This Research Topic focuses on novel strategies that are being developed to regulate coagulation and fibrinolysis, and also to highlight basic science studies that identify and characterize these processes and mechanisms. This section will also explore translational implications of basic and clinical research into patient care and thrombotic disease management/treatment.

McMaster University

University of Michigan

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Frontiers in Cardiovascular Medicine

Thrombosis and Haemostasis

Developing Novel Strategies to Regulate and Characterize Coagulation and Fibrinolysis

BackgroundPatients successfully resuscitated from cardiac arrest often develop organ dysfunction caused by systemic inflammation and increased coagulation, leading to disseminated intravascular coagulation (DIC). The involvement of histones in DIC and organ dysfunction in patients with sepsis and trauma has been previously reported, raising the probability that histones may also be associated with pathophysiology in patients after cardiac arrest and resuscitation. This study evaluated the relationship between histones and organ dysfunction related to coagulofibrinolytic changes in patients with post-cardiac arrest syndrome (PCAS).</sec>MethodsThis prospective single-center observational study assessed 35 adult patients with PCAS who were divided into two groups, i.e., 15 patients with multiple organ dysfunction syndrome (MODS) and 20 patients without MODS. MODS was defined as a sequential organ failure assessment score of ≥12. The plasma levels of histones and coagulofibrinolytic markers, including soluble fibrin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, plasmin-alpha 2-plasmin inhibitor complex (PIC), and soluble thrombomodulin, were measured in patients with PCAS immediately after admission to the emergency department, and 3 and 24 h after arriving at the hospital.</sec>ResultsPCAS patients with MODS had higher DIC scores [4 (3.0–5.0) vs. 1 (0.0–3.0), p = 0.012] and higher mortality rates (66.7% vs. 20.0%, p = 0.013) than those without MODS. Moreover, patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period. Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation (rho = 0.367, p = 0.030) and PIC 3 h after arriving at the hospital (rho = 0.480, p = 0.005). This correlation was prominent in the patient population with MODS (soluble fibrin: rho = 0.681, p = 0.005, PIC: rho = 0.742, p = 0.002).</sec>ConclusionsThis study demonstrated that elevated histone levels were associated with increased levels of thrombin, and subsequent plasmin generation in PCAS patients, especially those with MODS. Further studies are required to elucidate the causal relationship between histones and organ dysfunction related to DIC in PCAS.</sec>

Background: Patients successfully resuscitated from cardiac arrest often develop organ dysfunction caused by systemic inflammation and increased coagulation, leading to disseminated intravascular coagulation (DIC). The involvement of histones in DIC and organ dysfunction in patients with sepsis and trauma has been previously reported, raising the probability that histones may also be associated with pathophysiology in patients after cardiac arrest and resuscitation. This study evaluated the relationship between histones and organ dysfunction related to coagulofibrinolytic changes in patients with post-cardiac arrest syndrome (PCAS).Methods: This prospective single-center observational study assessed 35 adult patients with PCAS who were divided into two groups, i.e., 15 patients with multiple organ dysfunction syndrome (MODS) and 20 patients without MODS. MODS was defined as a sequential organ failure assessment score of ≥12. The plasma levels of histones and coagulofibrinolytic markers, including soluble fibrin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, plasmin-alpha 2-plasmin inhibitor complex (PIC), and soluble thrombomodulin, were measured in patients with PCAS immediately after admission to the emergency department, and 3 and 24 h after arriving at the hospital.Results: PCAS patients with MODS had higher DIC scores [4 (3.0–5.0) vs. 1 (0.0–3.0), p = 0.012] and higher mortality rates (66.7% vs. 20.0%, p = 0.013) than those without MODS. Moreover, patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period. Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation (rho = 0.367, p = 0.030) and PIC 3 h after arriving at the hospital (rho = 0.480, p = 0.005). This correlation was prominent in the patient population with MODS (soluble fibrin: rho = 0.681, p = 0.005, PIC: rho = 0.742, p = 0.002).Conclusions: This study demonstrated that elevated histone levels were associated with increased levels of thrombin, and subsequent plasmin generation in PCAS patients, especially those with MODS. Further studies are required to elucidate the causal relationship between histones and organ dysfunction related to DIC in PCAS.

Association of Histones With Coagulofibrinolytic Responses and Organ Dysfunction in Adult Post-cardiac Arrest Syndrome

IntroductionRadial artery occlusion (RAO) after transradial access is a common thrombotic complication. A meta-analysis has proven that RAO incidence in transradial coronary angiography (TRCA) settings was significantly higher than that in percutaneous coronary intervention settings. This prospective observational cohort aimed to evaluate radial artery protection after TRCA with different antiplatelet strategies.</sec>MethodsA total of 2,316 patients undergoing TRCA was enrolled and divided into two groups: single-antiplatelet and dual-antiplatelet groups. Radial artery patency was evaluated by ultrasound before, at 24 h, and 30 days after TRCA. The primary endpoint was RAO incidence at 30 days after TRCA.</sec>ResultsA total of 66 RAO was found on ultrasonography at 30-day follow-up (incidence: 2.8%). In the dual-antiplatelet group, the rate of RAO was significantly lower compared with the single-antiplatelet group (1.8 vs. 4.0%; odds ratio (OR): 0.41; 95% confidence interval (CI): 0.24–0.70; p = 0.001). The rate of self-recanalization in the dual-antiplatelet group was significantly higher than that in the single-antiplatelet group (73.68 vs. 44.12%, p < 0.001). However, there was no statistical difference in delayed occlusion of radial artery between the two groups (0.5 vs. 0.2%, p = 0.140). Unexpectedly, this study also showed no significant difference in bleeding risk between the groups.</sec>ConclusionDual-antiplatelet therapy for 1 month after TRCA was associated with a reduced risk of RAO and deemed safe.</sec>

Introduction: Radial artery occlusion (RAO) after transradial access is a common thrombotic complication. A meta-analysis has proven that RAO incidence in transradial coronary angiography (TRCA) settings was significantly higher than that in percutaneous coronary intervention settings. This prospective observational cohort aimed to evaluate radial artery protection after TRCA with different antiplatelet strategies.Methods: A total of 2,316 patients undergoing TRCA was enrolled and divided into two groups: single-antiplatelet and dual-antiplatelet groups. Radial artery patency was evaluated by ultrasound before, at 24 h, and 30 days after TRCA. The primary endpoint was RAO incidence at 30 days after TRCA.Results: A total of 66 RAO was found on ultrasonography at 30-day follow-up (incidence: 2.8%). In the dual-antiplatelet group, the rate of RAO was significantly lower compared with the single-antiplatelet group (1.8 vs. 4.0%; odds ratio (OR): 0.41; 95% confidence interval (CI): 0.24–0.70; p = 0.001). The rate of self-recanalization in the dual-antiplatelet group was significantly higher than that in the single-antiplatelet group (73.68 vs. 44.12%, p &lt; 0.001). However, there was no statistical difference in delayed occlusion of radial artery between the two groups (0.5 vs. 0.2%, p = 0.140). Unexpectedly, this study also showed no significant difference in bleeding risk between the groups.Conclusion: Dual-antiplatelet therapy for 1 month after TRCA was associated with a reduced risk of RAO and deemed safe.

Different Antiplatelet Strategies for Radial Artery Protection After Transradial Coronary Angiography—A Prospective Observational Cohort Study

BackgroundBoth venoarterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous mechanical thrombectomy (PMT) are increasingly used to treat acute life-threatening pulmonary embolism (PE). However, there are little data regarding their effectiveness. This study aimed to present the short-term outcomes after managing nine patients with acute life-threatening massive or submassive PE by VA-ECMO with or without complemented PMT and propose a preliminary treatment algorithm.</sec>MethodsThis study was a single-center retrospective review of a prospectively maintained registry. It included nine consecutive patients with massive or submassive pulmonary embolism who underwent VA-ECMO for initial hemodynamic stabilization, with or without PMT, from August 2018 to November 2021.</sec>ResultsMean patient age was 54.7 years. Four of nine patients (44.4%) required cardiopulmonary resuscitation before or during VA-ECMO cannulation. All cannulations (100%) were successfully performed percutaneously. Overall survival was 88.9% (8 of 9 patients). One patient died from a hemorrhagic stroke. Of the survivors, the median ECMO duration was 8 days in patients treated with ECMO alone and 4 days in those treated with EMCO and PMT. Five of nine patients (55.6%) required concomitant PMT to address persistent right heart dysfunction, with the remaining survivors (44.4%) receiving VA-ECMO and anticoagulation alone. For survivors receiving VA-ECMO plus PMT, median hospital lengths of stay were 7 and 13 days, respectively.</sec>ConclusionsAn ECMO-first strategy complemented with PMT can be performed effectively and safely for acute life-threatening massive or submassive PE. VA-ECMO is feasible for initial stabilization, serving as a bridge to therapy primarily in inoperable patients with massive PE. Further evaluation in a larger cohort of patients is warranted to assess whether VA-ECMO plus PMT may offer an alternative or complementary therapy to thrombolysis or surgical thrombectomy.</sec>Type of ResearchSingle-center retrospective review of a prospectively maintained registry.</sec>

Background: Both venoarterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous mechanical thrombectomy (PMT) are increasingly used to treat acute life-threatening pulmonary embolism (PE). However, there are little data regarding their effectiveness. This study aimed to present the short-term outcomes after managing nine patients with acute life-threatening massive or submassive PE by VA-ECMO with or without complemented PMT and propose a preliminary treatment algorithm.Methods: This study was a single-center retrospective review of a prospectively maintained registry. It included nine consecutive patients with massive or submassive pulmonary embolism who underwent VA-ECMO for initial hemodynamic stabilization, with or without PMT, from August 2018 to November 2021.Results: Mean patient age was 54.7 years. Four of nine patients (44.4%) required cardiopulmonary resuscitation before or during VA-ECMO cannulation. All cannulations (100%) were successfully performed percutaneously. Overall survival was 88.9% (8 of 9 patients). One patient died from a hemorrhagic stroke. Of the survivors, the median ECMO duration was 8 days in patients treated with ECMO alone and 4 days in those treated with EMCO and PMT. Five of nine patients (55.6%) required concomitant PMT to address persistent right heart dysfunction, with the remaining survivors (44.4%) receiving VA-ECMO and anticoagulation alone. For survivors receiving VA-ECMO plus PMT, median hospital lengths of stay were 7 and 13 days, respectively.Conclusions: An ECMO-first strategy complemented with PMT can be performed effectively and safely for acute life-threatening massive or submassive PE. VA-ECMO is feasible for initial stabilization, serving as a bridge to therapy primarily in inoperable patients with massive PE. Further evaluation in a larger cohort of patients is warranted to assess whether VA-ECMO plus PMT may offer an alternative or complementary therapy to thrombolysis or surgical thrombectomy.Type of Research: Single-center retrospective review of a prospectively maintained registry.

Extracorporeal Membrane Oxygenation—First Strategy for Acute Life-Threatening Pulmonary Embolism

Background: Atrial fibrillation (AF) represents an important risk factor for cardioembolic stroke, and most atrial thrombi originate from the left atrial appendage (LAA). Although the CHA2DS2-VASc score is widely used to estimate the risk of cardioembolic stroke in AF patients, yet greatly affected by many factors. This study was undertaken to determine the association between contrast agent retention in LAA after LAA angiography and risks of cardioembolic stroke in patients with AF.Methods: This is a retrospective study. The demographic and clinical data of AF patients undergone left atrial appendage occlusion (LAAO) with or without catheter radiofrequency ablation were retrospectively analyzed. The patients were classified into either stroke or non-stroke group by the history with cardioembolic stroke or transient ischemic attack (TIA).Results: Sixty-two consecutive patients undergone LAAO were finally included, in whom 31 AF patients had a history of cardioembolic stroke or TIA (one TIA), and significantly higher CHA2DS2-VASc score (4.2 ± 1.4 vs. 3.3 ± 1.3; P = 0.006) as well as incidence of contrast agent retention in LAA (n = 20 vs. n = 7; P = 0.001) compared to the patients in non-stroke group. In addition, the relative proportion of distinctive morphological types of LAA was significantly different between groups (P < 0.001). Multivariate logistic regression analysis showed that higher CHA2DS2-VASc scores (OR = 1.7, 95% CI: 1.0–3.0, P = 0.046) and LAA contrast agent retention (OR = 5.1, 95% CI: 1.1–23.9, P = 0.002) were associated with increased risks of cardioembolic stroke. The patients with Windsock type LAA (OR = 7.8, 95% CI: 1.1–57.2, P = 0.044) and Cauliflower LAA (OR = 20.2, 95% CI: 3.2–125.5, P = 0.001) were more prone to cardioembolic stroke compared to those with Chicken Wing type LAA.Conclusion: Left atrial appendage contrast agent retention after LAA angiography is associated with the risks of cardioembolic stroke in patients with AF, and cardioembolic stroke is more seen in AF patients with Windsock or Cauliflower type LAA.

Background: Atrial fibrillation (AF) represents an important risk factor for cardioembolic stroke, and most atrial thrombi originate from the left atrial appendage (LAA). Although the CHA2DS2-VASc score is widely used to estimate the risk of cardioembolic stroke in AF patients, yet greatly affected by many factors. This study was undertaken to determine the association between contrast agent retention in LAA after LAA angiography and risks of cardioembolic stroke in patients with AF.Methods: This is a retrospective study. The demographic and clinical data of AF patients undergone left atrial appendage occlusion (LAAO) with or without catheter radiofrequency ablation were retrospectively analyzed. The patients were classified into either stroke or non-stroke group by the history with cardioembolic stroke or transient ischemic attack (TIA).Results: Sixty-two consecutive patients undergone LAAO were finally included, in whom 31 AF patients had a history of cardioembolic stroke or TIA (one TIA), and significantly higher CHA2DS2-VASc score (4.2 ± 1.4 vs. 3.3 ± 1.3; P = 0.006) as well as incidence of contrast agent retention in LAA (n = 20 vs. n = 7; P = 0.001) compared to the patients in non-stroke group. In addition, the relative proportion of distinctive morphological types of LAA was significantly different between groups (P &lt; 0.001). Multivariate logistic regression analysis showed that higher CHA2DS2-VASc scores (OR = 1.7, 95% CI: 1.0–3.0, P = 0.046) and LAA contrast agent retention (OR = 5.1, 95% CI: 1.1–23.9, P = 0.002) were associated with increased risks of cardioembolic stroke. The patients with Windsock type LAA (OR = 7.8, 95% CI: 1.1–57.2, P = 0.044) and Cauliflower LAA (OR = 20.2, 95% CI: 3.2–125.5, P = 0.001) were more prone to cardioembolic stroke compared to those with Chicken Wing type LAA.Conclusion: Left atrial appendage contrast agent retention after LAA angiography is associated with the risks of cardioembolic stroke in patients with AF, and cardioembolic stroke is more seen in AF patients with Windsock or Cauliflower type LAA.

Post-angiography Retention of the Contrast Agent in the Left Atrial Appendage Is Associated With Risk of Cardioembolic Stroke in Patients With Atrial Fibrillation: A Retrospective Study

Objective: In this study, we conducted a meta-analysis to assess the impact of age, sex, and renal function on the efficacy and safety of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) for the treatment of acute venous thromboembolism (VTE).Methods: Electronic databases (accessed till June 2021) were systematically searched to investigate randomized clinical trials evaluating apixaban, dabigatran, edoxaban, and rivaroxaban vs. VKAs for the treatment of acute VTE. Results were presented as odds ratio (OR) and 95% CIs.Results: Direct oral anticoagulants were associated with a borderline higher efficacy in women (OR: 0.79, 95% CI: 0.62–1.02), a significantly higher efficacy in patients with age more than 75 years (OR: 0.51, 95% CI: 0.32–0.80), and creatinine clearance <50 ml/min (OR: 0.57, 95% CI: 0.32–0.99). The primary safety endpoint of major or clinically relevant non-major bleeding was significantly reduced in DOACs as compared to VKAs in both patients with age <75 years (OR: 0.79, 95% CI: 0.70–0.89) and patients with age more than 75 years (OR: 0.75, 95% CI: 0.59–0.96). DOACs also show an advantage in terms of major or clinically relevant non-major bleeding in men (OR: 0.72, 95% CI: 0.60–0.86) and patients with creatinine clearance of more than 50 ml/min (OR: 0.75, 95% CI: 0.67–0.84).Conclusions: Direct oral anticoagulants have exhibited clinical preference among patients with acute VTE with decreased thrombosis and bleeding events, especially in patients with age more than 75 years and creatinine clearance <50 ml/min.

Objective: In this study, we conducted a meta-analysis to assess the impact of age, sex, and renal function on the efficacy and safety of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) for the treatment of acute venous thromboembolism (VTE).Methods: Electronic databases (accessed till June 2021) were systematically searched to investigate randomized clinical trials evaluating apixaban, dabigatran, edoxaban, and rivaroxaban vs. VKAs for the treatment of acute VTE. Results were presented as odds ratio (OR) and 95% CIs.Results: Direct oral anticoagulants were associated with a borderline higher efficacy in women (OR: 0.79, 95% CI: 0.62–1.02), a significantly higher efficacy in patients with age more than 75 years (OR: 0.51, 95% CI: 0.32–0.80), and creatinine clearance &lt;50 ml/min (OR: 0.57, 95% CI: 0.32–0.99). The primary safety endpoint of major or clinically relevant non-major bleeding was significantly reduced in DOACs as compared to VKAs in both patients with age &lt;75 years (OR: 0.79, 95% CI: 0.70–0.89) and patients with age more than 75 years (OR: 0.75, 95% CI: 0.59–0.96). DOACs also show an advantage in terms of major or clinically relevant non-major bleeding in men (OR: 0.72, 95% CI: 0.60–0.86) and patients with creatinine clearance of more than 50 ml/min (OR: 0.75, 95% CI: 0.67–0.84).Conclusions: Direct oral anticoagulants have exhibited clinical preference among patients with acute VTE with decreased thrombosis and bleeding events, especially in patients with age more than 75 years and creatinine clearance &lt;50 ml/min.

Impact of Age, Sex, and Renal Function on the Efficacy and Safety of Direct Oral Anticoagulants vs. Vitamin K Antagonists for the Treatment of Acute Venous Thromboembolism: A Meta-Analysis of 22,040 Patients