Oral Anticoagulants Beyond Warfarin.

Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.

Cellular Components Contributing to the Development of Venous Thrombosis in Patients with Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE.

The effect of current antithrombotic therapy on mortality in nursing home residents with COVID-19: a multicentre retrospective cohort study.

BACKGROUND: The first wave of COVID led to an alarmingly high mortality rate among nursing home residents (NHRs). In hospitalised patients, the use of anticoagulants may be associated with a favourable prognosis. However, it is unknown whether the use of antithrombotic medication also protected NHRs from COVID-19-related mortality. OBJECTIVES: To investigate the effect of current antithrombotic therapy in NHRs with COVID-19 on 30-day all-cause mortality during the first COVID-19 wave. METHODS: We performed a retrospective cohort study linking electronic health records and pharmacy data in NHRs with COVID-19. A propensity score was used to match NHRs with current use of therapeutic dose anticoagulants to NHRs not using anticoagulant medication. The primary outcome was 30-day all-cause mortality, which was evaluated using a logistic regression model. In a secondary analysis, multivariable logistic regression was performed in the complete study group to compare NHRs with current use of therapeutic dose anticoagulants and those with current use of antiplatelet therapy to those without such medication. RESULTS: We included 3521 NHRs with COVID-19 based on a positive RT-PCR for SARS-CoV-2 or with a well-defined clinical suspicion of COVID-19. In the matched propensity score analysis, NHRs with current use of therapeutic dose anticoagulants had a significantly lower all-cause mortality (OR = 0.73; 95% CI: 0.58-0.92) compared to NHRs who did not use therapeutic anticoagulants. In the secondary analysis, current use of therapeutic dose anticoagulants (OR: 0.62; 95% CI: 0.48-0.82) and current use of antiplatelet therapy (OR 0.80; 95% CI: 0.64-0.99) were both associated with decreased mortality. CONCLUSIONS: During the first COVID-19 wave, therapeutic anticoagulation and antiplatelet use were associated with a reduced risk of all-cause mortality in NHRs. Whether these potentially protective effects are maintained in vaccinated patients or patients with other COVID-19 variants, remains unknown.

Incidence and predictors of post-thrombotic syndrome in patients with proximal DVT in a real-world setting: findings from the GARFIELD-VTE registry.

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient's self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician's evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection was performed using stepwise algorithm, and predictors of severe PTS were incorporated into a multivariable risk model. The optimistic adjusted c-index was calculated using bootstrapping techniques. Over 36-months, 27.8% of patients developed incident PTS (mild in 18.7%, moderate in 5.7%, severe in 3.4%). Patients with incident PTS were older, had a lower prevalence of transient risk factors of DVT and a higher prevalence of persistent risk factors of DVT. Self-assessment of overall PTS at 24 months showed an agreement of 63.4% with respect to physician's evaluations at 36 months. The severe PTS multivariable model provided an optimistic adjusted c-index of 0.68 (95% CI 0.59-0.77). Approximately a quarter of DVT patients experienced PTS over 36 months after VTE diagnosis. Patient's self-assessment after 24 months provided added value for estimating incident PTS over 36 months. Multivariable risk analysis allowed good discrimination for severe PTS.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Clinical utility of the 4S-AF scheme in predicting progression of atrial fibrillation: data from the RACE V study.

AIMS: The recent 4S-AF (scheme proposed by the 2020 ESC AF guidelines to address stroke risk, symptom severity, severity of AF burden and substrate of AF to provide a structured phenotyping of AF patients in clinical practice to guide therapy and assess prognosis) scheme has been proposed as a structured scheme to characterize patients with atrial fibrillation (AF). We aimed to assess whether the 4S-AF scheme predicts AF progression in patients with self-terminating AF. METHODS AND RESULTS: We analysed 341 patients with self-terminating AF included in the well-phenotyped Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilization in the Progression of AF (RACE V) study. Patients had continuous monitoring with implantable loop recorders or pacemakers. AF progression was defined as progression to persistent or permanent AF or progression of self-terminating AF with >3% burden increase. Progression of AF was observed in 42 patients (12.3%, 5.9% per year). Patients were given a score based on the components of the 4S-AF scheme. Mean age was 65 [interquartile range (IQR) 58-71] years, 149 (44%) were women, 103 (49%) had heart failure, 276 (81%) had hypertension, and 38 (11%) had coronary artery disease. Median CHA2DS2-VASc (the CHA2DS2-VASc score assesses thromboembolic risk. C, congestive heart failure/left ventricular dysfunction; H, hypertension; A2, age ≥ 75 years; D, diabetes mellitus; S2, stroke/transient ischaemic attack/systemic embolism; V, vascular disease; A, age 65-74 years; Sc, sex category (female sex)) score was 2 (IQR 2-3), and median follow-up was 2.1 (1.5-2.6) years. The average score of the 4S-AF scheme was 4.6 ± 1.4. The score points from the 4S-AF scheme did not predict the risk of AF progression [odds ratio (OR) 1.1 95% CI 0.88-1.41, C-statistic 0.53]. However, excluding the symptoms domain, resulting in the 3S-AF (4S-AF scheme without the domain symptom severity, only including stroke risk, severity of AF burden and substrate of AF) scheme, predicted the risk of progression (OR 1.59 95% CI 1.15-2.27, C-statistic 0.62) even after adjusting for sex and age. CONCLUSIONS: In self-terminating AF patients, the 4S-AF scheme does not predict AF progression. The 3S-AF scheme, excluding the symptom domain, may be a more appropriate score to predict AF progression. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov NCT02726698 for RACE V.

Pitfalls in anticoagulant-related nephropathy.

Anticoagulant-related nephropathy (ARN) is a rare but important disease and often misdiagnosed. The hallmark of the diagnosis is acute kidney injury (AKI) superimposed on preexisting kidney disease due to anticoagulation-induced glomerular hemorrhage with histologic features of widespread tubular obstruction by red blood cells and red cell casts. As ARN is a diagnosis of exclusion only proven by renal biopsy, the diagnosis is often unlikely to be confirmed histologically because of fear of biopsy-related bleeding during anticoagulant therapy. Given the large differential diagnosis in AKI, diagnosing ARN remains a challenge for clinicians. A case report and the pitfalls related to diagnosis and management will be discussed in this paper.

Longitudinal Trends in Bleeding Complications on Extracorporeal Life Support Over the Past Two Decades-Extracorporeal Life Support Organization Registry Analysis.

OBJECTIVES: Data about inhospital outcomes in bleeding complications during extracorporeal life support (ECLS) have been poorly investigated. DESIGN: Retrospective observational study. SETTING: Patients reported in Extracorporeal Life Support Organization Registry. PATIENTS: Data of 53.644 adult patients (greater than or equal to 18 yr old) mean age 51.4 ± 15.9 years, 33.859 (64.5%) male supported with single ECLS run between 01.01.2000 and 31.03.2020, and 19.748 cannulated for venovenous (V-V) ECLS and 30.696 for venoarterial (V-A) ECLS. INTERVENTIONS: Trends in bleeding complications, bleeding risk factors, and mortality. MEASUREMENT AND MAIN RESULTS: Bleeding complications were reported in 14.786 patients (27.6%), more often in V-A ECLS compared with V-V (30.0% vs 21.9%; p < 0.001). Hospital survival in those who developed bleeding complications was lower in both V-V ECLS (49.6% vs 66.6%; p < 0.001) and V-A ECLS (33.9 vs 44.9%; p < 0.001). Steady decrease in bleeding complications in V-V and V-A ECLS was observed over the past 20 years (coef., -1.124; p < 0.001 and -1.661; p < 0.001). No change in mortality rates was reported over time in V-V or V-A ECLS (coef., -0.147; p = 0.442 and coef., -0.195; p = 0.139).Multivariate regression revealed advanced age, ecls duration, surgical cannulation, renal replacement therapy, prone positioning as independent bleeding predictors in v-v ecls and female gender, ecls duration, pre-ecls arrest or bridge to transplant, therapeutic hypothermia, and surgical cannulation in v-a ecls. CONCLUSIONS: A steady decrease in bleeding over the last 20 years, mostly attributable to surgical and cannula-site-related bleeding has been found in this large cohort of patients receiving ECLS support. However, there is not enough data to attribute the decreasing trends in bleeding to technological refinements alone. Especially reduction in cannulation site bleeding is also due to changes in timing, patient selection, and ultrasound guided percutaneous cannulation. Other types of bleeding, such as CNS, have remained stable, and overall bleeding remains associated with a persistent increase in mortality.

Clinical impact of assessing thrombus age using magnetic resonance venography prior to catheter-directed thrombolysis.

OBJECTIVES: Magnetic resonance venography (MRV) is underutilized in the evaluation of thrombus properties prior to endovascular treatment but may improve procedural outcomes. We therefore investigated the clinical impact of using a dedicated MRV scoring system to assess thrombus characteristics prior to endovascular intervention for iliofemoral deep vein thrombosis (DVT). METHODS: This is a post hoc analysis of data from the CAVA trial ( Clinicaltrials.gov :NCT00970619). MRV studies of patients receiving ultrasound-accelerated catheter-directed thrombolysis (CDT) for iliofemoral DVT were reviewed. Thrombus age-related imaging characteristics were scored and translated into an overall score (acute, subacute, or old). MRV scores were compared to patient-reported complaints. MRV-scored groups were compared for CDT duration and success rate. RESULTS: Fifty-six patients (29 men; age 50.8 ± 16.4 years) were included. Using MRV, 27 thrombi were classified acute, 17 subacute, and 12 old. Based on patient-reported complaints, 11 (91.7%) of these old thrombi would have been categorized acute or subacute, and one (3.7%) of the acute thrombi as old. Average duration of CDT to > 90% restored patency differed significantly between groups (p < 0.0001): average duration was 23 h for acute thromboses (range: 19-25), 43 h for subacute (range: 41-62), and 85 h for old thromboses (range: 74-96). CDT was almost eleven times more successful in thromboses characterized as acute and subacute compared to old thromboses (OR: 10.7; 95% CI 2.1-55.5). CONCLUSION: A dedicated MRV scoring system can safely discriminate between acute, subacute, and old thromboses. MRV-based selection is predictive of procedural duration and success rate and can help avoid unnecessary complications. KEY POINTS: • Thrombus age, characterized by MRV as acute, subacute, and old, can predict CDT duration and probability of success. • Accurate pre-interventional MRV-based thrombus aging has the potential to facilitate identification of eligible patients and may thus prevent CDT-related complications.

Different circulating biomarkers in women and men with paroxysmal atrial fibrillation: results from the AF-RISK and RACE V studies.

AIMS: The clinical risk profile of atrial fibrillation (AF) patients is different in men and women. Our aim was to identify sex differences in blood biomarkers in patients with paroxysmal AF. METHODS AND RESULTS: Sex differences in 92 blood biomarkers were measured in 364 patients included in our discovery cohort, the identification of a risk profile to guide atrial fibrillation therapy (AF-RISK) study, assessed by multivariable logistic regression and enrichment pathway analysis. Findings were subsequently confirmed in 213 patients included in our validation cohort, the Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) study. In the discovery cohort, mean age was 59 ± 12 years, 41% were women. CHA2DS2-VASc-score was 1.6 ± 1.4. A total of 46% had hypertension, 10% diabetes, and 50% had heart failure, predominantly with preserved ejection fraction (47%). In women, activated leucocyte cell adhesion molecule (ALCAM) and fatty acid binding protein-4 (FABP-4) were higher. In men, matrix metalloproteinase-3 (MMP-3), C-C motif chemokine-16 (CCL-16), and myoglobin were higher. In the validation cohort, four out of five biomarkers could be confirmed: levels of ALCAM (P = 1.73 × 10-4) and FABP-4 (P = 2.46 × 10-7) and adhesion biological pathways [false discovery rate (FDR) = 1.23 × 10-8] were higher in women. In men, levels of MMP-3 (P = 4.31 × 10-8) and myoglobin (P = 2.10 × 10-4) and markers for extracellular matrix degradation biological pathways (FDR = 3.59 × 10-9) were higher. CONCLUSION: In women with paroxysmal AF, inflammatory biomarkers were more often higher, while in men with paroxysmal AF, biomarkers for vascular remodelling were higher. Our data support the clinical notion that pathophysiological mechanisms in women and men with AF may differ. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01510210 for AF-RISK; Clinicaltrials.gov NCT02726698 for RACE V.

Relationships between coagulation factors and thrombin generation in a general population with arterial and venous disease background.

BACKGROUND: The current study aims to identify the relationships between coagulation factors and plasma thrombin generation in a large population-based study by comparing individuals with a history of arterial or venous thrombosis to cardiovascular healthy individuals. METHODS: This study comprised 502 individuals with a history of arterial disease, 195 with history of venous thrombosis and 1402 cardiovascular healthy individuals (reference group) from the population-based Gutenberg Health Study (GHS). Calibrated Automated Thrombography was assessed and coagulation factors were measured by means of BCS XP Systems. To assess the biochemical determinants of TG variables, a multiple linear regression analysis, adjusted for age, sex and antithrombotic therapy, was conducted. RESULTS: The lag time, the time to form the first thrombin, was mainly positively associated with the natural coagulant and anti-coagulant factors in the reference group, i.e. higher factors result in a longer lag time. The same determinants were negative for individuals with a history of arterial or venous thrombosis, with a 10 times higher effect size. Endogenous thrombin potential, or area under the curve, was predominantly positively determined by factor II, VIII, X and IX in all groups. However, the effect sizes of the reported associations were 4 times higher for the arterial and venous disease groups in comparison to the reference group. CONCLUSION: This large-scale analysis demonstrated a stronger effect of the coagulant and natural anti-coagulant factors on the thrombin potential in individuals with a history of arterial or venous thrombosis as compared to healthy individuals, which implicates sustained alterations in the plasma coagulome in subjects with a history of thrombotic vascular disease, despite intake of antithrombotic therapy.

COVID-19 Coagulopathy: From Pathogenesis to Treatment.

Coronavirus disease 2019 (COVID-19) has emerged as a pandemic at the end of 2019 and continues to exert an unfavorable worldwide health impact on a large proportion of the population. A remarkable feature of COVID-19 is the precipitation of a hypercoagulable state, mainly in severe cases, leading to micro- and macrothrombosis, respiratory failure, and death. Despite the implementation of various therapeutic regimes, including anticoagulants, a large number of patients suffer from such serious complications. This review aims to describe the current knowledge on the pathophysiology of the coagulation mechanism in COVID-19. We describe the interplay between three important mediators of the disease and how this may lead to a hyperinflammatory and prothrombotic state that affects outcome, namely, the endothelium, the immune system, and the coagulation system. In line with the hypercoagulability state during COVID-19, we further review on the rare but severe vaccine-induced thrombotic thrombocytopenia. We also summarize and comment on available anticoagulant treatment options and include suggestions for some future treatment considerations for COVID-19 anticoagulation therapy.

Long-Term Adherence to Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Comparative Cross-Sectional Study.

BACKGROUND: Long-term treatment with direct oral anticoagulants (DOAC) is required for the majority of patients with nonvalvular atrial fibrillation (AF) to prevent ischemic stroke and systemic embolism. Adherence to therapy may impact clinical outcomes. Therefore, the purpose of this study was to assess the potential impact of structured follow-up on long-term adherence to DOAC therapy compared to standard care. METHODS: This is a cross sectional study on the implementation phase of medication adherence to DOACs, comparing patients with AF following completion of structured follow-up of minimally 1 year with those who received standard care. All patients used DOACs for more than 2 years and completed a questionnaire on adherence. Adherence was measured with the Morisky Medication Adherence Scale-8 (MMAS-8) score and assessed via an online web portal. RESULTS: A total of 212 patients were included. The mean MMAS-8 score was 7.55 (SD 0.93) after structured follow-up and 7.25 (SD 1.01) for standard care; p = 0.045. Following structured follow-up 64.1% of patients had a high adherence (MMAS score of 8) compared to 50% receiving standard care; p = 0.05. Patients following structured follow-up on a once daily DOAC regime had higher MMAS-8 scores compared to those on a twice daily regime; 7.74 (SD 0.74) versus 7.00 (SD 1.22); p < 0.001. The rates of minor bleedings were 10.6% versus 21.4% respectively, p = 0.038. CONCLUSION: In patients on long-term DOAC treatment, adherence to therapy was significantly increased after receiving an initial period of structured follow-up compared to standard care. Additionally, adherence to DOAC therapy was higher with once-daily treatment regimen. Significant more minor bleedings were reported in the standard care group. These results indicate that implementation of structured follow-up of patients with AF using DOACs merits further evaluation.

HEROES V-A: HEmoRrhagic cOmplications in veno-arterial Extracorporeal life Support: Development and internal validation of a multivariable prediction model in adult patients.

BACKGROUND: Risk factors for bleeding complications during extracorporeal life support (ECLS) indicated for cardiac support remain poorly investigated. The aim is to develop and internally validate a prediction model to calculate the risk for bleeding complications in adult patients receiving veno-arterial (V-A) ECLS. METHODS: Data of the Extracorporeal Life Support Organization registry of adult patients undergoing V-A ECLS between 2010 and 2020 were analyzed. The primary outcome was bleeding complications recorded during V-A ECLS. Multivariable logistic regression with backward stepwise elimination was used to develop the prediction model. Performance of the model was tested by discriminative ability and calibration with receiver operator characteristic, area under the curve, and visual inspection of the calibration plot. Internal validation was performed to detect overfitting of the model. RESULTS: In total 28 767 adult patients were included, of which 29.0% developed bleeding complications. Sex, body mass index, surgical cannulation, pre-ECLS respiratory and hemodynamic variables, pre-ECLS support and interventions, and different type of diagnosis were included in the prediction model. This prediction model showed a predictive capability with an AUC of 0.66. CONCLUSION: The model is based on the largest cohort of V-A ECLS patients and is the best available predictive model for bleeding events given the predictors that are available in V-A ECLS compared to current literature. The model can help in identifying patients at high risk for bleeding complications and will help in developing further research and decision-making in terms of anticoagulation management. External validation is warranted to extrapolate this model in the clinical setting.

HEROES V-V-HEmorRhagic cOmplications in Veno-Venous Extracorporeal life Support-Development and internal validation of multivariable prediction model in adult patients.

BACKGROUND: During extracorporeal life support (ECLS), bleeding is one of the most frequent complications, associated with high morbidity and increased mortality, despite continuous improvements in devices and patient care. Risk factors for bleeding complications in veno-venous (V-V) ECLS applied for respiratory support have been poorly investigated. We aim to develop and internally validate a prediction model to calculate the risk for bleeding complications in adult patients receiving V-V ECLS support. METHODS: Data from adult patients reported to the extracorporeal life support organization (ELSO) registry between the years 2010 and 2020 were analyzed. The primary outcome was bleeding complications recorded during V-V ECLS. Multivariable logistic regression with backward stepwise elimination was used to develop the predictive model. The performance of the model was tested by discriminative ability and calibration with receiver operating characteristic curves and visual inspection of the calibration plot. RESULTS: In total, 18 658 adult patients were included, of which 3 933 (21.1%) developed bleeding complications. The prediction model showed a prediction of bleeding complications with an AUC of 0.63. Pre-ECLS arrest, surgical cannulation, lactate, pO2 , HCO3 , ventilation rate, mean airway pressure, pre-ECLS cardiopulmonary bypass or renal replacement therapy, pre-ECLS surgical interventions, and different types of diagnosis were included in the prediction model. CONCLUSIONS: The model is based on the largest cohort of V-V ECLS patients and reveals the most favorable predictive value addressing bleeding events given the predictors that are feasible and when compared to the current literature. This model will help identify patients at risk of bleeding complications, and decision making in terms of anticoagulation and hemostatic management.

Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1.

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the 'supernatant of (hirudin-treated) coagulated plasma' (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin αIIbß3 activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.

Plasma Biomarkers to Predict Cardiovascular Outcome in Patients With Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events. Numerous plasma biomarkers have been investigated in lower extremity PAD, but none are used for clinical risk assessment. We aimed to provide a comprehensive overview of biomarker testing in PAD as a first step to improve risk stratification. Approach and Results: A systematic literature review in MEDLINE/PubMed, Cochrane, and Embase was performed, identifying all studies investigating plasma biomarkers in association with cardiovascular events and mortality in lower extremity PAD. Forty-seven studies comprising 21 473 PAD patients met our criteria and were included. Effect estimates were provided by the studies based on a minimum follow-up of 1 year. Meta-analyses were performed by pooling studies per biomarker for each end point. Patients with increased high-sensitivity CRP (C-reactive protein) levels had a relative risk of 1.86 (1.48-2.33) for major adverse cardiovascular events and a relative risk of 3.49 (2.35-5.19) for mortality. Increased fibrinogen and d-dimer levels were associated with an increased relative risk of mortality of 2.08 (1.46-2.97) and 2.22 (1.24-3.98), respectively. Additionally, patients with increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cTnT (cardiac troponin T) levels were at an even higher risk of mortality with relative risks of 4.50 (2.98-6.81) and 3.33 (2.70-4.10), respectively. CONCLUSIONS: This systematic review identifies promising biomarkers representing different pathophysiological processes implicated in lower extremity PAD, including high-sensitivity CRP, neutrophil-lymphocyte ratio, fibrinogen, d-dimer, NT-proBNP, and high-sensitivity cTnT. Clinical implementation should be preceded by a management study to test the utility of a combination of these markers for individual risk stratification. Ultimately, this may contribute to tailored treatment and increased effectiveness of current treatment strategies in PAD.

Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX.

OBJECTIVES: FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. CONCLUSIONS: We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

Potential value of the calibrated automated thrombogram in patients after a cerebral venous sinus thrombosis; an exploratory study.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a relatively rare, but potentially lethal condition. In approximately 15% of the patients, the cause of CVST remains unclear. Conventional clotting tests such as prothrombin time and activated partial thromboplastin time are not sensitive enough to detect prothrombotic conditions nor mild haemostatic abnormalities. The calibrated automated thrombogram (CAT) is a physiological function test that might be able to detect minor aberrations in haemostasis. Therefore, we aimed to detect the presence of a prothrombotic state in patients who endured idiopathic CVST with the CAT assay. METHODS: Five adult patients with an idiopathic, radiologically proven CVST that had been admitted during the past 3 years were included in this study. The control group consisted of five age/gender matched healthy volunteers. Exclusion criteria were known haematological disorders, malignancy (current/past) or hormonal and anticoagulant therapy recipients. We obtained venous blood samples from all participants following cessation of anticoagulation. Using the CAT assay, we determined lag time, normalized endogenous thrombin potential (ETP), ETP reduction and normalized peak height. In addition, prothrombin concentrations were determined. RESULTS: We found no significant differences in lag time (4.7 min [4.5-4.9] vs 5.3 min [3.7-5.7], p = 0.691), normalized ETP (142% [124-148] vs 124% [88-138], p = 0.222), ETP reduction (29% [26-35] vs 28% [24-58], p > 0.999), and normalized peak height (155% [153-175] vs 137 [94-154], p = 0.056) between patients and their age/gender matched controls. In addition, prothrombin concentrations did not significantly differ between patients and controls (120% [105-132] vs 127% [87-139], p > 0.999). CONCLUSION: Reasons for absent overt hypercoagulability within this study population may be the small patient sample, long time since the event (e.g. 3 years) and avoidance of acquired risk factors like oral contraception. Given the fact that CVST is a serious condition with a more than negligible risk of venous thrombosis event recurrence, exclusion of clinically relevant hypercoagulability remains a challenging topic to further study at the acute and later time points, particularly in patients with idiopathic CVST.