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
Background Atrial fibrillation (AF) can lead to the loss of microvascular integrity thereby enhancing AF progression. Mechanistically, the pro-coagulant state that drives the risk of stroke in... Show moreBackground Atrial fibrillation (AF) can lead to the loss of microvascular integrity thereby enhancing AF progression. Mechanistically, the pro-coagulant state that drives the risk of stroke in patients with AF may also play a causal role in microvascular loss. Direct oral anticoagulants (DOACs), the preferred anticoagulants for AF, can target factors upstream (factor Xa [FXa]) or downstream (thrombin) in the coagulation cascade and mediate differential vascular effects through interaction with protease-activated receptors (PARs). Objective To investigate the potential effect of different DOACs on vascular integrity. Methods To model the impact of DOACs on vascular integrity, we utilized platelet-free plasma in thrombin generation assays and endothelial barrier assays under identical experimental conditions. These multifactorial systems provide all coagulation factors and their respective natural inhibitors in physiological ratios in combination with the pro-coagulant endothelial surface on which coagulation is initiated. Furthermore, the system provides pro- and anti-barrier factors and monitoring both assays simultaneously permits coupling of thrombin kinetics to endothelial barrier dynamics. Results We provide evidence that the anti-FXa DOAC rivaroxaban and the anti-thrombin DOAC dabigatran are efficient in blocking their target proteases. However, while rivaroxaban could preserve endothelial barrier function, dabigatran failed to protect endothelial integrity over time, which could be prevented in the presence of a custom-made peptide that blocks thrombin's exosite-I. Conclusions Proteolytically inactive thrombin in complex with dabigatran evokes loss of barrier function that can be prevented by a protease-activated receptor-1 mimicking peptide blocking thrombin's exosite-I. Show less
Purpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping... Show morePurpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations. Methods This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18-50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-beta; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort. Results rHuEPO increased P-selectin (+ 7.8% (1.5-14.5),p = 0.02) and E-selectin (+ 8.6% (2.0-15.7),p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0-24.3%),p = 0.0004) higher E-selectin and 32.1% ((4.6-66.8%),p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group. Conclusion In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use. Show less
Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on... Show moreThrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism. Show less
Heestermans, M.; Salloum-Asfar, S.; Streef, T.; Laghmani, E.; Salvatori, D.; Luken, B.M.; ... ; Vlijmen, B.J.M. van 2019
Tissue factor, coagulation factor XII, platelets, and neutrophils are implicated as important players in the pathophysiology of (experimental) venous thrombosis (VT). Their role became evident in... Show moreTissue factor, coagulation factor XII, platelets, and neutrophils are implicated as important players in the pathophysiology of (experimental) venous thrombosis (VT). Their role became evident in mouse models in which surgical handlings were required to provoke VT. Combined inhibition of the natural anticoagulants antithrombin (Serpinc1) and protein C (Proc) using small interfering RNA without additional triggers also results in a venous thrombotic phenotype in mice, most notably with vessel occlusion in large veins of the head. VT is fatal but is fully rescued by thrombin inhibition. In the present study, we used this VT mouse model to investigate the involvement of tissue factor, coagulation factor XII, platelets, and neutrophils. Antibody-mediated inhibition of tissue factor reduced the clinical features of VT, the coagulopathy in the head, and fibrin deposition in the liver. In contrast, genetic deficiency in, and small interfering RNA-mediated depletion of, coagulation factor XII did not alter VT onset, severity, or thrombus morphology. Antibodymediated depletion of platelets fully abrogated coagulopathy in the head and liver fibrin deposition. Although neutrophils were abundant in thrombotic lesions, depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, thrombus morphology, or liver fibrin deposition. In conclusion, VT after inhibition of antithrombin and protein C is dependent on the presence of tissue factor and platelets but not on coagulation factor XII and circulating neutrophils. This study shows that distinct procoagulant pathways operate in mouse VT, dependent on the triggering stimulus. Show less
Spronk, H.M.H.; Padro, T.; Siland, J.E.; Prochaska, J.H.; Winters, J.; Wal, A.C. van der; ... ; Cate, H. ten 2018
