IMPORTANCE Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone... Show moreIMPORTANCE Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen.OBJECTIVE To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase.DESIGN, SETTING, AND PARTICIPANTS This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled.INTERVENTIONS Patients were randomized (1:1) to receive a bolus of 5mg of intravenous alteplase and 40mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9mg/kg of intravenous alteplase (control).MAIN OUTCOMES AND MEASURES The primary outcomewas any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors.RESULTS A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ss = 65mg/dL; 95% CI, 26-105mg/dL).CONCLUSIONS AND RELEVANCE In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04256473 Show less
Background: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong... Show moreBackground: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID-19. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear. Objective: To investigate if LA is associated with thrombosis in critically ill patients with COVID-19. Patients/Methods: The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID-19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) reagents. Results: Of 169 patients with COVID-19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1-5.7), which increased to 4.5 (95% CI, 1.4-14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3-11.4) and disappeared after adjustment for C-reactive protein. Conclusion: Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID-19, especially in patients aged less than 65 years. Show less
The presence of blood flow influences the interaction between von Willebrand factor (VWF) and blood cells, affecting characteristics of forming blood clots. The interactions between coagulation and... Show moreThe presence of blood flow influences the interaction between von Willebrand factor (VWF) and blood cells, affecting characteristics of forming blood clots. The interactions between coagulation and inflammation have mainly been studied in thrombosis models, but it remains unclear whether these interactions might also play a role in reduced bleeding in patients with bleeding disorders. In this systematic review, we provide an overview of the literature investigating the interactions between VWF and blood cells in flow models. For article selection, a systematic search was performed in Embase, Medline-Ovid, Cochrane Library, Web of Science databases, and Google Scholar. After selection, 24 articles were included. These articles describe direct or platelet-dependent interactions between VWF and neutrophils, monocytes, erythrocytes, or lymphocytes under different flow conditions. Almost all the described interactions required the presence of activated platelets. Only erythrocytes, monocytes, and natural killer cells were capable of directly binding the VWF multimers. Overall, interactions between VWF and blood cells mainly occurred in the presence of platelets. Because of the large variation in study design and used flow rates, further research is necessary to compare the results between studies and draw firm conclusions on when and under what conditions these interactions can occur. After our findings, many questions remained unanswered. This review might provide a starting point for future research. Extended knowledge on the influence of blood flow on VWF and blood cell interactions can contribute to improved understanding of the variation in bleeding in patients with bleeding disorders. Show less
Background Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an... Show moreBackground Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an integrated interdisciplinary national research program. Objectives The SYMPHONY consortium strives to orchestrate personalized treatment in patients with an inborn bleeding disorder, by unraveling the mechanisms behind interindividual variations of bleeding phenotype. Patients The SYMPHONY consortium will investigate patients with an inborn bleeding disorder, both diagnosed and not yet diagnosed. Results Research questions are categorized under the themes: (1) diagnosis, (2) treatment, and (3) fundamental research, and consist of work packages addressing specific domains. Importantly, collaborations between patients and talented researchers from different areas of expertise promise to augment the impact of the SYMPHONY consortium, leading to unique interactions and intellectual property. Conclusions SYMPHONY will perform research on all aspects of care, treatment individualization in patients with inborn bleeding disorders, as well as diagnostic innovations and results of molecular genetics and cellular model technology with regard to the hemostatic process. We believe that these research investments will lead to health-care innovations with long-term clinical and societal impact. This consortium has been made possible by a governmental, competitive grant from the Netherlands Organization for Scientific Research (NWO) within the framework of the NWA-ORC Call grant agreement NWA.1160.18.038. Show less
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... Show moreBackground: 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 Syn-drome 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. Lon-gitudinal 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. Show less
Tahitu, M.; Ramler, P.I.; Gillissen, A.; Caram-Deelder, C.; Henriquez, D.D.C.A.; Maat, M.P.M. de; ... ; Bom, J.G. van der 2021
Introduction: Coagulopathy may be the result of hyperfibrinolysis and could exacerbate bleeding following childbirth. Timely recognition of hyperfibrinolysis during the earliest stages of... Show moreIntroduction: Coagulopathy may be the result of hyperfibrinolysis and could exacerbate bleeding following childbirth. Timely recognition of hyperfibrinolysis during the earliest stages of postpartum hemorrhage could identify women at risk of more severe blood loss who may benefit from targeted anti-fibrinolytic therapy. Rotational thromboelastometry (ROTEM (R)) is a point-of-care test that could detect hyperfibrinolysis. The aim of this study was to evaluate whether early assessment of hyperfibrinolysis by ROTEM during postpartum hemorrhage could predict progression to severe postpartum hemorrhage.Material and methods: During a prospective cohort study in the Netherlands among women with postpartum hemorrhage (total blood loss at least 1000 ml within 24 h after childbirth) ROTEM measurements were performed following 800-1500 ml of blood loss. Hyperfibrinolysis was defined as an enzymatic fibrinolysis index (ROTEM EXTEM maximum clot lysis [ML] minus the ROTEM APTEM ML) above 15%. Severe postpartum hemorrhage was defined as a composite end point of total blood loss greater than 2000 ml, transfusion of four or more units of packed cells, and/or need for an invasive intervention. The predictive value of hyperfibrinolysis for progression to severe postpartum hemorrhage was assessed by area under the receiver operating curve ( AUC) and positive and negative predictive values.Trial registration: ClinicalTrials. gov (NCT02149472).Results: Of 390 women included, 82 (21%) had severe postpartum hemorrhage. Four (1%) women had thromboelastometric evidence of hyperfibrinolysis, of whom two developed severe postpartum hemorrhage. The AUC for enzymatic fibrinolysis index more than 15% for progression to severe postpartum hemorrhage was 0.47 (95% CI 0.40-0.54). Positive and negative predictive values for this index were 50.0% (95% CI 6.8-93.2) and 79.3% (95% CI 74.9-83.2), respectively.Conclusions: Thromboelastometric evidence of hyperfibrinolysis was rare in women with postpartum hemorrhage when assessed between 800 and 1500 ml of blood loss. The clinical predictive value of viscoelastometric point-of-care testing for hyperfibrinolysis for progression to severe postpartum hemorrhage during early postpartum hemorrhage is limited. Show less
Ramler, P.I.; Gillissen, A.; Henriquez, D.D.C.A.; Caram-Deelder, C.; Markovski, A.A.; Maat, M.P.M. de; ... ; Bom, J.G. van der 2021
Introduction To evaluate rotational fibrin-based thromboelastometry (ROTEM(R) FIBTEM) with amplitude of clot firmness at 5 min (A5) as an early point-of-care parameter for predicting progression to... Show moreIntroduction To evaluate rotational fibrin-based thromboelastometry (ROTEM(R) FIBTEM) with amplitude of clot firmness at 5 min (A5) as an early point-of-care parameter for predicting progression to severe postpartum hemorrhage, and compare its predictive value with that of fibrinogen.Material and methods Prospective cohort study in the Netherlands including women with 800-1500 ml of blood loss within 24 h following birth. Blood loss was quantitatively measured by weighing blood-soaked items and using a fluid collector bag in the operating room. Both FIBTEM A5 values and fibrinogen concentrations (Clauss method) were measured between 800 and 1500 ml of blood loss. Predictive accuracy of both biomarkers for the progression to severe postpartum hemorrhage was measured by area under the receiver operating curves (AUC). Severe postpartum hemorrhage was defined as a composite endpoint of (1) total blood loss >2000 ml, (2) transfusion of >= 4 packed cells, and/or (3) need for an invasive intervention to cease bleeding.Results Of the 391 women included, 72 (18%) developed severe postpartum hemorrhage. Median (IQR) volume of blood loss at blood sampling was 1100 ml (1000-1300) with a median (interquartile range [IQR]) fibrinogen concentration of 3.9 g/L (3.4-4.6) and FIBTEM A5 value of 17 mm (13-20). The AUC for progression to severe postpartum hemorrhage was 0.53 (95% confidence interval [CI] 0.46-0.61) for FIBTEM A5 and 0.58 (95% CI 0.50-0.65) for fibrinogen. Positive predictive values for progression to severe postpartum hemorrhage for FIBTEM A5 <= 12 mm was 22.5% (95% CI 14-33) and 50% (95% CI 25-75) for fibrinogen <= 2 g/L.Conclusions The predictive value of FIBTEM A5 compared to fibrinogen concentrations measured between 800 and 1500 ml of blood loss following childbirth was poor to discriminate between women with and without progression towards severe postpartum hemorrhage. Show less
Boender, J.; Atiq, F.; Cnossen, M.H.; Bom, J.G. van der; Fijnvandraat, K.; Meris, J. de; ... ; Leebeek, F.W.G. 2021
Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting... Show moreVon Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], P < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], P < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], P < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: beta = -7.6 (-13.0 to -2.1), P = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients. Show less
Background: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF... Show moreBackground: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD.Objectives: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD.Methods: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score.Results: ADAMTS-13 activity was similar in individuals with VWD (109% +/- 20.6%) and controls (110% +/- 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, -0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, -2.1% to 4.9%).Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD. Show less
Moort, I. van; Bukkems, L.H.; Heijdra, J.M.; Schutgens, R.E.G.; Laros-van Gorkom, B.A.P.; Nieuwenhuizen, L.; ... ; OPTI-CLOT Study Grp 2020
Background von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is... Show moreBackground von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting. Aim To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial. Methods Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding. Results Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8-60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery (p < 0.001). Lowest VWF:Ag quartile (0.43-0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2-50 mL/h) compared with highest VWF antigen quartile (1.70-3.84 IU/mL). VWF levels were not associated with perioperative bleedingF(4,227) = 0.54,p = 0.710. Conclusion VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage. Show less
We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce... Show moreWe conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non-rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8 center dot 75 min (95% CI -13 center dot 8 to -3 center dot 72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (-0 center dot 05 U/ml; 95% CI -0 center dot 07 to -0 center dot 02 and -4 center dot 77%; 95% CI -6 center dot 81 to -2 center dot 73, respectively). PAI-1 levels did not change and fibrinogen levels were 0 center dot 17 g/l (95% CI 0 center dot 04-0 center dot 29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non-statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE. Show less
The bleeding phenotype of patients with type 1 von Willebrand disease (VWD) is very heterogeneous. We hypothesized that this heterogeneity may partly be explained by variability in response of von... Show moreThe bleeding phenotype of patients with type 1 von Willebrand disease (VWD) is very heterogeneous. We hypothesized that this heterogeneity may partly be explained by variability in response of von Willebrand factor (VWF) and factor VIII (FVIII) levels to stress during hemostatic challenges. We therefore investigated whether VWF and FVIII levels after administration of desmopressin, which mimic in vivo hemostatic response during hemostatic challenges, explain the heterogeneity in bleeding phenotype of patients with type 1 VWD. We performed a retrospective cohort study in 122 patients with type 1 VWD. All patients received a test dose of desmopressin shortly after diagnosis. Patients' mean age was 47 = 14 years, and the mean Tosetto bleeding score was 10 +/- 7. Higher FVIII activity during the complete time course after desmopressin administration (1, 3, and 5-6 hours), and higher VWF and FVIII levels combined at 3 hours after desmopressin administration, were associated with a lower bleeding score: beta = -0.9 (-1.7; -0.1) and beta = -1.2 (-1.9; -0.5), respectively, adjusted for age, sex, body mass index (BMI), and comorbidities. Patients with FVIII activity in the highest quartile 3 hours after desmopressin administration had a much lower bleeding score compared with patients in the other 3 quartiles (beta = -5.1 1-8.2; -2.01) and also had a lower chance of an abnormal bleeding score (odds ratio - 0.210.1-0.51), both adjusted for age, sex, BMI, and comorbidities. In conclusion, VWF and FVIII levels after desmopressin administration, which mimic hemostatic response to hemostatic challenges, are associated with the bleeding phenotype of patients with type 1 VWD. This may partly explain the variability in bleeding phenotype of these patients. Show less
BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and... Show moreBackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies. Show less
Haemostatic treatment in women experiencing postpartum haemorrhage is increasingly based on point-of-care devices such as ROTEM (R) thromboelastometry. Recently, a fully automated successor of the... Show moreHaemostatic treatment in women experiencing postpartum haemorrhage is increasingly based on point-of-care devices such as ROTEM (R) thromboelastometry. Recently, a fully automated successor of the ROTEM (R) Delta device, the ROTEM (R) Sigma was introduced. To determine whether these devices provide similar results, we compared ROTEM (R) parameters using the ROTEM (R) Delta and Sigma devices in women experiencing postpartum haemorrhage. Prospective observational cohort study of 23 women experiencing postpartum haemorrhage. ROTEM (R) INTEM, EXTEM, FIBTEM and APTEM measurements handled by the ROTEM (R) Delta and Sigma devices were compared. ROTEM (R) FIBTEM values were also related to Clauss fibrinogen values. A correlation of Spearman's r (r(s)) varying between 0.76 and 0.95 was displayed between clot firmness measured in millimeters at 5 (A5), 10 (A10) and 20 (A20) minutes after start of clot formation measured by EXTEM, INTEM and APTEM assays executed on both devices; A5, A10 and A20 of FIBTEM correlated less well (r(s) between 0.71 and 0.74), especially after five and ten minutes. Correlation between both devices regarding clotting time (CT) was poor. The observed correlation between levels of Clauss fibrinogen and FIBTEM A5 was r(s) = 0.70, (95% confidence interval (CI): 0.38 to 0.87) for Delta and r(s) = 0.85, (CI 0.65 to 0.94) for Sigma. A5, A10 and A20 measured in EXTEM, INTEM and APTEM obtained from ROTEM (R) Delta and Sigma devices were similar. EXTEM, FIBTEM and APTEM CT values from both devices showed no correlation. Substantial variation was found between FIBTEM assays of the devices. Consequently, results of FIBTEM assays should always be interpreted in the context of device-specific reference values. Correlation with Clauss fibrinogen was better in the ROTEM (R) Sigma device. Show less
Boender, J.; Eikenboom, J.; Bom, J.G. van der; Meijer, K.; Meris, J. de; Fijnvandraat, K.; ... ; WiN Study Grp 2018
