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Whole-body ischemia and reperfusion due to cardiac arrest and subsequent return of spontaneous circulation constitute post-cardiac arrest syndrome (PCAS), which consists of four syndromes including systemic ischemia/reperfusion responses and post-cardiac arrest brain injury. The major pathophysiologies underlying systemic ischemia/reperfusion responses are systemic inflammatory response syndrome and increased coagulation, leading to disseminated intravascular coagulation (DIC), which clinically manifests as obstruction of microcirculation and multiple organ dysfunction. In particular, thrombotic occlusion in the brain due to DIC, referred to as the \"no-reflow phenomenon,\" may be deeply involved in post-cardiac arrest brain injury, which is the leading cause of mortality in patients with PCAS. Coagulofibrinolytic changes in patients with PCAS are characterized by tissue factor-dependent coagulation, which is accelerated by impaired anticoagulant mechanisms, including antithrombin, protein C, thrombomodulin, and tissue factor pathway inhibitor. Damage-associated molecular patterns (DAMPs) accelerate not only tissue factor-dependent coagulation but also the factor XII- and factor XI-dependent activation of coagulation. Inflammatory cytokines are also involved in these changes the expression of tissue factor on endothelial cells and monocytes, the inhibition of anticoagulant systems, and the release of neutrophil elastase from neutrophils activated by inflammatory cytokines. Hyperfibrinolysis in the early phase of PCAS is followed by inadequate endogenous fibrinolysis and fibrinolytic shutdown by plasminogen activator inhibitor-1. Moreover, cell-free DNA, which is also a DAMP, plays a pivotal role in the inhibition of fibrinolysis. DIC diagnosis criteria or fibrinolysis markers, including d-dimer and fibrin/fibrinogen degradation products, which are commonly tested in patients and easily accessible, can be used to predict the mortality or neurological outcome of PCAS patients with high accuracy. A number of studies have explored therapy for this unique pathophysiology since the first report on \"no-reflow phenomenon\" was published roughly 50 years ago. However, the optimum therapeutic strategy focusing on the coagulofibrinolytic changes in cardiac arrest or PCAS patients has not yet been established. The elucidation of more precise pathomechanisms of coagulofibrinolytic changes in PCAS may aid in the development of novel therapeutic targets, leading to an improvement in the outcomes of PCAS patients.

Background: Deep vein thrombosis (DVT) is a common complication and the second leading cause of death in cancer patients. Proinflammatory stimuli in the cancer microenvironment induce nuclear factor kappa B (NF-[KAPPA]B) signaling pathway that plays an integral role in immunothrombosis mechanism. Objective: To investigate the role of inflammatory and coagulation biomarkers in the development of DVT in cancer patients with high risk of thrombosis (Khorana score [greater than or equal to]2). Subjects and methods: This study was a cross-sectional study at Dr. Kariadi General Hospital. The serum levels of proinflammatory cytokines, ie, NF-[KAPPA]B, interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-[alpha]), and coagulation biomarkers, ie, tissue factor (TF), prothrombin fragment F1+2 (F1+2), fibrinogen and D-dimer were measured in newlydiagnosed cancer patients with a highrisk of thrombosis. Color duplex sonography was used for DVT screening. Results: From January to November 2021, there were 83 eligible patients. DVT was confirmed in 8 subjects (9.63%). Univariate analysis revealed a significant difference between the median age of patients with DVT compared to non-DVT patients, 49.5 years (range: 23-60 years) and 42 years (range: 19-60 years), with p=0.046. D-dimer level was higher in DVT patients [(6.020 [micro]g/L, range 2.090-20.000) vs (1.940 [micro]g/L, range 270-20.000), p=0.005]. Multivariate analysis revealed age and D-dimer were significantly correlated with DVT incidence. In all patients, there were significant positive correlations between several inflammatory and coagulation activation parameters, which were IL-6 with D-dimer and F1+2, CRP with F1+2 and D-dimer as well as TNF-a with F1+2. However, these findings were not shown in DVT patients. Conclusion: In cancer patients with a high risk of thrombosis, age and D-dimer level are the significant variables towards the incidence of DVT. In patients with DVT, there was no significant correlation between inflammatory and coagulation activation parameters. Keywords: inflammation, activation of coagulation, DVT, high-risk thrombosis, cancer patients

Over 50 million people in the world have a chronic liver disease. Interestingly, as a result of liver disease, patients often acquire complex alterations in their coagulation cascade. The coagulation cascade plays a critical role in preventing hemorrhage after vascular injury through the formation of a blood clot. There is also evidence suggest that the activation of the coagulation cascade worsens the progression of liver disease. However, the mechanisms underlying the activation of coagulation during liver disease are poorly understood. If the mechanisms whereby coagulation is activated during liver disease were known, one could develop targeted strategies to inhibit pathologic coagulation in patients with liver disease.The coagulation cascade is controlled by a complex composed of tissue factor (TF) and its plasma ligand, factor FVIIa (FVIIa). Within the liver, the TF:FVIIa complex exists in a non-procoagulant, ‘encrypted’ state on hepatocytes. Prior studies focusing on encrypted TF:FVIIa have identified several potential mechanisms underlying the activation of TF:FVIIa. However, the in vivo relevance of these mechanisms has remained unclear, because examples of TF:FVIIa activation triggered by (patho)physiologically-relevant mediators are lacking.A major focus of the work described in this dissertation was to identify activators of coagulation during liver injury. Interestingly, bile acids, cholesterol metabolites produced in the liver, accumulate within the liver parenchyma and plasma during liver disease. Exploring the possibility for bile acids to activate coagulation, I found that pathologically relevant concentrations of the bile acid, glycochenodeoxycholic acid, increased hepatocyte TF:FVIIa activity. Expanding on this finding, I tested the hypothesis that bile acids directly increase TF:FVIIa activity by using TF:FVIIa relipidated in unilamellar vesicles and soluble TF:FVIIa. The bile acids, glycochenodeoxycholic and taurochenodeoxycholic acid, directly increased the activity of relipidated and soluble TF:FVIIa. Interestingly, it was found that not all bile acids act through the same mechanism. Taurocholic acid did not directly activate TF:FVIIa but increased hepatocyte TF:FVIIa activity through the non-apoptotic externalization of phosphatidylserine in vitro. These results indicate that bile acids increase TF:FVIIa procoagulant activity through both direct and indirect mechanisms.Although prior studies have focused on hepatocyte TF, it is unknown if hepatocyte TF is universally required to activate coagulation after challenge with hepatotoxicants. Another focus of this work was to determine the role of hepatocyte TF in acute and chronic challenge with carbon tetrachloride (CCl4). Contrary to my hypothesis that hepatocyte TF drives coagulation after CCl4 challenge, there was no change in the activation of coagulation in mice deficient of hepatocyte TF versus control mice after acute and chronic challenge with CCl4. This suggests another cellular source of TF is driving coagulation after CCl4 challenge. Notably, deficiency in hepatocyte TF did not affect the development of fibrosis. In summary, contrasting other models of liver injury, this suggests hepatocyte TF does not drive coagulation after CCl4 challenge.In summary, these results indicate that bile acids increase TF:FVIIa procoagulant activity, which suggests the possibility for bile acids to activate coagulation during liver disease. Additionally, it was found that hepatocyte TF does not contribute to the activation of coagulation in all models of liver injury, which suggests the potential for another cellular source of TF that is driving coagulation. Overall, this work expands our knowledge of how coagulation is regulated within the liver and identifies potential activators of coagulation that increase during liver disease.

IntroductionComprehensive studies investigating sustained hypercoagulability, endothelial function, and/or inflammation in relation to post-COVID-19 (PCC) symptoms with a prolonged follow-up are currently lacking. Therefore, the aim of this single-centre cohort study was to investigate serum biomarkers of coagulation activation, microvascular dysfunction, and inflammation in relation to persisting symptoms two years after acute COVID-19.MethodsPatients diagnosed with acute SARS-CoV-2 infection between February and June 2020 were recruited. Outcome measures included the CORona Follow-Up (CORFU) questionnaire, which is based on an internationally developed and partially validated basic questionnaire on persistent PCC symptoms. Additionally, plasma biomarkers reflecting coagulation activation, endothelial dysfunction and systemic inflammation were measured.Results167 individuals were approached of which 148 (89%) completed the CORFU questionnaire. At 24 months after acute infection, fatigue was the most prevalent PCC symptom (84.5%). Over 50% of the patients experienced symptoms related to breathing, cognition, sleep or mobility; 30.3% still experienced at least one severe or extreme (4 or 5 on a 5-point scale) PCC symptom. Multiple correlations were found between several PCC symptoms and markers of endothelial dysfunction (endothelin-1 and von Willebrand factor) and systemic inflammation (Interleukin-1 Receptor antagonist). No positive correlations were found between PCC symptoms and coagulation complexes.DiscussionIn conclusion, this study shows that at 24 months after acute COVID-19 infection patients experience a high prevalence of PCC symptoms which correlate with inflammatory cytokine IL-1Ra and markers of endothelial dysfunction, especially endothelin-1. Our data may provide a rationale for the selection of treatment strategies for further clinical studies.Trial registrationThis study was performed in collaboration with the CORona Follow-Up (CORFU) study (NCT05240742,https://clinicaltrials.gov/ct2/show/NCT05240742).

Purpose Up to 30% of patients with glioblastoma (GBM) develop venous thromboembolism (VTE) over the course of the disease. Although not as high, the risk for VTE is also increased in patients with meningioma. Direct measurement of peak thrombin generation (TG) allows quantitative assessment of systemic coagulation activation in patients with GBM and meningioma. Our aim was to determine the extent of systemic coagulation activation induced by brain tumors, to measure the shift between pre- and post-operative peak TG in patients with GBM, and to assess the relationship between pre-surgical peak TG and pre-operative brain tumor volume on imaging. Methods Pre- and post-surgical plasma samples were obtained from successive patients with GBM and once from patients with meningioma and healthy age- and sex-matched blood donor controls. TG was measured using the calibrated automated thrombogram (CAT) assay, and tumor volumes were measured in pre-surgical MRI scans. Results Pre-surgical peak TG was higher in patients with GBM than in controls (288.6 ± 54.1 nM vs 187.1 ± 41.7 nM, respectively, P  < 0.001), and, in the nine patients with GBM and paired data available, peak TG was significantly reduced after surgery (323 ± 38 nM vs 265 ± 52 nM, respectively, P  = 0.007). Similarly, subjects with meningioma demonstrated higher peak TG compared to controls (242.2 ± 54.9 nM vs 177.7 ± 57.0 nM, respectively, P  < 0.001). There was no association between peak TG and pre-operative tumor volume or overall survival. Conclusion Our results indicate that systemic coagulation activation occurs with both meningioma and GBM, but to a greater degree in the latter. Preoperative peak TG did not correlate with tumor volume, but removal of GBM caused a significant decrease in coagulation activation.

The state of the coagulation-fibrinolysis system plays a pivotal role in thrombosis; however, its significance in guiding early revascularization for ischemic stroke remains inadequately understood. To explore the correlation between coagulation activation markers and early neurological function and infarction volume in acute ischemic stroke (AIS), and to evaluate their predictive value for stroke severity. This retrospective cohort study enrolled 135 patients with acute ischemic stroke. Participants were stratified into two groups based on admission National Institutes of Health Stroke Scale (NIHSS)scores: mild stroke group (NIHSS≤3, n=95) and moderate-to-severe stroke group (NIHSS>3, n=40). Five coagulation activation markers were quantified: thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), tissue plasminogen activator-inhibitor complex (t-PAIC), and D-dimer. The associations between these biomarkers and stroke severity were evaluated using logistic regression models and receiver-operating characteristic (ROC) curve analyses. Infarct volume and its spatial distribution across distinct brain regions were quantified using dedicated neuroimaging software. Subsequently, the correlation between the five coagulation markers and both total infarct volume and region-specific infarction volumes were assessed. Plasma levels of TAT, t-PAIC, and D-dimer were significantly elevated in the moderate-to-severe stroke group compared to the mild stroke group (p<0.05). Multivariate logistic regression analysis identified D-dimer as an independent risk factor for moderate-to-severe stroke (OR=1.002,95% CI:1.000-1.004). The area under the curve (AUC) values for TAT, t-PAIC, and D-dimer in predicting moderate-to-severe stroke were 0.62,0.63, and 0.59, respectively. The combined predictive model achieved an AUC of 0.67. Furthermore, within the moderate-to-severe stroke group, TAT levels demonstrated a positive correlation with anterior circulation cortical infarction volume (R=0.61, p<0.05). Additionally, D-dimer levels exhibited positive correlations with both total infarct volume and anterior circulation cortical infarction volume (R=0.74, p<0.05; R=0.79, p<0.05). TAT, t-PAIC and D-dimer serve as predictors for the severity of acute ischemic stroke, and can be used as a simple and rapid auxiliary tool combined with imaging evaluation to provide synergistic guidance for clinical decision-making.

Background Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer. Methods Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I–IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence. Results Median follow up was 95 months (range 6–112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly. Conclusions We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.

During the last two decades, several cases of venous thrombosis (VTE) after a prolonged period at a computer have been described, denominated as “eThrombosis”. Video gaming on a computer has become very popular and can be a social activity where several players gather to play against each other or in a virtual environment for several days (“LAN (i.e., Local Area Network) parties”) where the participants are sedentary and consuming calorie-rich food items. The aim of this study was to investigate potential coagulation activation during a 42 h LAN party. Nine male gamers volunteered for the LAN party. Citrated blood was sampled before and every 6 h, and plasma was analyzed for thrombin generation, thrombin–antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), and D-dimer. Thrombin generation increased slightly but not significantly during the LAN party, whereas the coagulation activation markers were unchanged. These results do not indicate that the coagulation system is activated significantly during 42 h of gaming with minimal physical activity. Although increased activity cannot be excluded, it does not directly indicate a risk of VTE in general.

Background Deep vein thrombosis (DVT) is a prevalent complication associated with malignancy. Clinical use of thromboprophylaxis is recommended, however its usage is limited due to bleeding complications, more cost associated, and reluctance to receive anticoagulant injections. Rivaroxaban a relatively easy to administer anticoagulant but it has a risk of bleeding and is expensive. Inflammation is the important factor in pathogenesis of cancer-associated thrombosis. Statins have the anti-inflammatory property that could decrease proinflammatory cytokines. Consequently, statins may be used as thromboprophylaxis for cancer patients receiving chemotherapy. Objective To provide comparison between atorvastatin and rivaroxaban on affecting inflammatory biomarkers (interleukin 6 [IL-6], C reactive protein [CRP]) and coagulation activation biomarkers (Tissue Factor [TF], prothrombin fragment 1 + 2 [F1 + 2], D-Dimer) in cancer patients at high risk of thrombosis receiving chemotherapy. Methods A randomized controlled study that was double-blinded and involved high-risk cancer patients undergoing chemotherapy. For up to ninety days, participants were randomized to receiver either atorvastatin 20 mg or rivaroxaban 10 mg daily. The level of plasma of IL-6, CRP, TF, F1 + 2, and D-dimer were assessed 24 h before chemotherapy, 30, 60, and 90 day after chemotherapy. The latest observation carried forward (LOCF) approach was used to examine the data. The laboratory results were evaluated using an independent T test or Mann-Whitney U test prior to and after chemotherapy. Results Eighty-six randomized patients were enrolled, although both groups showed a decreasing trend in plasma level of IL-6, CRP, TF, F1 + 2, and D-dimer, there were no significant differences between the two groups ( p  > 0.05). In the atorvastatin group, there was a significant correlation between delta level of IL-6 and F1 + 2 ( r  = 0.313, p  = 0.043) and delta level of CRP and F1 + 2 ( r  = 0.398, p  = 0.009), whereas in the rivaroxaban group there was a significant correlation between delta CRP and D-dimer level ( r  = 0.387, p  = 0.009). Conclusion Atorvastatin decreases IL-6 and CRP level, which also decreases F1 + 2 level. Atorvastatin did not substantially differ from rivaroxaban in decreasing plasma levels of inflammatory biomarkers IL-6, CRP, and coagulation activation biomarkers TF, F1 + 2, D-dimer in high-risk cancer patients undergoing chemotherapy. Trial registration ISRCTN71891829, Registration Date: 17/12/2020.

Background Sepsis is the leading cause of death in critically ill patients, with an in-hospital mortality rate of approximately 25% to 40%. Coagulation activation serves as an initial factor to the progression of sepsis into multiple organ dysfunction syndrome (MODS). Therefore, anticoagulant therapy may be beneficial. Both preclinical experiments and clinical studies have evaluated the protective effect of nafamostat mesilate (NM) in sepsis. However, there is still a lack of randomized controlled trials (RCTs) to further confirm the therapeutic effect and safety of NM in sepsis patients. Methods This multicenter, double-blind, RCT was designed to recruit 778 subjects who met Sepsis 3.0 criteria. Participants will be randomly assigned (1:1) to receive either intravenous administration of NM or glucose along with standard treatment. The primary outcome is the all-cause mortality rate in the intensive care unit (ICU), and the secondary outcomes include the improvement in SOFA scores, changes in Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH) scores, 28-day all-cause mortality rate, and the incidence of adverse events. The allocation will remain concealed from investigators, participants, and statisticians to maintain blinding. Discussion The EASNMS trial aims to assess the efficacy and safety of NM for treating sepsis across various regions in China. As an additional treatment option, NM may potentially enhance the prognosis of sepsis patients. Ethics and dissemination Ethical approval has been obtained from all ethics committees of the involved centers. The findings of this study will be shared in peer-reviewed journals and will be presented at conferences. Trial registration ClinicalTrials.gov NCT06078839. Registered on September 20, 2023.