Prothrombotic State Research Articles

Circulating levels of erythrocytes-derived vesicles related to poor glycaemia control in type 2 diabetes mellitus patients with atrial fibrillation

Abstract Background Previous studies demonstrated that insulin resistance, hyperglycemia contribute to the development of a pro-thrombotic state characterized by increased platelet activation, activation of coagulation cascade and elevated number of extracellular vesicles (EVs) in type 2 diabetes mellitus (T2DM) patients. There is a less known impact of glycaemia control in T2DM patients with concomitant heart failure (HF) and atrial fibrillation (AF) on a number of erythrocytes-derived EVs. The aim of the study was to elucidate whether glucose control in T2DM patients with HF and AF affect a circulating number of erythrocytes-derived EVs. Methods The entire patient population composes of 417 patients (231 male, 55.4% and 186 female, 44.6%) with average age of 53 years as well as 25 healthy volunteers and 30 T2DM non-HF individuals. As inclusion, age ≥ 18 years, T2DM, established HF, and written consent to participate in the study was used. Patients after successful ablation procedure (mainly radiofrequency ablation) were included in the group non-AF in 6 weeks after procedure if cardiac rhythm is sinus. All patients were divided into two groups depending on criteria of poor glycemic control (HbA1c < 6.9% and ≥7.0%, respectively). Hemodynamics features, conventional biochemistry parameters and EVs measure were performed at the baseline. Flow cytometry was performed according to conventional protocol with FMO standards to detect and measure EVs. Results Circulating levels of CD235a+ PS+ erythrocytes-derived vesicles differed amongst T2DM patients depending on HF presentation when compared with healthy volunteers (Figure 1). Figure 2 illustrated the differences in circulating amount of CD235a+ PS+ RBC-derived vesicles in AF and non-AF patients with T2DM and HF depending on glycaemia control. There were significantly lower levels of CD235a+ PS+ RBC-derived vesicles were detected in those with HbA1c < 6.9% than in patients with HbA1c ≥ 7.0%. To note, there were no significant differences in circulating amount of CD235a+ PS+ erythrocytes-derived vesicles between patients in entire cohort (p = 0.24) and in non-AF sub-cohort (p = 0.40) with HbA1c < 6.9% and HbA1c ≥ 7.0%, respectively. The Receive Operation Characteristics curve analysis revealed that the well-balanced cut-off point for circulating amount of CD235a+ PS+ erythrocytes-derived vesicles (HbA1c ≥ 7.0% versus HbA1c < 6.9%) were 545 particles in µL (area under curve = 0.91, sensitivity = 74.2%, specificity = 90.3%; p = 0.0001). Multivariate linear regression yielded that NT-proBNP (OR = 1.07; 95% CI = 1.02–1.10, p = 0.04) and CD235a+ PS+ erythrocytes-derived vesicles ≥ 545 particles in µL (OR = 1.06; 95% CI = 1.01–1.11, p = 0.044) remained independent predictors for HbA1c ≥ 7.0%. Conclusion Poor glycaemia control is associated with elevated levels of CD235a+ PS+ EVs, which were found to be independent predictor for AF presentation in T2DM patients with HF.Circulating levels of EVsEVs in AF and non-AF patients

Daytime plasma cortisol and cortisol response to dexamethasone suppression are associated with a prothrombotic state in hypertension.

A prothrombotic state was demonstrated in patients with Cushing's syndrome and is involved in the development and progression of cardiovascular and renal damage in hypertensive patients. This study was designed to examine the relationships between cortisol secretion and the hemostatic and fibrinolytic systems in hypertension. In 149 middle-aged, nondiabetic, essential hypertensive patients free of cardiovascular and renal complications, we measured hemostatic markers that express the spontaneous activation of the coagulation and fibrinolytic systems and assessed daily cortisol levels (8 AM, 3 PM, 12 AM; area under the curve, AUC-cortisol) together with the cortisol response to dexamethasone overnight suppression (DST-cortisol). Plasma levels of D-dimer (D-dim), prothrombin fragment 1+2 (F1+2), and von Willebrand factor (vWF) were progressively and significantly higher across tertiles of AUC-cortisol and DST-cortisol, whereas no differences were observed in fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, protein C, and protein S. D-dim, F1+2, and vWF were significantly and directly correlated with age and both AUC-cortisol and DST-cortisol. Multivariate regression analysis showed that both AUC-cortisol and DST-cortisol were related to plasma D-dim, F1+2, and vWF independently of age, body mass index, blood pressure, and renal function. Greater daily cortisol profile and cortisol response to overnight suppression are independently associated with a prothrombotic state in hypertensive patients and might contribute to the development of organ damage and higher risk of cardiovascular complications.

Associations between “Cancer Risk”, “Inflammation” and “Metabolic Syndrome”: A Scoping Review

Background: Individuals with metabolic syndrome exhibit simultaneously pro-thrombotic and pro-inflammatory conditions which more probably can lead to cardiovascular diseases progression, type 2 diabetes mellitus, and some types of cancer. The present scoping review is aimed at highlighting the association between cancer risk, inflammation, and metabolic syndrome. Methods: A search strategy was performed, mixing keywords and MeSH terms, such as “Cancer Risk”, “Inflammation”, “Metabolic Syndrome”, “Oncogenesis”, and “Oxidative Stress”, and matching them through Boolean operators. A total of 20 manuscripts were screened for the present study. Among the selected papers, we identified some associations with breast cancer, colorectal cancer, esophageal adenocarcinoma, hepatocellular carcinoma (HCC), and cancer in general. Conclusions: Cancer and its related progression may also depend also on a latent chronic inflammatory condition associated with other concomitant conditions, including type 2 diabetes mellitus, metabolic syndrome, and obesity. Therefore, prevention may potentially help individuals to protect themselves from cancer.

Clinical Profile and Risk Factors of Cerebral Venous Sinus Thrombosis

Background: Cerebral venous sinus thrombosis (CVST) is a rare but serious neurovascular disorder that can lead to life-threatening complications such as hemorrhage and cerebral edema. This condition presents with a wide array of symptoms due to the formation of blood clots in the cerebral venous sinuses, impairing the drainage of deoxygenated blood and cerebrospinal fluid from the brain. Objective: The aim of this study was to elucidate the clinical profile and risk factors associated with CVST, enhancing the understanding of its epidemiology and facilitating better diagnostic and therapeutic strategies. Methods: This prospective cross-sectional study was conducted at the Department of Neurology, Jinnah Postgraduate Medical Centre, Karachi, Pakistan. A total of 135 participants diagnosed with CVST were enrolled through non-probability consecutive sampling. Participants underwent comprehensive physical and neurological examinations using a structured Clinical Patient Assessment Form. Diagnostic imaging included MRI, MRV, CT, and CT venography, although the principal diagnostic tools were CT and MRV. Data collection focused on demographics, clinical manifestations, and risk factors, with all information analyzed using SPSS version 25. Results: The study population predominantly consisted of females (74.8%) with the age group of 31-40 years being the most common (31.1%). Headache was the most frequently reported symptom (90.4%), followed by hemiparesis (53.3%) and seizures (40%). Significant risk factors included postpartum status (50.4%), iron deficiency anemia (25.9%), and genetic prothrombotic conditions (9.6%). Imaging studies revealed that the transverse sinus was the most affected site (74.1%). Conclusion: CVST exhibits a diverse range of clinical presentations and is associated with multiple demographic and physiological risk factors. Early diagnosis and management are crucial to prevent severe outcomes. This study highlights the importance of considering a detailed clinical and risk factor profile in patients presenting with neurological symptoms to aid in timely and accurate diagnosis of CVST.

A 31-year-old female with diffuse pulmonary infiltrates and intracardiac thrombus

Intracardiac masses on echocardiography can represent thrombi, vegetations, or tumors. Cardiac Magnetic Resonance Imaging (MRI) is a sensitive tool that differentiates between the three. Intracardiac thrombi can develop during various pathological conditions that cause stasis of blood and predispose to the aggregation of thrombotic material. Atrial clots can occur in conditions like atrial fibrillation, structural heart diseases, thrombophilia, and chronic inflammations. Tuberculosis (TB) is a prothrombotic state and can predispose to venous and sometimes arterial clot formation. But intracardiac clots in TB are rare. We report a young patient presenting with bilateral intracardiac clots and diagnosed to have disseminated tuberculosis. Treatment with anti-tubercular therapy and therapeutic anticoagulation leads to complete resolution of the thrombi.

Low dose sublingual estradiol decreases protein s, generating a potentially pro-thrombotic state: interim results of a controlled prospective pilot study of treatment-naive trans women

Low dose sublingual estradiol decreases protein s, generating a potentially pro-thrombotic state: interim results of a controlled prospective pilot study of treatment-naive trans women

Curcumin as a Promising Therapy for COVID-19: A Review

The ongoing COVID-19 pandemic has spurred intense research efforts to identify effective therapeutic options. Among the potential candidates, curcumin, a naturally occurring polyphenol obtained from turmeric, has gained considerable attention due to its diverse pharmacological properties. This review examines the existing literature on curcumin’s potential as a new promising treatment for COVID-19. Curcumin demonstrates antiviral effects by modulating key signaling pathways for entry and multiplication of SARS-CoV-2 in host cells. It limits viral entry in host cells as it binds and inhibits S-protein, TMPRSS2, and ADAM17 enzymes required for cytoadherence and membrane fusion. It also downregulates SARS-CoV-2 replication by preventing the release of the viral genomic RNA into the cytoplasm from virus-containing vacuoles and subsequently inhibits enzymes required for viral replication. Rennin–angiotensin–aldosterone system (RAS) dysfunction, especially increased angiotensin-converting enzyme (ACE)-Angiotensin II-AT1R axis activity, is associated with prothrombotic state, acute respiratory distress syndrome, and lung injury in COVID-19 patients. Curcumin increases soluble ACE2 cellular ACE2 activity, restores RAS normal function, and mitigates these complications. Curcumin also exerts anti-inflammatory and immunomodulatory actions. It reduces the secretion of pro-inflammatory cytokines through inhibition of toll-like receptors (TLRs), namely, TLR2, TLR4, and TLR9, and enhances the production of anti-inflammatory cytokines like interleukin-10. In addition, it prevents the progression of tissue damage and inflammation by reactive oxygen species (ROS) through ROS scavenging enzymes. Due to its antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties, curcumin has emerged as an attractive candidate for combating various aspects of COVID-19 pathogenesis, such as excessive inflammation, oxidative stress, viral multiplication, and immune dysregulation. However, limited clinical evidence is currently available to support its efficacy, specifically against COVID-19. Thus, further research, including clinical trials, is warranted to evaluate curcumin’s therapeutic potential and determine its optimal dosage, formulation, and safety for COVID-19 patients. Overall, based on its favorable pharmacological properties and promising preclinical data, curcumin holds promise as a treatment for COVID-19, but its clinical utility requires further exploration.

Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19

BackgroundCOVID-19 can cause profound inflammation and coagulopathy, and while many mechanisms have been proposed, there is no known common pathway leading to a prothrombotic state. ObjectivesFrom the beginning of the COVID-19 pandemic, elevated levels of extracellular histones have been found in plasma of patients infected with SARS-CoV-2. We hypothesized that platelet activation triggered by extracellular histones might represent a unifying mechanism leading to increased thrombin generation and thrombosis. MethodsWe utilized blood samples collected from an early clinical trial of hospitalized COVID-19 patients (NCT04360824) and recruited healthy subjects as controls. Using plasma samples, we measured the procoagulant and prothrombotic potential of circulating extracellular histones and extracellular vesicles (EVs). Platelet prothrombotic activity was assessed via thrombin generation potential and platelet thrombus growth. Circulating EVs were assessed for thrombin generation potential in vitro in plasma and enhancement of thrombotic susceptibility in vivo in mice. ResultsCompared with controls, COVID-19 patients had elevated plasma levels of citrullinated histone H3, cell-free DNA, nucleosomes, and EVs. Plasma from COVID-19 patients promoted platelet activation, platelet-dependent thrombin generation, thrombus growth under venous shear stress, and release of platelet-derived EVs. These prothrombotic effects of COVID-19 plasma were inhibited by an RNA aptamer that neutralizes both free and DNA-bound histones. EVs isolated from COVID-19 plasma enhanced thrombin generation in vitro and potentiated venous thrombosis in mice in vivo. ConclusionWe conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial.

The Review of Ophthalmic Symptoms in COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 had a significant impact on the health of the global human population, affecting almost every human organ, including the organ of vision. Research focus on understanding the pathophysiology, identifying symptoms and complications of the disease. Eye-related pathologies are important foci of research due to the potential for direct impact of the virus. Ophthalmologists around the world are reporting various symptoms of eye infections and ocular pathologies associated with SARS-CoV-2. The review of ophthalmic symptoms was conducted to help physicians of various specialties recognize possible ophthalmic manifestations of this viral disease. A literature review was conducted from January 2020 to July 2023 in the PubMed, MEDLINE, Science Direct, Scopus, Scielo and Google Scholar databases. The review of the literature showed that conjunctivitis is the most common ophthalmic symptom observed during the course of COVID-19 and can occur at any stage of the disease. Changes in the eye may result from the direct effect of the virus, immune response, prothrombotic states, comorbidities, and medications used. Symptoms related to the organ of vision can be divided into: changes affecting the protective apparatus of the eye, the anterior eye segment, the posterior eye segment, neuro-ophthalmic, and orbital changes. Ocular symptoms may suggest COVID-19 infection or appear several weeks after recovery. Following COVID-19 vaccinations, a diverse range of ophthalmic symptoms was observed in various locations and at different times, mirroring the ocular symptoms experienced throughout the course of the COVID-19 illness. It is important for physicians of all specialties to be aware of possible potential connections between eye diseases and SARS-CoV-2, in order to effectively diagnose and treat patients.

Collateral after Splenic Vein Thrombosis

A 46-year-old man presented to the emergency department because of relapsing abdominal pain in the left abdominal quadrants. At admission, he was in good general condition and his vital signs were normal. The only abnormal laboratory findings were a C-reactive protein of 30 mg/L and thrombocytes of 127 G/L. An abdominal computed tomography (CT) scan showed a thrombosis of the distal splenic vein (panel A, double arrow) with the presence of a superior and an inferior spleno-mesenteric collateral (panel A, asterisks). The axial CT scan (panel V, arrows) and Doppler sonography (panel C) showed that the thick collaterals developed below the abdominal wall. A gastroscopy showed stage I fundic varices, but no esophageal varices. (1-10) This patient was diagnosed with a smoldering multiple myeloma 5 years earlier with regular follow-up in the hemato-oncology department. No other pro-thrombotic conditions were found and in a follow-up CT scan 6 months later the findings were un-changed despite anticoagulation. Splenic vein thrombosis is frequently diagnosed in the chronic stage, when collaterals have already developed (11-18). In this case, the presence of two major spontaneous shunts between the splenic vein and the superior mesenteric vein is preventing complications (19-23) such as porto-systemic encephalopathy and variceal bleeding

Study of Platelet Indices as a Predictive Parameter for Diabetic Complications in Type II Diabetes Mellitu-A Cross Sectional Study

Introduction: Diabetes Mellitus is a prothrombotic state with enhanced platelet activity. The enhanced platelet activity may result in the development of microvascular and macrovascular complications. Platelet indices i.e. Mean Platelet volume (MPV), Platelet Distribution Width (PDW) are routinely available in alllaboratories and can be used to study as a prognostic marker for the patients. Aim: To evaluate platelet indices in patients with type 2 diabetes mellitus. Methods and Material: Cross sectional study was conducted in the Department of Pathology at a tertiary care centre over a period of 18 months. Samples of 120 patients of type 2 diabetes with and without complicationswere investigated. Haematological (platelet count and platelet indices i.e. Mean platelet indices and Platelet distribution width) and biochemical parameters (Fasting blood sugar and HbA1c) were compared between diabetic patients with and without complications. Platelet indices were measured using automated haematology analyser. Statistical evaluation was performed using SPSS version 16.0. Results: In DM with complication17 (28.33%) out of 60 cases were between the age group of 51-60 years, 14 (23.33%) out 60 belonged to the age group of 61-70 years and 12 (20%) patients were >70 years of age. The mean platelet volume was 12.74±3.076 and 8.65±1.58 for diabetes with and without complications. The mean platelet distribution width was 15.54 and 13.94±2.66 for diabetes with and without complications. The mean HbA1c was 8.33 and 6.75 for diabetes with and without complications. The mean platelet count was 3.12 Lac/mm3 and 2.45 Lac/mm3 for diabetes with and without complications. The mean fasting blood sugar was 219.65 and 109.96 for diabetes with and without complications. Conclusion: Diabetes is responsible for endothelial dysfunction and platelet hyperactivity. In our study, diabetic patients with uncontrolled glycaemic index and raised fasting blood sugar level had raised platelet indices in comparison to patients without complication where the platelet count, platelet indices level and glycaemic index were within normal limits. These indices can also be used as a prognostic tool.

Protein C deficiency with venous and arterial thromboembolic events

Protein C (PC) is a key component of the vitamin K-dependent coagulation pathway. It exerts anticoagulant effects by inactivating factors V and VIII. Acquired or inherited PC deficiency results in a prothrombotic state, with presentations varying from asymptomatic to venous thromboembolism. However, there has been an increasing number of reports linking PC deficiency to arterial thromboembolic events, such as myocardial infarction and ischemic stroke. This editorial focuses on the association between PC deficiency and thromboembolism, which may provide some insights for treatment strategy and scientific research.

Demography and Etiology of Ischemic Stroke in 18–45 Years

Introduction: The objective of our study was to examine the clinical characteristics and underlying risk factors of acute ischemic stroke in patients aged 18–45. Materials and Methods: We prospectively studied etiology of patients aged 18–45 with acute ischemic stroke presenting to our hospital from September to December of the following year. We aimed for 80% statistical power at a 5% significance level with a precision of 0.15, which led us to a calculated sample size of 39. Results: Fifty patients were observed. The main risk factors identified were alcohol use (36%), smoking (30%), and hypertension (22%). Prothrombotic states were found to be a significant risk factor in cases where the stroke’s origin was undetermined. The most common stroke subtype was large-artery atherosclerosis, which was followed by strokes with other underlying causes. There was a statistically significant association between hypertension and ischemic stroke subtypes ( P = 0.01). Hypertension was associated with small-vessel disease (92.3%) and strokes with undetermined causes (56.5%), with P = 0.023 and P <0.001, respectively. Conclusions: Hypertension was associated with multiple stroke subtypes in young individuals. Therefore, it is essential to strictly control hypertension through antihypertensive therapy and lifestyle changes. As alcohol use and smoking are becoming more prevalent among young individuals, early implementation of awareness programs targeting primary stroke prevention is highly desirable.

Platelet, Antiplatelet Therapy and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

Thrombosis in severely ill patients admitted in ICU due to COVID-19 pneumonia. Data from a Greek Hospital

Background: SARS-CoV-2 can lead to a prothrombotic state and the activation of the body's coagulation mechanism, resulting in thrombotic episodes, especially in critically ill patients. The rates of thromboembolic disease in patients with COVID-19 vary and range from 10-40%, while in Greece the existing epidemiological data on the incidence of thromboembolic disease in the ICU are limited. Aim This study aimed to determine the proportion of hospitalized COVID-19 patients who developed thromboembolic disease (pulmonary embolism, deep vein thrombosis, or arterial embolism). It was also crucial to investigate at the relationship between the incidence of VTE (venothrombosis-VTE) and Covid infection in ICU patients. After 28 days from ICU admission, the survival rate of patients with Covid infection admitted to ICUs within the specified time frame was also noted. Method and Material: The study included 85 patients with Covid-19 infection who were hospitalized in two ICU departments in a large adult hospital in Athens between June and September 2021. The occurrence of VTE was diagnosed by computed tomography angiography, regarding the pulmonary embolism and with triplex veins of the lower extremities. Various epidemiological factors, laboratory findings and characteristics of the patients' hospitalization in the Intensive Care Unit were recorded. Results: The incidence of VTE in patients with Covid-19 infection admitted to the Intensive Care Unit was 14% (12/85 patients). Patients who experienced VTE during their hospitalization in the Intensive Care Unit had more days on mechanical ventilation support, more days on vasoconstrictor drugs, and had been transfused more times with blood plasma. In the multivariate analysis that followed, it was found that total days of mechanical ventilation (p=0.02), total days of vasoconstrictor administration (p=0.03) and plasma transfusion (p=0.03) were still statistically significant. Conclusion: In patients with Covid-19 infection and hospitalization in the Intensive Care Unit, longer stay on mechanical respiratory support, more days of vasoconstrictor drug administration and plasma administration are independent predisposing factors for the occurrence of VTE.

RhoA/rho kinase pathway activation in age-associated endothelial cell dysfunction and thrombosis.

The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.

Right heart overload – possible long-term sequelae of Covid-19: a narrative review

The United Nations announced the COVID-19 Pandemic in March 2019, and since then, many efforts have been made to understand better the multiple consequences of the virus on one's health. Notably, such viral infection leads to an increase in the formation of thrombi and microthrombi. However, mechanisms are not precise yet, neither are these complication consequences and management. It is essential to acknowledge these aspects of the disease, so patients receive better health care when dealing with COVID-19. This article's extensive search involved PubMed, SCOPUS, Cochrane, and Google Scholar databases; authors used keywords to find relevant studies on the subject. SARS-CoV2 creates a pro-thrombotic state through direct endothelial damage and a cytokine storm, affecting the lung, among other organs, leading to hypoxia and a rise in vascular resistance. Increased vascular resistance makes patients prone to cardiac stress, with a known association with right heart failure, among other insults to the heart. This condition affects both outpatients and inpatients, hypertension being a significant risk factor. The cardiac damage can be observed by cardiac injury biomarkers, imaging, and heart failure symptoms. Considering the massive number of infected during the pandemic, we suggest that right heart failure secondary to increased vascular resistance in the COVID/post-COVID state presents as a long-term sequel of the infection. Moreover, we believe it deserves attention so that patients may receive early and adequate health care.

Elevated factor XI is associated with recurrent left ventricular thrombus of unknown origin.

Elevated factor XI (FXI) has been shown to predispose to thromboembolism. We investigated whether it is associated with left ventricular thrombus (LVT) formation, its recurrence and subsequent thromboembolic events. In 54 patients with prior LVT of unknown origin, who stopped anticoagulation and 54 controls, we determined FXI, along with plasma clot permeability (Ks), fibrinolysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (vWF) and fibrinolysis proteins. During follow-up, the primary endpoint involving the recurrence of LVT a symptomatic ischemic stroke or systemic embolism was recorded. Elevated (>120%) FXI levels were more often observed in LVT patients when compared to the control group (14 [25.9%] vs. 6 [11.1%], p = .048) in association with the presence of active FXI. FXI correlated with age (r = .406, p = .002), Ks (r = -.542, p < .001) and CLT (r = .406, p = .002), also after adjustment for age, but not with ETP, vWF or fibrinolysis proteins. During follow-up of 77.6 ± 18.5 months the primary endpoint occurred in 17 (31.5%) LVT patients, including 11 (20.4%) recurrent LVT, and in 4 (7.4%) controls (annual incidence rate 4.9% vs. 1.1%, respectively; p = .002). On multivariate logistic regression analysis, elevated FXI was independently associated with the primary endpoint (OR 1.18; 95% CI 1.09-1.28). Elevated FXI in association with a prothrombotic state characterizes patients with prior LVT of unknown origin and predisposes to its recurrence and/or ischemic stroke during follow-up. It might be speculated that the measurement of FXI helps identify patients who could benefit from prolonged anticoagulation and FXI inhibitors in the future.

Acute and subacute effects of strenuous exercise on platelet aggregation, coagulation and fibrinolysis in patients with stable coronary artery disease

IntroductionStrenuous exercise may occasionally cause coronary thrombosis with myocardial infarction and sudden cardiac death. Materials and methodsPatients with stable coronary artery disease (CAD) (n = 164) and healthy individuals (n = 25) performed strenuous exercise on a bicycle ergometer. Blood was drawn at baseline, immediately after exercise and 2 h later. Platelet aggregation was measured with Multiplate® Analyzer. Thrombin generation was determined using a thrombogram and by measuring prothrombin fragment 1 + 2 (F1 + 2). A clot lysis assay was used to investigate fibrinolysis. ResultsFrom baseline to immediately after exercise, thrombin receptor activating peptide (TRAP)-induced platelet aggregation increased in CAD patients (Δ77 AU × min, 95 % confidence interval (CI): 46;107) and in healthy individuals (Δ153 AU × min, 95%CI: 75;232). Endogenous thrombin potential (ETP) was unaffected by exercise, whilst F1 + 2 increased (Δ17%, 95%CI: 11;24) in CAD patients. Fibrin clot lysis time increased by 9 % (95%CI: 1–17) in CAD patients and by 26 % (95%CI: 8;45) in healthy individuals. When comparing baseline to 2 h post-exercise, TRAP-induced platelet aggregation remained slightly elevated in both CAD patients (Δ53 AU × min, 95%CI: 22;84) and healthy individuals (Δ140 AU × min, 95%CI: 62;219). In contrast, ETP and F1 + 2 decreased in CAD patients (Δ-6 %, 95%CI: −10;-1 and Δ-8 %, 95%CI: -14;-2). Moreover, clot lysis time decreased (Δ-19 %, 95%CI: −27;-11) in patients with CAD and returned to baseline in healthy individuals. All p-values were <0.05. ConclusionsPlatelet aggregation and F1 + 2 were substantially elevated immediately after exercise in CAD patients, indicating a pro-thrombotic state. After 2 h of recovery, they exhibited a markedly increase in fibrinolysis. Similar results were observed in healthy individuals.

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F-mediated phosphatidylserine exposure.

Oxidized low-density lipoprotein(oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL-induced human aortic endothelial cells (HAECs) and high-fat diet (HFD)-fed mice as a hyperlipidemia model. Phosphatidylserine(PS) exposure, cytosolic Ca2+, reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity(PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL-inducedPS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL-induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantlyinhibited PS exposure in oxLDL-induced HAECs. Moreover, we observed that HFD-fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3-induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F-mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.