two cohorts in 1:1 ratio on age, gender, and fifteen other baseline comorbidities. Univariate analysis pre and post-match along with binary logistic regression analysis post-match were used to analyze outcomes.</p></div><div><h3>Results</h3><p>Out of a total of 37,344 patients with AML, 996 had DIC. DIC patients were younger, predominantly males, and had lower prevalence of baseline cardiovascular comorbidities. DIC patients had statistically significant higher mortality (30.2 % vs 7.8 %), acute myocardial infarction (5.1 % vs 1.8 %), acute pulmonary edema (2.3 % vs 0.7 %), cardiac arrest (6.4 % vs 0.9 %), and acute DVT/PE (6.6 % vs 2.7 %). Logistic regression model after matching showed similar outcomes along with significantly higher rates of acute heart failure in DIC patients.</p></div><div><h3>Conclusion</h3><p>These findings highlight the importance of close cardiovascular monitoring and prompt recognition of complications in AML patients with DIC. The underlying mechanisms involve a complex interplay of procoagulant factors, cytokine release, and endothelial dysfunction. Further studies are needed to develop targeted interventions for prevention and management of these complications.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.thromres.2024.109041
Taocui Zhang , Lisha Lin , Lin Ren , Huifang Sun , Weili Wang , Shuang Liu , Shanni Li , Chuang Xiao , Na Gao , Jinhua Zhao
The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc3S4S-α(1,3)-L-Δ4,5GlcA-α(1,3)-{D-GalNAc4S6S-β(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-β(1,3)-}3-D-GalNAc4S6S-β(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (Cmax) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching Cmax (Tmax) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.
{"title":"Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor","authors":"Taocui Zhang , Lisha Lin , Lin Ren , Huifang Sun , Weili Wang , Shuang Liu , Shanni Li , Chuang Xiao , Na Gao , Jinhua Zhao","doi":"10.1016/j.thromres.2024.109041","DOIUrl":"10.1016/j.thromres.2024.109041","url":null,"abstract":"<div><p>The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc<sub>3S4S</sub>-α(1,3)-L-Δ<sup>4,5</sup>GlcA-α(1,3)-{D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-β(1,3)-}<sub>3</sub>-D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity <em>in vitro</em> and antithrombotic effect <em>in vivo</em> comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (<em>C</em><sub><em>max</em></sub>) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching <em>C</em><sub><em>max</em></sub> (<em>T</em><sub><em>max</em></sub>) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141130731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1016/j.thromres.2024.109038
Celestina Mazzotta , Julie R. Ingelfinger , Eric F. Grabowski
Background
Shiga toxin (Stx) can activate inflammatory signaling, leading to vascular dysfunction and promotion of a pro-thrombotic tissue microenvironment. Stx can trigger the development of the enterohemorrhagic (childhood) hemolytic uremic syndrome (eHUS), a triad of thrombocytopenia, hemolytic anemia, and acute kidney injury, often requiring dialysis. Additional features may include damage to other organs, including the gastrointestinal tract, pancreas, brain and cardiovascular system; death occurs in 2–5 %. eHUS is a thrombotic microangiopathy; thus, endothelial cell (EC) injury and platelet fibrin thrombus formation in glomerular arterioles and in the arterioles of other affected organs are likely. To elucidate mechanisms of this microangiopathy, we examined in human ECs the regulation of the platelet adhesion proteins P-selectin and von Willebrand factor (VWF), along with the downregulation of erythroblast-transformation-specific transcription factor (ERG) a key regulator of angiogenesis and megakaryocyte development.
Methods
VWF, P-selectin, and ERG levels were determined using immunofluorescence and Western blot in human umbilical endothelial cells (HUVECs). HUVECs were treated with tumor necrosis factor-alpha (TNF-α), Stx-1 or both, versus normal controls. Capillary morphogenesis on Matrigel was performed using HUVECs treated, for 22 h with TNF-α, Stx-1, or both, or treated 4 h with Stx-1 alone or in combination with TNF-α for 22 h.
Results
Stx-1 significantly reduced ERG and VWF expression on HUVECs, but upregulated P-selectin expression. ERG levels decreased with Stx-1 alone or in combination with TNF-α, in the nuclear, perinuclear and cytoplasmatic regions. Stx-1 reduced capillary morphogenesis, while Stx-1-TNF-α combined treatment reduced capillary morphogenesis still further.
Conclusions
In the presence of Stx-1 or TNF-α or both treatments, ECs were activated, expressing higher levels of P-selectin and lower levels of VWF. Our findings, further, provide evidence that Stx-1 downregulates ERG, repressing angiogenesis in vitro.
{"title":"Shiga toxin down-regulates ERG protein in endothelial cells and impairs angiogenesis","authors":"Celestina Mazzotta , Julie R. Ingelfinger , Eric F. Grabowski","doi":"10.1016/j.thromres.2024.109038","DOIUrl":"10.1016/j.thromres.2024.109038","url":null,"abstract":"<div><h3>Background</h3><p>Shiga toxin (Stx) can activate inflammatory signaling, leading to vascular dysfunction and promotion of a pro-thrombotic tissue microenvironment. Stx can trigger the development of the enterohemorrhagic (childhood) hemolytic uremic syndrome (eHUS), a triad of thrombocytopenia, hemolytic anemia, and acute kidney injury, often requiring dialysis. Additional features may include damage to other organs, including the gastrointestinal tract, pancreas, brain and cardiovascular system; death occurs in 2–5 %. eHUS is a thrombotic microangiopathy; thus, endothelial cell (EC) injury and platelet fibrin thrombus formation in glomerular arterioles and in the arterioles of other affected organs are likely. To elucidate mechanisms of this microangiopathy, we examined in human ECs the regulation of the platelet adhesion proteins P-selectin and von Willebrand factor (VWF), along with the downregulation of erythroblast-transformation-specific transcription factor (ERG) a key regulator of angiogenesis and megakaryocyte development.</p></div><div><h3>Methods</h3><p>VWF, P-selectin, and ERG levels were determined using immunofluorescence and Western blot in human umbilical endothelial cells (HUVECs). HUVECs were treated with tumor necrosis factor-alpha (TNF-α), Stx-1 or both, <em>versus</em> normal controls. Capillary morphogenesis on Matrigel was performed using HUVECs treated, for 22 h with TNF-α, Stx-1, or both, or treated 4 h with Stx-1 alone or in combination with TNF-α for 22 h.</p></div><div><h3>Results</h3><p>Stx-1 significantly reduced ERG and VWF expression on HUVECs, but upregulated P-selectin expression. ERG levels decreased with Stx-1 alone or in combination with TNF-α, in the nuclear, perinuclear and cytoplasmatic regions. Stx-1 reduced capillary morphogenesis, while Stx-1-TNF-α combined treatment reduced capillary morphogenesis still further.</p></div><div><h3>Conclusions</h3><p>In the presence of Stx-1 or TNF-α or both treatments, ECs were activated, expressing higher levels of P-selectin and lower levels of VWF. Our findings, further, provide evidence that Stx-1 downregulates ERG, repressing angiogenesis <em>in vitro</em>.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141144404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1016/j.thromres.2024.109040
Yasser Emad , Yasser Ragab , Harrison W. Farber , Doruk Erkan , Ossama Ibrahim , Michael Kindermann , Jasna Tekavec-Trkanjec , Balakrishnan Jayakrishnan , Nashwa El-Shaarawy , Melek Kechida , Pablo Young , Sonia Pankl , Marianna Fabi , Parag Bawaskar , Issam Kably , Sergio Ghirardo , Faten Frikha , Alaa Abou-Zeid , Maged Hassan , Cal Robinson , Johannes J. Rasker
Background and aim
Hughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS.
Methods
This retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified.
Results
The mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (p < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Parenchymal hemorrhage was also more frequent in HSS compared to PE (P < 0.001).
Conclusion
Major vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas “in-situ thrombosis” seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications.
背景和目的Hughes-Stovin 综合征(HSS)是一种罕见的全身性血管炎,伴有广泛的静脉/动脉血栓形成和肺血管炎。在 HSS 早期阶段区分肺栓塞(PE)和原位血栓是一项挑战。本研究旨在比较确诊为 PE 和 HSS 患者的临床、实验室和计算机断层扫描肺血管造影(CTPA)特征。比较了两组患者的人口统计学特征、临床和实验室检查结果以及血管血栓事件。对 CTPA 结果进行了回顾,重点关注其分布、与壁间的粘连、肺梗塞、磨玻璃不透明和肺泡内出血。结果HSS患者的平均年龄为(35 ± 12.3)岁,PE患者的平均年龄为(58.4 ± 17)岁(P < 0.0001)。在 PE 患者中,有 39 人(78%)患有并发症,而在 HSS 患者中,没有人患有并发症。与 PE 不同的是,在 HSS 中,主要的静脉和动脉血栓形成事件均有发生。在 HSS 组中观察到各种 PAA,而在 PE 中则完全没有。结论大血管血栓形成和动脉瘤形成是 HSS 的特征。PE通常表现为松散粘连和移动,而HSS中的 "原位血栓 "则与壁层紧密粘连。壁层增强和 PAA 是 HSS 的独特肺部发现。后者具有重要的治疗意义。
{"title":"Pulmonary embolism versus pulmonary vasculitis in Hughes-Stovin syndrome: Characteristic computed tomography pulmonary angiographic findings and diagnostic and therapeutic implications. HSS International Study Group","authors":"Yasser Emad , Yasser Ragab , Harrison W. Farber , Doruk Erkan , Ossama Ibrahim , Michael Kindermann , Jasna Tekavec-Trkanjec , Balakrishnan Jayakrishnan , Nashwa El-Shaarawy , Melek Kechida , Pablo Young , Sonia Pankl , Marianna Fabi , Parag Bawaskar , Issam Kably , Sergio Ghirardo , Faten Frikha , Alaa Abou-Zeid , Maged Hassan , Cal Robinson , Johannes J. Rasker","doi":"10.1016/j.thromres.2024.109040","DOIUrl":"https://doi.org/10.1016/j.thromres.2024.109040","url":null,"abstract":"<div><h3>Background and aim</h3><p>Hughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS.</p></div><div><h3>Methods</h3><p>This retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified.</p></div><div><h3>Results</h3><p>The mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (<em>p</em> < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Parenchymal hemorrhage was also more frequent in HSS compared to PE (<em>P</em> < 0.001).</p></div><div><h3>Conclusion</h3><p>Major vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas “in-situ thrombosis” seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0049384824001725/pdfft?md5=e2415bb62c1dde36da256fb5b4ea5196&pid=1-s2.0-S0049384824001725-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141089900","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}