Background: Fractional-dosed intradermal (i.d.) vaccination produces antibody concentrations above the proposed proxy for protection against severe disease as compared with intramuscular (i.m.)... Show moreBackground: Fractional-dosed intradermal (i.d.) vaccination produces antibody concentrations above the proposed proxy for protection against severe disease as compared with intramuscular (i.m.) vaccination and may be associated with a decreased prothrombotic effect. Objectives: To assess changes in coagulation following standard dosed i.m. or fractional-dosed i.d. (one-fifth of i.m.) mRNA-1273 SARS-CoV-2 vaccine and to determine the association between the inflammatory response and coagulation. Methods: This study was embedded in a randomized controlled trial assessing the immunogenicity of an i.d. fractional-dosed mRNA-1273 vaccine. Healthy participants, aged 18 to 30 years, were randomized (2:1) to receive either 2 doses of i.d. or i.m. vaccine. Blood was drawn prior to first and second vaccination doses and 1 and 2 weeks after the second dose. The outcomes were changes in coagulation parameters (primary endpoint peak height of the thrombin generation curve) and inflammation (highsensitivity C-reactive protein [hs-CRP]). Results: One hundred twenty-three participants were included (81 i.d.; 42 i.m.). Peak height increased after vaccination (i.m., 28.8 nmol; 95% CI, 6.3-63.8; i.d., 17.3 nmol; 95% CI, 12.5-47.2) and recovered back to baseline within 2 weeks. I.m. vaccination showed a higher inflammatory response compared with i.d. vaccination (extra increase hs-CRP, 0.92 mg/L; 95% CI, 0.2-1.7). Change in endogenous thrombin potential was associated with change in hs-CRP (beta, 28.0; 95% CI, 7.6-48.3). Conclusion: A transient increase in coagulability after mRNA-1273 SARS-CoV-2 vaccination occurred, which was associated with the inflammatory response. While i.d. administration showed antibody concentrations above the proposed proxy for protection against severe disease, it was associated with less systemic inflammation. Hence, i.d. vaccination may be safer Show less
Lopuhaä, B.V.; Guzel, C.; Lee, A. van der; Bosch, T.P.P. van den; Kemenade, F.J. van; Huisman, M.; ... ; Thüsen, J.H. von der 2024
AimsCOVID-19 pneumonia is characterized by an increased rate of deep venous thrombosis and pulmonary embolism. To better understand the pathophysiology behind thrombosis in COVID-19, we performed... Show moreAimsCOVID-19 pneumonia is characterized by an increased rate of deep venous thrombosis and pulmonary embolism. To better understand the pathophysiology behind thrombosis in COVID-19, we performed proteomics analysis on SARS-CoV-2 infected lung tissue.MethodsLiquid chromatography mass spectrometry was performed on SARS-CoV-2 infected postmortem lung tissue samples. Five protein profiling analyses were performed: whole slide lung parenchyma analysis, followed by analysis of isolated thrombi and endothelium, both stratified by disease (COVID-19 versus influenza) and thrombus morphology (embolism versus in situ). Influenza autopsy cases with pulmonary thrombi were used as controls.ResultsCompared to influenza controls, both analyses of COVID-19 whole-tissue and isolated endothelium showed upregulation of proteins and pathways related to liver metabolism including urea cycle activation, with arginase being among the top upregulated proteins in COVID-19 lung tissue. Analysis of isolated COVID-19 thrombi showed significant downregulation of pathways related to platelet activation compared to influenza thrombi. Analysis of isolated thrombi based on histomorphology shows that in situ thrombi have significant upregulation of coronavirus pathogenesis proteins.ConclusionsThe decrease in platelet activation pathways in severe COVID-19 thrombi suggests a relative increase in venous thromboembolism, as thrombi from venous origin tend to contain fewer platelets than arterial thrombi. Based on histomorphology, in situ thrombi show upregulation of various proteins related to SARS-CoV-2 pathogenesis compared to thromboemboli, which may indicate increased in situ pulmonary thrombosis in COVID-19. Therefore, this study supports the increase of venous thromboembolism without undercutting the involvement of in situ thrombosis in severe COVID-19.A decrease in platelet activation pathways in COVID-19 thrombi suggests a relative increase in venous thromboembolism, as thrombi from venous origin tend to contain fewer platelets than arterial thrombi. In situ thrombi show upregulation of SARS-CoV-2 pathogenesis proteins compared to thromboemboli, underscoring the significance of in situ pulmonary thrombosis in COVID-19. image Show less
Persistence of serum antiphospholipid antibodies (aPL) is associated with a high thrombotic risk, both arterial and venous, and with pregnancy complications. Due to the potential morbidity and... Show morePersistence of serum antiphospholipid antibodies (aPL) is associated with a high thrombotic risk, both arterial and venous, and with pregnancy complications. Due to the potential morbidity and mortality associated with the presence of aPL, identifying and recognizing risk factors for the development of aPL and thrombosis in aPL carriers may help to prevent and reduce the burden of disease. Multiple elements are involved in the pathomechanism of aPL development and aPL-related thrombosis such as genetics, malignancy, and infections. This review will address the role of both well-known risk factors and their evolution, and of emerging risk factors, including COVID-19, in the development of aPL and thrombosis in aPL carriers. Show less
Cohen, A.T.; Creeper, K.J.; Alikhan, R.; Er, C.; Connors, J.M.; Huisman, M.V.; ... ; Becattini, C. 2024
Background In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated... Show moreBackground In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE.Methods The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding.Results In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group.Conclusion The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE. Show less
The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play... Show moreThe Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ- specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/ or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of- the- art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i. e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID- 19-associated coagulopathy is revisited. Show less
Bhoelan, S.; Howard, J.B.; Tichelaar, V.; Daele, P. van; Hak, L.; Voskuyl, A.; ... ; Meijer, K. 2022
BackgroundRecurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. AimTo determine the recurrence risk of SLE-associated VTE overall and by presence... Show moreBackgroundRecurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. AimTo determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares. MethodsA multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. ResultsEighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE. ConclusionAntiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk. 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
Wiegers, H.M.G.; Knijp, J.; Es, N. van; Coppens, M.; Moll, S.; Klok, F.A.; Middeldorp, S. 2022
Background The risk of recurrence after a venous thromboembolism (VTE) related to estrogen-containing contraceptives is a key driver to guide anticoagulant treatment decisions. Objective To... Show moreBackground The risk of recurrence after a venous thromboembolism (VTE) related to estrogen-containing contraceptives is a key driver to guide anticoagulant treatment decisions. Objective To estimate the incidence rate of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives. Methods Embase, MEDLINE, and the CENTRAL were searched from 1 January 2008 to 27 May 2021 for prospective and retrospective studies reporting on recurrence after a first VTE related to estrogen-containing contraceptives. Risk of bias was assessed using QUIPS tool. Recurrence rates per 100 patient-years were pooled using Knapp-Hartung random-effects meta-analysis. Incidence rates were reported separately based on study follow-up duration (<= 1 year, 1-5 years, and >5 years) and for several subgroups. Results A total of 4,120 studies were identified, of which 14 were included. The pooled recurrence rate was 1.57 (95%-CI: 1.10-2.23; I-2 = 82%) per 100 patient-years. Recurrence rates per 100 patient-years were 2.73 (95%-CI: 0.00-3643; I-2 = 80%) for studies with <= 1 year follow-up, 1.35 (95%-CI: 0.68-2.68; I-2 = 44%) for studies with 1-5 years follow-up, and 1.42 (95%-CI: 0.84-2.42; I-2 = 78%) for studies with >5 years follow-up. Conclusion Among women with VTE associated with estrogen-containing contraceptives, the risk of recurrence after stopping anticoagulation is low, which favors short-term anticoagulation. Large prospective studies on VTE recurrence rates and risk factors after stopping short-term anticoagulants are needed. Show less
Data regarding angiographic characteristics, clinical profile, and inhospital outcomes of patients with coronavirus disease 2019 (COVID-19) referred for coronary angiography (CAG) are scarce. This... Show moreData regarding angiographic characteristics, clinical profile, and inhospital outcomes of patients with coronavirus disease 2019 (COVID-19) referred for coronary angiography (CAG) are scarce. This is an observational study analyzing confirmed patients with COVID-19 referred for CAG from 10 European centers. We included 57 patients (mean age: 66 +/- 15 years, 82% male) , of whom 18% had previous myocardial infarction (MI) and 29% had renal insufficiency and chronic pulmonary disease. ST-segment elevation myocardial infarction (STEMI) was the most frequent indication for CAG (58%). Coronavirus disease 2019 was confirmed after CAG in 86% and classified as mild in 49%, with 21% fully asymptomatic. A culprit lesion was identified in 79% and high thrombus burden in 42%; 7% had stent thrombosis. At 40 days follow-up, 16 (28%) patients experienced a major adverse cardiovascular event (MACE): 12 deaths (92% noncardiac), 1 MI, 2 stent thrombosis, and 1 stroke. In an European multicenter registry, patients with confirmed COVID-19 infection referred for CAG during the first wave of the severe acute respiratory syndrome coronavirus 2 pandemic presented mostly with STEMI and were predominantly males with comorbidities. Severity of COVID-19 was in general noncritical and 21% were asymptomatic at the time of CAG. Culprit coronary lesions with high thrombus burden were frequently identified, with a rate of stent thrombosis of 7%. The incidence of MACE at 40 days was high (28%), mostly due to noncardiac death. Show less
Brouw, B. op den; Ghezellou, P.; Casewell, N.R.; Ali, S.A.; Fathinia, B.; Fry, B.G.; ... ; Ikonomopoulou, M.P. 2021
Venoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the... Show moreVenoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the pharmacological potential of crude Pseudocerastes and Eristicophis snake venoms in haematological disorders and cancer treatment. We assessed their antithrombotic potential using fibrinogen thromboelastography, fibrinogen gels with and without protease inhibitors, and colourimetric fibrinolysis assays. These assays indicated that the anticoagulant properties of the venoms are likely induced by the hydrolysis of phospholipids and by selective fibrinogenolysis. Furthermore, while most fibrinogenolysis occurred by the direct activity of snake venom metalloproteases and serine proteases, modest evidence indicated that fibrinogenolytic activity may also be mediated by selective venom phospholipases and an inhibitory venom-derived serine protease. We also found that the Pseudocerastes venoms significantly reduced the viability of human melanoma (MM96L) cells by more than 80%, while it had almost no effect on the healthy neonatal foreskin fibroblasts (NFF) as determined by viability assays. The bioactive properties of these venoms suggest that they contain a number of toxins suitable for downstream pharmacological development as candidates for antithrombotic or anticancer agents. Show less
To improve the quality and accuracy of the patient-reported outcome measures that assess health-related quality of life (HRQoL), guidelines have been developed to standardize the development and... Show moreTo improve the quality and accuracy of the patient-reported outcome measures that assess health-related quality of life (HRQoL), guidelines have been developed to standardize the development and validation process. Considering the increasing importance of HRQoL questionnaires in research, we set out to review the literature and evaluate whether existing questionnaires developed for deep vein thrombosis (DVT) and pulmonary embolism (PE) fulfill state-of-the-art requirements. The literature search was conducted in March 2019 and updated in September 2020. Seven databases were searched. No time limit was set for the search to include all available questionnaires. The inclusion criteria were original publications describing the development of disease-specific HRQoL questionnaires specific to DVT or PE in adults and available in English. The questionnaires were assessed to determine whether they fulfill the requirements in the latest guidelines. A total of 3826 references were identified. After the exclusion process, 15 papers were reviewed in full, of which 7 were included. Four questionnaires were developed for chronic venous disease, two were specific to DVT, and one was specific to PE. Most questionnaires we found in this review, fulfilled some but none fulfilled all recommendations in existing guidelines. Because the development of current available HRQoL questionnaires specific to DVT or PE do not fulfil all recommendations of existing guidelines, there is room for improvements within this field. Such improvements could likely enhance the quality associated with the use of these end points in clinical trials and practice. Show less
Background: Whereas accumulating studies on patients with coronavirus disease 2019 (COVID-19) report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in... Show moreBackground: Whereas accumulating studies on patients with coronavirus disease 2019 (COVID-19) report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in patients with other respiratory tract infections are lacking. How this high risk in COVID-19 patients compares to those observed in hospitalized patients with other viral pneumonias such as influenza is unknown.Objectives: To assess the incidence of venous and arterial thrombotic complications in hospitalized patients with influenza as opposed to that observed in hospitalized patients with COVID-19.Methods: This was a retrospective cohort study; we used data from Statistics Netherlands (study period: 2018) on thrombotic complications in hospitalized patients with influenza. In parallel, we assessed the cumulative incidence of thrombotic complications-adjusted for competing risk of death-in patients with COVID-19 in three Dutch hospitals (February 24 to April 26, 2020).Results: Of the 13 217 hospitalized patients with influenza, 437 (3.3%) were diagnosed with thrombotic complications, versus 66 (11%) of the 579 hospitalized patients with COVID-19. The 30-day cumulative incidence of any thrombotic complication in influenza was 11% (95% confidence interval [CI], 9.4-12) versus 25% (95% CI, 18-32) in COVID-19. For venous thrombotic (VTC) complications and arterial thrombotic complications alone, these numbers were, respectively, 3.6% (95% CI, 2.7-4.6) and 7.5% (95% CI, 6.3-8.8) in influenza versus 23% (95% CI, 16-29) and 4.4% (95% CI, 1.9-8.8) in COVID-19.Conclusions: The incidence of thrombotic complications in hospitalized patients with influenza was lower than in hospitalized patients with COVID-19. This difference was mainly driven by a high risk of VTC complications in the patients with COVID-19 admitted to the Intensive Care Unit. Remarkably, patients with influenza were more often diagnosed with arterial thrombotic complications. Show less
Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to... Show moreGlucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self-controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3 center dot 51 [95% confidence interval (CI) 2 center dot 55-4 center dot 80]. This IRR was 2 center dot 53 (95% CI 1 center dot 10-5 center dot 72) in the week before treatment started, 5 center dot 28 (95% CI 2 center dot 89-9 center dot 53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1 center dot 55 (95% CI 0 center dot 85-3 center dot 12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2 center dot 72 (95% CI 1 center dot 64-4 center dot 78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription. Show less
Roth, P.; Pace, A.; Rhun, E. le; Weller, M.; Ay, C.; Moyal, E.C.J.; ... ; ESMO Guidelines Comm 2021
The incidence of venous thrombosis, mostly pulmonary embolism (PE), ranging from local immunothrombosis to central emboli, but also deep vein thrombosis (DVT) in people with coronavirus disease... Show moreThe incidence of venous thrombosis, mostly pulmonary embolism (PE), ranging from local immunothrombosis to central emboli, but also deep vein thrombosis (DVT) in people with coronavirus disease 2019 (COVID-19) is reported to be remarkably high. The relevance of better understanding, predicting, treating, and preventing COVID-19-associated venous thrombosis meets broad support, as can be concluded from the high number of research, review, and guideline papers that have been published on this topic. The Dutch COVID & Thrombosis Coalition (DCTC) is a multidisciplinary team involving a large number of Dutch experts in the broad area of venous thrombosis and hemostasis research, combined with experts on virology, critically ill patients, pulmonary diseases, and community medicine, across all university hospitals and many community hospitals in the Netherlands. Within the consortium, clinical data of at least 5000 admitted COVID-19-infected individuals are available, including substantial collections of biobanked materials in an estimated 3000 people. In addition to considerable experience in preclinical and clinical thrombosis research, the consortium embeds virology-hemostasis research models within unique biosafety facilities to address fundamental questions on the interaction of virus with epithelial and vascular cells, in relation to the coagulation and inflammatory system. The DCTC has initiated a comprehensive research program to answer many of the current questions on the pathophysiology and best anticoagulant treatment of COVID-19-associated thrombotic complications. The research program was funded by grants of the Netherlands Thrombosis Foundation and the Netherlands Organization for Health Research and Development. Here, we summarize the design and main aims of the research program. Show less
The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE),... Show moreThe risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods. Show less
The purpose was to compare time-based vs anti-Xa-based anticoagulation strategies in patients on ECMO. We conducted a systematic review and meta-analysis using multiple electronic databases and... Show moreThe purpose was to compare time-based vs anti-Xa-based anticoagulation strategies in patients on ECMO. We conducted a systematic review and meta-analysis using multiple electronic databases and included studies from inception to July 19, 2019. The proportion of bleeding, thrombosis, and mortality were evaluated. Twenty-six studies (2,086 patients) were included. Bleeding occurred in 34.2% (95%CI 25.1;43.9) of the patients with anti-Xa-based versus 41.6% (95%CI 24.9;59.4) of the patients with time-based anticoagulation strategies. Thrombosis occurred in 32.6% (95%CI 19.1;47.7) of the patients with anti-Xa-based versus 38.4% (95%CI 22.2;56.1) of the patients with time-based anticoagulation strategies. And mortality rate was 35.4% (95%CI 28.9;42.1) of the patients with anti-Xa-based versus 42.9% (95%CI 36.9;48.9) of the patients with time-based anticoagulation strategies. Among the seven studies providing results from both anticoagulation strategies, significantly fewer bleeding events occurred in the anti-Xa-based anticoagulation strategy (adjusted OR 0.49 (95%CI 0.32;0.74),p < 0.001) and a significantly lower mortality rate (adjusted OR 0.61 (95%CI 0.40;0.95),p = 0.03). There was no significant difference in thrombotic events (adjusted OR 0.91 (95%CI 0.56;1.49),p = 0.71). In these seven observational studies, only a small fraction of the patients were adults, and data were insufficient to analyze the effect of the type of ECMO. In this meta-analysis of observational studies of patients on ECMO, an anti-Xa-based anticoagulation strategy, when compared to a time-based strategy, was associated with fewer bleeding events and mortality rate, without an increase in thrombotic events. Show less
Background and Purpose-If a relationship between stroke etiology and thrombus computed tomography characteristics exists, assessing these characteristics in clinical practice could serve as a... Show moreBackground and Purpose-If a relationship between stroke etiology and thrombus computed tomography characteristics exists, assessing these characteristics in clinical practice could serve as a useful additional diagnostic tool for the identification of stroke subtype. Our purpose was to study the association of stroke etiology and thrombus computed tomography characteristics in patients with acute ischemic stroke due to a large vessel occlusion.Methods-For 1429 consecutive patients enrolled in the MR CLEAN Registry, we determined stroke cause as defined by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. The association of stroke etiology with the hyperdense artery sign, clot burden score, and thrombus location was estimated with univariable and multivariable binary and ordinal logistic regression. Additionally, for 367 patients with available thin-section imaging, we assessed the association of stroke etiology with absolute and relative thrombus attenuation, distance from internal carotid artery-terminus to thrombus, thrombus length, and thrombus attenuation increase with univariable and multivariable linear regression.Results-Compared with cardioembolic strokes, noncardioembolic strokes were associated with presence of hyperdense artery sign (odds ratio, 2.2 [95% CI, 1.6-3.0]), lower clot burden score (common odds ratio, 0.4 [95% CI, 0.3-0.6]), shift towards a more proximal thrombus location (common odds ratio, 0.2 [95% CI, 0.2-0.3]), higher absolute thrombus attenuation (beta, 3.6 [95% CI, 0.9-6.4]), decrease in distance from the ICA-terminus (beta, -5.7 [95% CI, -8.3 to -3.0]), and longer thrombi (beta, 8.6 [95% CI, 6.5-10.7]), based on univariable analysis. Thrombus characteristics of strokes with undetermined cause were similar to those of cardioembolic strokes.Conclusions-Thrombus computed tomography characteristics of cardioembolic stroke are distinct from those of noncardioembolic stroke. Additionally, our study supports the general hypothesis that many cryptogenic strokes have a cardioembolic cause. Further research should focus on the use of thrombus computed tomography characteristics as a diagnostic tool for stroke cause in clinical practice. Show less
Background Genome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot... Show moreBackground Genome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot formation upon vascular injury.Objective To further investigate the role of SLC44A2 in VT by utilizing SLC44A2 deficient mice (Slc44a2(-)(/)(-)) in two representative disease models.Methods Mice were included in a hypercoagulability model driven by siRNA-mediated hepatic gene silencing of anticoagulants Serpinc1 (antithrombin) and Proc (protein C) and a flow restriction (stenosis) model induced by partial ligation of the inferior vena cava.Results In the hypercoagulability model, no effect in onset was observed in Slc44a2(-)(/)(-) animals; however, a drop in plasma fibrinogen and von Willebrand factor coinciding with an increase in blood neutrophils was recorded. In the neutrophil dependent stenosis model after 48 hours, Slc44a2(-)(/)(-) mice had significantly smaller thrombi both in length and weight with less platelet accumulation as a percentage of the total thrombus area. During the initiation of thrombosis at 6 hours post-stenosis, Slc44a2(-)(/)(-) mice also had smaller thrombi both in length and weight, with circulating platelets remaining elevated in Slc44a2(-)(/)(-) animals. Platelet activation and aggregation under both static- and venous and arterial shear conditions were normal for blood from Slc44a2(-)(/)(-) mice.Conclusions These studies corroborate the original GWAS findings and establish a contributing role for SLC44A2 during the initiation of VT, with indications that this may be related to platelet-neutrophil interaction. The precise mechanism however remains elusive and warrants further investigation. Show less
Wiegers, E.J.A.; Mulder, M.J.H.L.; Jansen, I.G.H.; Venema, E.; Compagne, K.C.J.; Berkhemer, O.A.; ... ; Lugt, A. van der 2020
Background and Purpose-Collateral circulation status at baseline is associated with functional outcome after ischemic stroke and effect of endovascular treatment. We aimed to identify clinical and... Show moreBackground and Purpose-Collateral circulation status at baseline is associated with functional outcome after ischemic stroke and effect of endovascular treatment. We aimed to identify clinical and imaging determinants that are associated with collateral grade on baseline computed tomography angiography in patients with acute ischemic stroke due to an anterior circulation large vessel occlusion.Methods-Patients included in the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; n=500) and MR CLEAN Registry (n=1488) were studied. Collateral status on baseline computed tomography angiography was scored from 0 (absent) to 3 (good). Multivariable ordinal logistic regression analyses were used to test the association of selected determinants with collateral status.Results-In total, 1988 patients were analyzed. Distribution of the collateral status was as follows: absent (7%, n=123), poor (32%, n=596), moderate (39%, n=735), and good (23%, n=422). Associations for a poor collateral status in a multivariable model existed for age (adjusted common odds ratio, 0.92 per 10 years [95% CI, 0.886-0.98]), male (adjusted common odds ratio, 0.64 [95% CI, 0.53-0.76]), blood glucose level (adjusted common odds ratio, 0.97 [95% CI, 0.95-1.00]), and occlusion of the intracranial segment of the internal carotid artery with occlusion of the terminus (adjusted common odds ratio 0.50 [95% CI, 0.41-0.61]). In contrast to previous studies, we did not find an association between cardiovascular risk factors and collateral status.Conclusions-Older age, male sex, high glucose levels, and intracranial internal carotid artery with occlusion of the terminus occlusions are associated with poor computed tomography angiography collateral grades in patients with acute ischemic stroke eligible for endovascular treatment. Show less
