Pub Date : 2024-11-15DOI: 10.1016/j.jtha.2024.10.035
Theodore E Warkentin, William Geerts, Jo-Ann I Sheppard, Cameron B Guest, Gideon Cohen, Pablo Perez d'Empaire, Ishac Nazy, Donald M Arnold
A 56-year-old woman required urgent cardiac surgery for Streptococcus mitis mitral valve infective endocarditis complicated by severe autoimmune HIT (aHIT). We reasoned that the combination of high-dose IVIG (to mitigate aHIT antibody-mediated platelet activation in the presence of heparin) together with the high concentrations of heparin attained during cardiac surgery (which typically produce less platelet activation in-vitro versus usual therapeutic heparin concentrations) might prove effective. Accordingly, our patient underwent cardiac surgery with heparin following high-dose IVIG (1g/kg×2), without intra- or postoperative thrombosis. Serial serotonin-release assays, using blood obtained pre-/post-IVIG, showed minimal platelet activation (∼30% serotonin-release) post-IVIG at heparin concentrations typically obtained during cardiac surgery (2-5 U/mL), and significantly less than pre-IVIG serum in heparin's absence (∼85% serotonin-release). In the setting of urgent cardiac surgery, preoperative high-dose IVIG appears to be a reasonable strategy to reduce platelet-activating effects of HIT (including aHIT) antibodies, permitting safe use of standard intraoperative heparin dosing.
{"title":"High-dose IVIG and usual heparin anticoagulation for urgent cardiac surgery in a patient with severe autoimmune HIT.","authors":"Theodore E Warkentin, William Geerts, Jo-Ann I Sheppard, Cameron B Guest, Gideon Cohen, Pablo Perez d'Empaire, Ishac Nazy, Donald M Arnold","doi":"10.1016/j.jtha.2024.10.035","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.035","url":null,"abstract":"<p><p>A 56-year-old woman required urgent cardiac surgery for Streptococcus mitis mitral valve infective endocarditis complicated by severe autoimmune HIT (aHIT). We reasoned that the combination of high-dose IVIG (to mitigate aHIT antibody-mediated platelet activation in the presence of heparin) together with the high concentrations of heparin attained during cardiac surgery (which typically produce less platelet activation in-vitro versus usual therapeutic heparin concentrations) might prove effective. Accordingly, our patient underwent cardiac surgery with heparin following high-dose IVIG (1g/kg×2), without intra- or postoperative thrombosis. Serial serotonin-release assays, using blood obtained pre-/post-IVIG, showed minimal platelet activation (∼30% serotonin-release) post-IVIG at heparin concentrations typically obtained during cardiac surgery (2-5 U/mL), and significantly less than pre-IVIG serum in heparin's absence (∼85% serotonin-release). In the setting of urgent cardiac surgery, preoperative high-dose IVIG appears to be a reasonable strategy to reduce platelet-activating effects of HIT (including aHIT) antibodies, permitting safe use of standard intraoperative heparin dosing.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.jtha.2024.10.025
Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold
Background and aims: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.
Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients.
Results: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.
Conclusions: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.
{"title":"Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.","authors":"Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold","doi":"10.1016/j.jtha.2024.10.025","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.025","url":null,"abstract":"<p><strong>Background and aims: </strong>Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.</p><p><strong>Methods: </strong>We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients.</p><p><strong>Results: </strong>Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.</p><p><strong>Conclusions: </strong>Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.jtha.2024.10.034
Juri Alessandro Giannotta, Andrea Artoni, Ilaria Mancini, Pasquale Agosti, Monica Carpenedo, Addolorata Truma, Syna Miri, Barbara Ferrari, Pasqualina De Leo, Prassede Salutari, Giorgia Mancini, Alfredo Molteni, Ermina Rinaldi, Monica Bocchia, Mariasanta Napolitano, Lucia Prezioso, Annarosa Cuccaro, Elisabetta Scarpa, Annalisa Condorelli, Daniele Grimaldi, Massimo Massaia, Flora Peyvandi
Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10-15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but available evidence is scarce and stems only from isolated reports in the pre-caplacizumab era.
Objectives: To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients.
Methods: We conducted a retrospective observational multicenter study among 13 Italian iTTP-treating centers, collecting data from May 2017 to May 2023 (caplacizumab licensed in Italy in January 2020).
Results: Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR 10-38), still ongoing in 6 patients at the time of data cut-off. Responders had fewer previous acute iTTP episodes than non-responders [median (IQR) 1 (1-2) vs 5.5 (2-7), p=0.03]. Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles.
Conclusion: Durable responses to bortezomib were registered in about 60% of multi-refractory iTTP patients, with mild-to-moderate toxicities. The occurrence of late responses (i.e., after 30 days) suggests a "watchful waiting" approach after bortezomib treatment.
{"title":"Bortezomib for rituximab-refractory immune-mediated thrombotic thrombocytopenic purpura in the caplacizumab era: an Italian multicenter study.","authors":"Juri Alessandro Giannotta, Andrea Artoni, Ilaria Mancini, Pasquale Agosti, Monica Carpenedo, Addolorata Truma, Syna Miri, Barbara Ferrari, Pasqualina De Leo, Prassede Salutari, Giorgia Mancini, Alfredo Molteni, Ermina Rinaldi, Monica Bocchia, Mariasanta Napolitano, Lucia Prezioso, Annarosa Cuccaro, Elisabetta Scarpa, Annalisa Condorelli, Daniele Grimaldi, Massimo Massaia, Flora Peyvandi","doi":"10.1016/j.jtha.2024.10.034","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.034","url":null,"abstract":"<p><strong>Background: </strong>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10-15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but available evidence is scarce and stems only from isolated reports in the pre-caplacizumab era.</p><p><strong>Objectives: </strong>To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients.</p><p><strong>Methods: </strong>We conducted a retrospective observational multicenter study among 13 Italian iTTP-treating centers, collecting data from May 2017 to May 2023 (caplacizumab licensed in Italy in January 2020).</p><p><strong>Results: </strong>Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR 10-38), still ongoing in 6 patients at the time of data cut-off. Responders had fewer previous acute iTTP episodes than non-responders [median (IQR) 1 (1-2) vs 5.5 (2-7), p=0.03]. Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles.</p><p><strong>Conclusion: </strong>Durable responses to bortezomib were registered in about 60% of multi-refractory iTTP patients, with mild-to-moderate toxicities. The occurrence of late responses (i.e., after 30 days) suggests a \"watchful waiting\" approach after bortezomib treatment.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.jtha.2024.11.003
Nathan G Avery, Isabelle R Young, Selena Lu, Jordan D Vaughan, Patrick S Korus, Tera N Richardson, Kenneth C Childers, Serge L Smirnov, P Clint Spiegel
Background: Following proteolytic activation, activated blood coagulation factor VIII (FVIIIa) binds to activated platelet membranes, forming the intrinsic tenase complex with activated factor IX (FIXa). Previous studies have identified the C1 and C2 domains as the membrane binding domains of FVIII through conserved arginine residues. A membrane binding model for the FVIII C domains proposes that surface exposed hydrophobic and positively charged residues at each C domain interact with the membrane, yet a comprehensive thermodynamic and structural description of this interaction is lacking.
Objective: To determine residues of interaction, thermodynamics, and membrane binding preference for FVIII membrane association.
Methods: Binding of FVIII constructs to lipid nanodiscs were characterized with nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), bio-layer interferometry (BLI), and X-ray crystallography.
Results: The thermodynamics of FVIII membrane binding indicate that the C1 domain associates through an enthalpically driven process while the C2 domain is entropically driven. Alanine mutations to surface-exposed hydrophobic residues in the C2 domain reveal differential effects on membrane binding, highlighting important determinants at the residue-level. The structure of a C2 double mutant, L2251A/L2252A, demonstrates that its decreased affinity is likely due to decreasing the surface area hydrophobicity. NMR studies with the C2 domain identified residues of interaction with soluble O-phospho-L-serine (OPLS) as well as lipid nanodiscs. Lastly, increasing phosphatidylethanolamine (PE) and decreasing PS content decreases overall FVIII affinity for membrane surfaces.
Conclusion: This study provides further insight into the molecular basis for how FVIII interacts with platelets to form the intrinsic tenase complex.
{"title":"Biophysical characterization of blood coagulation factor VIII binding to lipid nanodiscs that mimic activated platelet surfaces.","authors":"Nathan G Avery, Isabelle R Young, Selena Lu, Jordan D Vaughan, Patrick S Korus, Tera N Richardson, Kenneth C Childers, Serge L Smirnov, P Clint Spiegel","doi":"10.1016/j.jtha.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.003","url":null,"abstract":"<p><strong>Background: </strong>Following proteolytic activation, activated blood coagulation factor VIII (FVIIIa) binds to activated platelet membranes, forming the intrinsic tenase complex with activated factor IX (FIXa). Previous studies have identified the C1 and C2 domains as the membrane binding domains of FVIII through conserved arginine residues. A membrane binding model for the FVIII C domains proposes that surface exposed hydrophobic and positively charged residues at each C domain interact with the membrane, yet a comprehensive thermodynamic and structural description of this interaction is lacking.</p><p><strong>Objective: </strong>To determine residues of interaction, thermodynamics, and membrane binding preference for FVIII membrane association.</p><p><strong>Methods: </strong>Binding of FVIII constructs to lipid nanodiscs were characterized with nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), bio-layer interferometry (BLI), and X-ray crystallography.</p><p><strong>Results: </strong>The thermodynamics of FVIII membrane binding indicate that the C1 domain associates through an enthalpically driven process while the C2 domain is entropically driven. Alanine mutations to surface-exposed hydrophobic residues in the C2 domain reveal differential effects on membrane binding, highlighting important determinants at the residue-level. The structure of a C2 double mutant, L2251A/L2252A, demonstrates that its decreased affinity is likely due to decreasing the surface area hydrophobicity. NMR studies with the C2 domain identified residues of interaction with soluble O-phospho-L-serine (OPLS) as well as lipid nanodiscs. Lastly, increasing phosphatidylethanolamine (PE) and decreasing PS content decreases overall FVIII affinity for membrane surfaces.</p><p><strong>Conclusion: </strong>This study provides further insight into the molecular basis for how FVIII interacts with platelets to form the intrinsic tenase complex.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.jtha.2024.11.002
Greg Hapgood, Kate Hill, Satomi Okano, Emad Abro, David Looke, Glen Kennedy, Gilbert Pavilion, Rosita Van Kuilenburg, Alanna Geary, Warren Joubert, Melissa Eastgate, Mark Jones, Peter Mollee
Background: Catheter-related thrombosis (CRT) is a complication of central venous access devices (CVADs). Evidence is variable regarding the significance of the side of catheter insertion. The role of the patient's hand dominance in predisposition to CRT remains uncertain.
Objectives: In a prospective randomised controlled trial, adult cancer patients were randomly allocated to either dominant or non-dominant side CVAD insertion. The primary endpoint of this trial examined the incidence of catheter-associated blood stream infection. Here, we report the secondary endpoint of the incidence of CRT.
Methods: 640 CVADs were randomised to the dominant (n=322) or non-dominant (n=318) side of insertion. Only symptomatic patients underwent ultrasound imaging to evaluate for CRT.
Results: The median patient age was 58, 60% of patients had haematological malignancies and 40% had solid tumours. CVADs used were peripherally-inserted central catheter line (PICC)(67%), tunnelled CVAD (23%) or non-tunnelled CVAD (10%). The CRT incidence rate was 0.65 vs 0.82 per 1000 line days in the dominant vs non-dominant group (HR 1.2; 95% CI 0.58-2.48, P=0.63). There was no significant difference in CRT incidence rate between left and right sided insertions (HR 0.63; 95% CI 0.30-1.32, P=0.22). The CRT incidence rate was lower in right-handed versus left-handed line inserters (HR 0.29; 95% CI 0.12-0.71, P=0.007).
Conclusions: The rate of CRT was not associated with whether CVAD insertion was on the patient's dominant or non-dominant side or the side of insertion. The role of inserter hand dominance requires further investigation.
背景:导管相关血栓(CRT)是中心静脉通路装置(CVAD)的一种并发症。关于导管插入侧的重要性证据不一。患者的手部优势对 CRT 易感性的作用仍不确定:在一项前瞻性随机对照试验中,成年癌症患者被随机分配到优势侧或非优势侧插入 CVAD。该试验的主要终点是检查导管相关血流感染的发生率。方法:640 例 CVAD 被随机分配到优势侧(322 例)或非优势侧(318 例)插入。只有无症状患者接受了超声成像以评估CRT:患者年龄中位数为58岁,60%的患者患有血液恶性肿瘤,40%的患者患有实体瘤。使用的CVAD包括外周置入中心导管线(PICC)(67%)、隧道式CVAD(23%)或非隧道式CVAD(10%)。显性组与非显性组的 CRT 发生率分别为每 1000 管路日 0.65 例与 0.82 例(HR 1.2;95% CI 0.58-2.48,P=0.63)。左侧插入与右侧插入的 CRT 发生率无明显差异(HR 0.63;95% CI 0.30-1.32,P=0.22)。右侧插管者的 CRT 发生率低于左侧插管者(HR 0.29;95% CI 0.12-0.71,P=0.007):结论:CRT发生率与CVAD插入时患者的惯用侧、非惯用侧或插入侧无关。插入者手部优势的作用需要进一步研究。
{"title":"Catheter-Related Thrombosis in Adults with Cancer: A Secondary Analysis of a Prospective Randomised Controlled Trial.","authors":"Greg Hapgood, Kate Hill, Satomi Okano, Emad Abro, David Looke, Glen Kennedy, Gilbert Pavilion, Rosita Van Kuilenburg, Alanna Geary, Warren Joubert, Melissa Eastgate, Mark Jones, Peter Mollee","doi":"10.1016/j.jtha.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.002","url":null,"abstract":"<p><strong>Background: </strong>Catheter-related thrombosis (CRT) is a complication of central venous access devices (CVADs). Evidence is variable regarding the significance of the side of catheter insertion. The role of the patient's hand dominance in predisposition to CRT remains uncertain.</p><p><strong>Objectives: </strong>In a prospective randomised controlled trial, adult cancer patients were randomly allocated to either dominant or non-dominant side CVAD insertion. The primary endpoint of this trial examined the incidence of catheter-associated blood stream infection. Here, we report the secondary endpoint of the incidence of CRT.</p><p><strong>Methods: </strong>640 CVADs were randomised to the dominant (n=322) or non-dominant (n=318) side of insertion. Only symptomatic patients underwent ultrasound imaging to evaluate for CRT.</p><p><strong>Results: </strong>The median patient age was 58, 60% of patients had haematological malignancies and 40% had solid tumours. CVADs used were peripherally-inserted central catheter line (PICC)(67%), tunnelled CVAD (23%) or non-tunnelled CVAD (10%). The CRT incidence rate was 0.65 vs 0.82 per 1000 line days in the dominant vs non-dominant group (HR 1.2; 95% CI 0.58-2.48, P=0.63). There was no significant difference in CRT incidence rate between left and right sided insertions (HR 0.63; 95% CI 0.30-1.32, P=0.22). The CRT incidence rate was lower in right-handed versus left-handed line inserters (HR 0.29; 95% CI 0.12-0.71, P=0.007).</p><p><strong>Conclusions: </strong>The rate of CRT was not associated with whether CVAD insertion was on the patient's dominant or non-dominant side or the side of insertion. The role of inserter hand dominance requires further investigation.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: While the number of models for predicting the risk of cancer-associated thrombosis has been rising, there is still a lack of comprehensive assessment for machine learning prediction models.
Objective: To critically appraise and quantify the performance studies using machine learning to predict cancer-associated thrombosis.
Methods: We conducted searches on PubMed, Embase, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and other related databases for the related publications (from inception to December 1, 2023). The Prediction Model Risk of Bias Assessment Tool checklist was employed to evaluate the risk of bias and applicability. The Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of evidence in systematic reviews. Meta-analyses were conducted using R (version 4.3.2).
Results: A total of thirty-two studies were included. Mostly included literature exhibits a high risk of bias, and the applicability of the prediction models is deemed acceptable. The twenty-one included studies in the meta-analysis demonstrated the high predictive capacity of the machine learning models for cancer-associated thrombosis.
Conclusion: Most of the prediction models included in the study showed good applicability and excellent prediction performance, but there was a high risk of bias.
背景:虽然预测癌症相关性血栓风险的模型数量不断增加,但目前仍缺乏对机器学习预测模型的全面评估:目的:对使用机器学习预测癌症相关血栓形成的研究进行严格评估和量化:我们在 PubMed、Embase、The Cochrane Library、Cumulative Index to Nursing and Allied Health Literature 等相关数据库中检索了相关出版物(从开始到 2023 年 12 月 1 日)。采用预测模型偏倚风险评估工具核对表来评估偏倚风险和适用性。建议分级评估、发展和评价系统用于评价系统综述的证据质量。使用 R(4.3.2 版)进行元分析:结果:共纳入 32 项研究。大部分纳入文献的偏倚风险较高,预测模型的适用性被认为是可以接受的。荟萃分析中纳入的 21 项研究表明,机器学习模型对癌症相关血栓的预测能力很强:结论:本研究纳入的大多数预测模型显示出良好的适用性和出色的预测性能,但存在较高的偏倚风险。
{"title":"Machine Learning Models for Risk Prediction of Cancer Associated Thrombosis: A Systematic Review and Meta-Analysis.","authors":"Keya Chen, Ying Zhang, Lufang Zhang, Wei Zhang, Yu Chen","doi":"10.1016/j.jtha.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.001","url":null,"abstract":"<p><strong>Background: </strong>While the number of models for predicting the risk of cancer-associated thrombosis has been rising, there is still a lack of comprehensive assessment for machine learning prediction models.</p><p><strong>Objective: </strong>To critically appraise and quantify the performance studies using machine learning to predict cancer-associated thrombosis.</p><p><strong>Methods: </strong>We conducted searches on PubMed, Embase, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and other related databases for the related publications (from inception to December 1, 2023). The Prediction Model Risk of Bias Assessment Tool checklist was employed to evaluate the risk of bias and applicability. The Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of evidence in systematic reviews. Meta-analyses were conducted using R (version 4.3.2).</p><p><strong>Results: </strong>A total of thirty-two studies were included. Mostly included literature exhibits a high risk of bias, and the applicability of the prediction models is deemed acceptable. The twenty-one included studies in the meta-analysis demonstrated the high predictive capacity of the machine learning models for cancer-associated thrombosis.</p><p><strong>Conclusion: </strong>Most of the prediction models included in the study showed good applicability and excellent prediction performance, but there was a high risk of bias.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.jtha.2024.10.032
Jin Mao, Jingyu Zhao, Hong Pan, Zhen Gao, Lele Zhang, Weiwang Li, Liwei Fang, Cuicui Liu, Pei Su, Hongtao Wang, Jiaxi Zhou, Jun Shi
Background: Aplastic anemia (AA) is a bone marrow failure disease for which the means of assessing and predicting the therapeutic effectiveness are still relatively limited. Thrombocytopenia is often the earliest and most severe symptom in patients newly diagnosed with AA (Dx-AA). While clinical consideration is usually given to the quantitative changes in platelets during treatment, there is little focus on the resolution of the molecular characteristics of platelets in AA.
Objectives: To investigate the changes in platelet molecular characteristics throughout the treatment process of AA, and to explore the use of transcriptomics for monitoring and predicting treatment outcomes.
Methods: We comprehensively analyzed platelet transcriptomic changes in AA patients at initial diagnosis and different stages of treatment effectiveness using bulk transcriptome sequencing.
Results: Genes associated with cell proliferation, erythroid function, and amino acid transport were elevated in Dx-AA. Conversely, genes linked to histones, thrombosis, mitochondrial energy metabolism, and signaling pathways were significantly downregulated. 60.6% of the differentially expressed genes were substantially restored following complete remission. Furthermore, through the examination of longitudinal samples, we identified recovery ascending genes (RAG) that could serve as viable biomarkers for assessing treatment effectiveness in AA. Besides, we observed that higher expression levels of RAG may predict superior long-term platelet counts recovery six months in advance in patients with partial response.
Conclusions: The platelet transcriptome undergoes profound changes and can serve as a potential indicator for assessing treatment effectiveness and predicting long-term platelet counts recovery in AA.
背景:再生障碍性贫血(AA)是一种骨髓衰竭疾病:再生障碍性贫血(AA)是一种骨髓衰竭疾病,其治疗效果的评估和预测手段仍然相对有限。血小板减少通常是新诊断为再生障碍性贫血(Dx-AA)的患者最早出现且最严重的症状。临床上通常考虑治疗过程中血小板的数量变化,但很少关注 AA 患者血小板分子特征的变化:研究AA治疗过程中血小板分子特征的变化,并探索利用转录组学监测和预测治疗结果:方法:我们利用批量转录组测序技术全面分析了AA患者在最初诊断和不同治疗效果阶段的血小板转录组变化:结果:与细胞增殖、红细胞功能和氨基酸转运相关的基因在Dx-AA中升高。相反,与组蛋白、血栓形成、线粒体能量代谢和信号通路相关的基因则明显下调。完全缓解后,60.6%的差异表达基因得到了大幅恢复。此外,通过对纵向样本的研究,我们发现了可作为评估 AA 治疗效果的生物标志物的恢复上升基因(RAG)。此外,我们还观察到,较高的 RAG 表达水平可提前 6 个月预示部分反应患者的血小板计数会有较好的长期恢复:血小板转录组发生了深刻变化,可作为评估治疗效果和预测 AA 患者血小板计数长期恢复的潜在指标。
{"title":"Application of platelet transcriptomics for assessing treatment effectiveness and predicting long-term platelet counts recovery in aplastic anemia.","authors":"Jin Mao, Jingyu Zhao, Hong Pan, Zhen Gao, Lele Zhang, Weiwang Li, Liwei Fang, Cuicui Liu, Pei Su, Hongtao Wang, Jiaxi Zhou, Jun Shi","doi":"10.1016/j.jtha.2024.10.032","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.032","url":null,"abstract":"<p><strong>Background: </strong>Aplastic anemia (AA) is a bone marrow failure disease for which the means of assessing and predicting the therapeutic effectiveness are still relatively limited. Thrombocytopenia is often the earliest and most severe symptom in patients newly diagnosed with AA (Dx-AA). While clinical consideration is usually given to the quantitative changes in platelets during treatment, there is little focus on the resolution of the molecular characteristics of platelets in AA.</p><p><strong>Objectives: </strong>To investigate the changes in platelet molecular characteristics throughout the treatment process of AA, and to explore the use of transcriptomics for monitoring and predicting treatment outcomes.</p><p><strong>Methods: </strong>We comprehensively analyzed platelet transcriptomic changes in AA patients at initial diagnosis and different stages of treatment effectiveness using bulk transcriptome sequencing.</p><p><strong>Results: </strong>Genes associated with cell proliferation, erythroid function, and amino acid transport were elevated in Dx-AA. Conversely, genes linked to histones, thrombosis, mitochondrial energy metabolism, and signaling pathways were significantly downregulated. 60.6% of the differentially expressed genes were substantially restored following complete remission. Furthermore, through the examination of longitudinal samples, we identified recovery ascending genes (RAG) that could serve as viable biomarkers for assessing treatment effectiveness in AA. Besides, we observed that higher expression levels of RAG may predict superior long-term platelet counts recovery six months in advance in patients with partial response.</p><p><strong>Conclusions: </strong>The platelet transcriptome undergoes profound changes and can serve as a potential indicator for assessing treatment effectiveness and predicting long-term platelet counts recovery in AA.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.jtha.2024.10.028
Kenji Miyazawa, Alan E Mast, Adam R Wufsus, Michael Dockal, Marianne Kjalke, Karin Leiderman
Background: Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits FXa, the TF-FVIIa-FXa complex, and early forms of the prothrombinase complex. Concizumab is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia.
Objectives: To examine how concizumab impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models.
Methods: A compartment model was used to estimate plasma concentrations of free concizumab and its complexes with TFPIα and TFPIβ. Concizumab was integrated into a flow-mediated mathematical model of coagulation and a small injury was simulated under hemophilia A conditions. Simulations were then analyzed to determine how concizumab's blockade of TFPI anticoagulant activities, specifically the inhibition of FXa in plasma and on platelets, inhibition of TF:VIIa at the subendothelium, and prior sequestration of plasma TFPIα to the endothelium via TFPIβ, altered thrombin generation.
Results: Concizumab improved simulated thrombin generation in hemophilia A by simultaneously altering all three mechanisms of TFPI anticoagulant blockade examined. Concizumab sequesters ∼75% of plasma TFPIα through formation of ternary TFPIα-concizumab-TFPIβ-complexes. For all TF levels, reducing the TFPIα plasma concentration had the largest impact on the lag time followed by blocking TFPIα inhibition of TF:VIIa:FXa and subsequently followed by blocking TFPIα inhibition of FXa in plasma and on the platelet surface.
Conclusions: The effectiveness of concizumab is mediated through blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of concizumab was sequestration of plasma TFPIα to the endothelium.
{"title":"Examining Downstream Effects of Concizumab in Hemophilia A with a Mathematical Modeling Approach.","authors":"Kenji Miyazawa, Alan E Mast, Adam R Wufsus, Michael Dockal, Marianne Kjalke, Karin Leiderman","doi":"10.1016/j.jtha.2024.10.028","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.028","url":null,"abstract":"<p><strong>Background: </strong>Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits FXa, the TF-FVIIa-FXa complex, and early forms of the prothrombinase complex. Concizumab is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia.</p><p><strong>Objectives: </strong>To examine how concizumab impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models.</p><p><strong>Methods: </strong>A compartment model was used to estimate plasma concentrations of free concizumab and its complexes with TFPIα and TFPIβ. Concizumab was integrated into a flow-mediated mathematical model of coagulation and a small injury was simulated under hemophilia A conditions. Simulations were then analyzed to determine how concizumab's blockade of TFPI anticoagulant activities, specifically the inhibition of FXa in plasma and on platelets, inhibition of TF:VIIa at the subendothelium, and prior sequestration of plasma TFPIα to the endothelium via TFPIβ, altered thrombin generation.</p><p><strong>Results: </strong>Concizumab improved simulated thrombin generation in hemophilia A by simultaneously altering all three mechanisms of TFPI anticoagulant blockade examined. Concizumab sequesters ∼75% of plasma TFPIα through formation of ternary TFPIα-concizumab-TFPIβ-complexes. For all TF levels, reducing the TFPIα plasma concentration had the largest impact on the lag time followed by blocking TFPIα inhibition of TF:VIIa:FXa and subsequently followed by blocking TFPIα inhibition of FXa in plasma and on the platelet surface.</p><p><strong>Conclusions: </strong>The effectiveness of concizumab is mediated through blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of concizumab was sequestration of plasma TFPIα to the endothelium.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.jtha.2024.10.029
Kevin Todd, Spencer J Hogue, James S Tweddell, James A Reagor, Eric Mullins, Mary G Block, Leah Rosenfeldt, Brenton Francisco, Sonata Jodele, Bal Krishan Sharma, Adam Lane, Craig Slusher, Mousa Kharnaf, David L S Morales, Joseph S Palumbo
Background: Understanding of the hemostatic and complement alterations associated with cardiopulmonary bypass (CPB) in pediatric patients and the impact of these alterations on outcome is limited.
Objectives: The present study prospectively characterized these alterations and their association with postoperative outcomes in pediatric CPB.
Patients/methods: All patients <21 years undergoing CPB at the authors' institution between 2020 and 2021 that weighed >3 kg, were >36 weeks gestational age, and had no known prothrombotic or hemorrhagic disorders were eligible. Blood samples were analyzed for multiple hemostatic and complement biomarkers pre-, intra-, and 24 hours post-CPB. Biomarker levels were compared to clinical outcomes, including chest tube output (CTO).
Results: Fifty consecutive patients were enrolled. CPB resulted in multiple significant alterations in hemostatic and complement components. Lower platelet counts (<80 x 109 platelets/L) at CPB termination were associated with increased postoperative CTO (p=0.003). Lower factor VIII levels (<60 IU/dl) at the end of CPB were associated with a longer hospital stay (p<0.001) and increased postoperative CTO (p<0.001). Patients undergoing staged single ventricle reconstruction were more likely to have lower platelet counts at CPB termination (p=0.009) and higher CTO postoperatively (p=0.001) than patients undergoing other types of surgical repair. These differences were not due to different preoperative platelet counts, increased incidences of circulatory arrest, or longer CPB times.
Conclusions: These data suggest that intraoperative alterations in hemostatic system components may predict postoperative outcomes in pediatric CPB. Further study is needed to determine if interventions targeting platelets or factor VIII could improve outcomes in pediatric CPB.
{"title":"Hemostatic derangements associated with cardiopulmonary bypass predict outcomes in pediatric patients undergoing corrective heart surgery.","authors":"Kevin Todd, Spencer J Hogue, James S Tweddell, James A Reagor, Eric Mullins, Mary G Block, Leah Rosenfeldt, Brenton Francisco, Sonata Jodele, Bal Krishan Sharma, Adam Lane, Craig Slusher, Mousa Kharnaf, David L S Morales, Joseph S Palumbo","doi":"10.1016/j.jtha.2024.10.029","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.029","url":null,"abstract":"<p><strong>Background: </strong>Understanding of the hemostatic and complement alterations associated with cardiopulmonary bypass (CPB) in pediatric patients and the impact of these alterations on outcome is limited.</p><p><strong>Objectives: </strong>The present study prospectively characterized these alterations and their association with postoperative outcomes in pediatric CPB.</p><p><strong>Patients/methods: </strong>All patients <21 years undergoing CPB at the authors' institution between 2020 and 2021 that weighed >3 kg, were >36 weeks gestational age, and had no known prothrombotic or hemorrhagic disorders were eligible. Blood samples were analyzed for multiple hemostatic and complement biomarkers pre-, intra-, and 24 hours post-CPB. Biomarker levels were compared to clinical outcomes, including chest tube output (CTO).</p><p><strong>Results: </strong>Fifty consecutive patients were enrolled. CPB resulted in multiple significant alterations in hemostatic and complement components. Lower platelet counts (<80 x 10<sup>9</sup> platelets/L) at CPB termination were associated with increased postoperative CTO (p=0.003). Lower factor VIII levels (<60 IU/dl) at the end of CPB were associated with a longer hospital stay (p<0.001) and increased postoperative CTO (p<0.001). Patients undergoing staged single ventricle reconstruction were more likely to have lower platelet counts at CPB termination (p=0.009) and higher CTO postoperatively (p=0.001) than patients undergoing other types of surgical repair. These differences were not due to different preoperative platelet counts, increased incidences of circulatory arrest, or longer CPB times.</p><p><strong>Conclusions: </strong>These data suggest that intraoperative alterations in hemostatic system components may predict postoperative outcomes in pediatric CPB. Further study is needed to determine if interventions targeting platelets or factor VIII could improve outcomes in pediatric CPB.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.jtha.2024.09.040
Patrick Ellsworth, Sheh-Li Chen, Lee Ann Jones, Alice Ma, Nigel Key
Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies to factor VIII (FVIII). The goals of treatment are two-fold, namely immunosuppressive therapy (IST) to eradicate the inhibitor and hemostatic management to control bleeding. Emicizumab, a bispecific antibody that acts as a factor VIIIa (FVIIIa) mimetic, has seen growing use in AHA following its approval for congenital hemophilia A (cHA). This review provides an overview of the epidemiology, pathophysiology, diagnosis, and treatment of AHA. Registry, trial, and case series data are assimilated and summarized with an emphasis on a standardized approach that integrates the use of emicizumab. With recent registry data suggesting the need to focus on immunosuppression-related mortality in AHA, we provide treatment recommendations in an algorithmic format that have become the standard of care at our institution. These recommendations are intended to minimize hemostatic product usage and potential toxicity related to IST, while reducing morbidity and re-hospitalization rates for bleeding. The proposed treatment algorithm, which includes key interventions by phase of therapy, can be readily implemented at centers that have rapid access to plasma FVIII activity using a one-stage assay. A case is presented to illustrate the proposed diagnostic and management considerations.
获得性血友病 A(AHA)是一种罕见的出血性疾病,由因子 VIII(FVIII)抑制性自身抗体引起。治疗的目标有两个方面,一是通过免疫抑制疗法(IST)消除抑制因子,二是通过止血治疗控制出血。Emicizumab是一种双特异性抗体,可作为因子VIIIa(FVIIIa)的模拟物,在被批准用于先天性A型血友病(cHA)治疗后,在AHA中的应用日益广泛。本综述概述了 AHA 的流行病学、病理生理学、诊断和治疗。对登记、试验和病例系列数据进行了吸收和总结,重点强调了整合使用埃米珠单抗的标准化方法。最近的登记数据表明,有必要关注 AHA 中与免疫抑制相关的死亡率,因此我们以算法的形式提供了治疗建议,这些建议已成为我们医院的标准治疗方法。这些建议旨在最大限度地减少止血产品的使用和与 IST 相关的潜在毒性,同时降低出血的发病率和再住院率。建议的治疗算法包括按治疗阶段划分的关键干预措施,可在使用单阶段检测法快速获取血浆 FVIII 活性的中心随时实施。本文介绍了一个病例,以说明建议的诊断和管理注意事项。
{"title":"Acquired Hemophilia A: A Narrative Review and Management Approach in the Emicizumab Era.","authors":"Patrick Ellsworth, Sheh-Li Chen, Lee Ann Jones, Alice Ma, Nigel Key","doi":"10.1016/j.jtha.2024.09.040","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.040","url":null,"abstract":"<p><p>Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies to factor VIII (FVIII). The goals of treatment are two-fold, namely immunosuppressive therapy (IST) to eradicate the inhibitor and hemostatic management to control bleeding. Emicizumab, a bispecific antibody that acts as a factor VIIIa (FVIIIa) mimetic, has seen growing use in AHA following its approval for congenital hemophilia A (cHA). This review provides an overview of the epidemiology, pathophysiology, diagnosis, and treatment of AHA. Registry, trial, and case series data are assimilated and summarized with an emphasis on a standardized approach that integrates the use of emicizumab. With recent registry data suggesting the need to focus on immunosuppression-related mortality in AHA, we provide treatment recommendations in an algorithmic format that have become the standard of care at our institution. These recommendations are intended to minimize hemostatic product usage and potential toxicity related to IST, while reducing morbidity and re-hospitalization rates for bleeding. The proposed treatment algorithm, which includes key interventions by phase of therapy, can be readily implemented at centers that have rapid access to plasma FVIII activity using a one-stage assay. A case is presented to illustrate the proposed diagnostic and management considerations.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}