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Introduction: Introducing point-of-care (POC) INR measurement to monitor anticoagulant therapy may be beneficial for both patients and anticoagulation clinics. However, agreement between POC and laboratory INR results is still unclear, especially at sub- and supratherapeutic levels. Therefore we investigated the analytical and clinical agreement between POC INR results of the Coaguchek XS and laboratory INR results of the STA-R Evolution. Materials and Methods: Paired POC and laboratory INR results were obtained and analyzed in 3257 patients aged 18-104 years between August 2008 and March 2014. Results: Mean difference between POC and laboratory results ranged from − 0.18 (95%CI − 0.20;-0.16) INR point for POC results 2.0-3.0, up to 1.14 (95%CI 0.87;1.42) INR point for POC results 7.1-8.0. In the therapeutic range (POC INR 2.0-4.0), mean difference between POC and laboratory results was − 0.13 (95%CI − 0.15;-0.12) INR point. At subtherapeutic (POC INR < 2.0) and supratherapeutic (POC INR > 4.0) INR levels, mean differences were − 0.13 (95%CI − 0.15;-0.11) and 0.72 (95%CI 0.63;0.80) INR point, respectively. Clinical agreement regarding therapeutic range was present in 92.0% (POC within range), 67.7% (POC below range) and 87.6% (POC above range) of the paired measurements. We observed ≥ 15% INR difference between the POC and laboratory result in 14.8% (POC INR 2.0-4.0), 17.0% (POC INR < 2.0) and 47.8% (POC INR > 4.0) of the paired measurements. Conclusions: POC and laboratory INR results were strongly correlated within the therapeutic range and differences between results become larger with increasing INR. Clinical disagreement between laboratory and POC results occurs often at both sub- and supratherapeutic INR levels. [ABSTRACT FROM AUTHOR]

Introduction Increased fibrinogen is associated with cardiovascular disease risk. It is, however, not known to what extend environmental and genetic factors and/or their interaction influence changes in total and γ' fibrinogen over time. We aimed to determine how variation within the fibrinogen gene as well as environmental factors influence the change in total and γ' fibrinogen over time, and also whether gene-environment interactions influence total and γ' fibrinogen on a cross-sectional and prospective level in Africans. Materials and methods This prospective study consisted of 2010 participants at baseline and 1288 participants at follow-up (5 years). Results The gene-environment interactions that were associated with fibrinogen concentration on a cross-sectional level were: FGA 2224 G>A (rs2070011) with age (p = 0.005), FGB Arg 448 Lys (rs4220) with HIV status (p < 0.0001) and FGB 1038 G>A (rs1800791) with HbA1c (p = 0.01). The only factor that independently influenced the change in total fibrinogen levels over time, was baseline CRP (p < 0.0001) and FGG 10034 C>T (rs2066865) was the only single nucleotide polymorphism that independently influenced the change in fibrinogen γ' levels over time (p = 0.02). Only the FGG 9340 T>C (rs1049636) with HbA1c interaction was found to predict change in total fibrinogen concentrations over time (p = 0.005). Conclusions Gene-environment interactions influenced fibrinogen levels cross-sectionally and also mediated changes in levels over time. Highlights • gene-environment interactions that influenced total fibrinogen cross-sectionally • gene-environment interactions that influenced total fibrinogen prospectively. •a genetic polymorphism that influenced the change in fibrinogen γ' over time. [ABSTRACT FROM AUTHOR]

Background: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection., Objectives: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis., Material and Methods: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed., Results: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation., Conclusions: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Understanding the underlying mechanisms in ischemic stroke (IS) in young adults remains challenging. Thrombin activates processes that contribute to the development and progression of arterial diseases. We investigated the association between thrombin generation (TG) and a first IS or transient ischemic attack (TIA) in young adults., Methods: In this case-control study, we included consecutive patients (≤45 years in men, ≤55 years in women) with a first IS or TIA (n = 160) and healthy controls (n = 160). TG was determined with the calibrated automated thrombogram (CAT) assay. Logistic regression was used to analyze the association between TG and IS. Men and women were analyzed separately., Results: TG started earlier, reached its peak earlier and was also terminated earlier in patients than in healthy controls. Peak height (PH) was higher in patients than in controls, 227 nM (25th-75th percentile 145-326) versus 179 nM (110-294), p = 0.02. The endogenous thrombin potential (ETP) was not different in patients and controls, 1530 nM·min (1089-2045) versus 1454 nM·min (1011-2139), p = 0.52. Lag time (LT) (Odds Ratio (OR) 0.91 (95% confidence interval (CI) 0.83-0.99)), time to peak (TTP) (OR 0.91, 95% CI 0.84-0.97) and time to tail (TTT) (OR 0.92, 95% CI 0.88-0.97) were associated with a first IS and TIA. In men LT, TTP and TTT were associated with IS, but not in women., Conclusions: We found that TG parameters are associated with a first IS in young patients. Further prospective studies are warranted to elucidate the role of TG in IS., (Copyright © 2021. Published by Elsevier Ltd.)

Background: While fibrinogen is a known cardiovascular disease (CVD) risk marker, its quantitative input to mortality risk is a topic of debate., Methods: We investigated the contribution of fibrinogen, among that of other biomarkers, to prevalent CVD and incident CVD mortality in 4487 participants of the US National Health and Nutrition Examination Survey (NHANES). Participants were observed for a median period of 14 years, resulting in more than 58,000 person-years., Results: At baseline 551 participants had CVD and during follow up, 1339 all-cause deaths occurred, 321 (24%) of which were due to CVD. Hierarchical cluster analysis and principal component analysis (PCA) were performed to derive clusters of association between biomarkers. Next, structural equation modelling was performed to investigate the association of these clusters with baseline CVD and all-cause and CVD mortality during follow-up. Mediation analysis was used to determine which biomarkers played a mediatory role between prevalent CVD and future mortality. Fibrinogen clustered with C-reactive protein only and was associated with CVD at baseline (p < 0.0001) and with all-cause (p < 0.001) and CVD (p < 0.001) mortality at follow-up. Only fibrinogen (4.7%), followed by gamma-glutamyl transferase (GGT) (3.5%) and uric acid (2.3%) were identified as possible mediators between CVD status and all-cause mortality, with fibrinogen (3.2%) and GGT (3.1%) the only mediators between CVD status and CVD mortality., Conclusion: This data shows that fibrinogen is not only cross-sectionally associated with CVD, but also contributes to all-cause and CVD mortality at follow-up. It furthermore appears to mediate the association between prevalent CVD and both all-cause and CVD mortality., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH)., Materials and Methods: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, β-antithrombin and anti-Xa activities were measured., Results: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R = 0.77) and LMWH (R = 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%., Conclusions: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Issues with laboratory measurement of dabigatran include: 1. Do coagulation assays reflect dabigatran plasma concentrations? 2. Do samples from patients treated with dabigatran have the same coagulability as dabigatran-spiked samples from healthy volunteers? 3. What is the long-term stability of dabigatran after storage at -80 °C? This study aims to evaluate these questions., Materials and Methods: Ecarin chromogenic assay (ECA), a laboratory-developed diluted thrombin time (LD-dTT), prothrombin time (PT) and activated partial thromboplastin time (APTT) and ROTEM® were used to measure dabigatran anticoagulant activity and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure dabigatran plasma concentrations. ROTEM® (EXTEM, INTEM, FIBTEM) was performed in whole blood and the other assays in platelet poor plasma (PPP), both in samples spiked with dabigatran (0, 25, 50, 100, 250, 500 and 1000 ng/mL) from healthy donors and in ex vivo samples from patients treated with dabigatran etexilate. Citrated PPP samples were frozen and stored at -80 °C, 1, 3, 6 and 12 months until analysis., Results: EXTEM and FIBTEM clotting time (CT), ECA and LD-dTT correlate well with dabigatran plasma concentrations. With the exception of few ROTEM® parameters, there were no differences between spiked and patient samples. Samples were stable for at least 12 months at -80 °C., Conclusions: EXTEM and FIBTEM CT, ECA and LD-dTT are suitable for measuring the effect of dabigatran in treated patients. In general, results from spiked plasma samples are similar to those of patient samples. Storage of dabigatran plasma samples for up to 12 months does not influence measured levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The fibrin matrix of the thrombus that is formed directly after wounding, is an important determinant of the success of the early phase of wound healing. This phase is often impaired in patients with diabetes. A promising approach to improve skin wound healing is the application of a pro-angiogenic fibrin matrix onto the wound. We studied this in 59 female WAG/RijCrl diabetic rats, in which we created two dorsal full-thickness wounds of which one was treated with a human physiological fibrin matrix (2mg/ml) and one with PBS as control. Wound healing parameters were determined at different time points. The wound closure was significantly improved in fibrin-treated wounds on day 3 and 7. Also, fibrin-treated wounds showed a significantly higher perfusion on day 28 and 35 compared to control wounds (p<0.05). CD68 staining revealed that human fibrin did not induce an immune response., In Conclusion: the application of a fibrin matrix on a diabetic wound showed improved perfusion and an increased early closure rate of the wound area., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Previous studies suggested that hypofibrinolysis is associated with increased risk of peripheral arterial disease. Thrombin activatable fibrinolysis inhibitor (TAFI) has been identified as an important inhibitor of fibrinolysis. The aim of our study was to assess the role of TAFI in young patients with peripheral arterial disease., Methods: In a single-center case-control study we measured plasma TAFI antigen levels and functional TAFI in consecutive young patients (men 18-45 years and women 18-55 years) with a first manifestation of peripheral arterial disease and compared these with a population-based control group., Results: A total of 47 peripheral arterial disease patients and 141 controls (mean age 43) were included. Intact TAFI antigen levels were significantly higher in patients with peripheral arterial disease (112.4±21.1%) than in controls (104.9±19.9%, p=0.03). The risk of peripheral arterial disease increased with 18% (OR 1.18; CI 1.01-1.34) per 10% increase of TAFI antigen. Functional TAFI levels were slightly higher in patients compared to controls, however this difference was not significant. For individuals with the highest functional TAFI levels, above the 90th percentile, the increased risk for peripheral arterial disease was most pronounced (OR 3.1; CI 1.02-9.41)., Conclusion: High TAFI levels are associated with increased risk of premature peripheral arterial disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)