Coagulation factor and protease pathways in thrombosis and cardiovascular disease

Cate, Hugo Ten; Hackeng, Tilman M.; Frutos, Pablo García de

doi:10.1160/th17-02-0079

Cited by 66 publications

(38 citation statements)

References 70 publications

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“…Adapted from Weitz, JI. Thromb Haemost 2014;112:924–31 and Ten Cate, H. Thromb Haemost 2017;117:1265–71 . PAR, protease‐activated receptor; TF, tissue factor; vWF, von Willebrand factor…”

Section: Pathophysiologymentioning

confidence: 99%

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

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Essentials A State of the Art lecture “Clotting factors and atherothrombosis” was presented at the ISTH congress 2017.Coagulation proteins are not only involved in hemostasis, they also play a role in atherogenesis.Inhibition of coagulation proteins could potentially protect the vessel wall against progression of atherosclerosis.Combining antiplatelet and anticoagulant therapy has been demonstrated to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Clinical manifestations of atherosclerotic disease include coronary artery disease (CAD), peripheral artery disease (PAD), and stroke. Although the role of platelets is well established, evidence is now accumulating on the contribution of coagulation proteins to the processes of atherosclerosis and atherothrombosis. Coagulation proteins not only play a role in fibrin formation and platelet activation, but also mediate various biological and pathophysiologic processes through activation of protease‐activated‐receptors (PARs). Thus far, secondary prevention in patients with CAD/PAD has been the domain of antiplatelet therapy, however, residual atherothrombotic risks remain substantial. Therefore, combining antiplatelet and anticoagulant therapy has gained more attention. Recently, net clinical benefit of combining aspirin with low‐dose rivaroxaban in patients with stable atherosclerotic disease has been demonstrated. In this review, based on the State of the Art lecture “Clotting factors and atherothrombosis” presented at the ISTH Congress 2017, we highlight the role of coagulation proteins in the pathophysiology of atherothrombosis, and specifically focus on therapeutic strategies to decrease atherothrombotic events by optimization of vascular protection.

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Section: Pathophysiologymentioning

confidence: 99%

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

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“…One of the most well studied aptamers is HD1, an aptamer targeting the exosite I moiety of thrombin (an important haemostatic protein) that was first described in 1992 [ 10 ]. Thrombin is central to the blood coagulation process, cleaving fibrinogen to fibrin, which forms the basis of a blood clot, amongst a number of other important activation steps [ 11 ]. The discovery of HD1 was soon followed by the development of a second thrombin targeting aptamer in 1997, HD22, which targets exosite II of the thrombin molecule [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Construction of a Bivalent Thrombin Binding Aptamer and Its Antidote with Improved Properties

Hughes

Gilmore

et al. 2017

Molecules

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Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson–Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of the human thrombin molecule, respectively, have been extensively studied due to their anticoagulant potentials. However, a fundamental issue preventing the clinical translation of many aptamers is degradation by nucleases and reduced pharmacokinetic properties requiring higher dosing regimens more often. In this study, we have chemically modified the design of previously described thrombin binding aptamers targeting exosites I, HD1, and exosite II, HD22. The individual aptamers were first modified with an inverted deoxythymidine nucleotide, and then constructed bivalent aptamers by connecting the HD1 and HD22 aptamers either through a triethylene glycol (TEG) linkage or four consecutive deoxythymidines together with an inverted deoxythymidine nucleotide at the 3′-end. The anticoagulation potential, the reversal of coagulation with different antidote sequences, and the nuclease stability of the aptamers were then investigated. The results showed that a bivalent aptamer RNV220 containing an inverted deoxythymidine and a TEG linkage chemistry significantly enhanced the anticoagulation properties in blood plasma and nuclease stability compared to the existing aptamer designs. Furthermore, a bivalent antidote sequence RNV220AD efficiently reversed the anticoagulation effect of RNV220 in blood plasma. Based on our results, we believe that RNV220 could be developed as a potential anticoagulant therapeutic molecule.

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“…Previously, it was suggested that a possible reason of PC reduction after bariatric surgery is due to a vitamin K dysregulation caused by malabsorption due to the surgical procedure [ 29 ]. We therefore measured PT, as this reflects the activities of the vitamin K dependent factors VII, X and II [ 31 ]. Furthermore, a strong correlation of factor VII activity with activity of PC, was shown [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Bariatric surgery in morbidly obese individuals affects plasma levels of protein C and thrombomodulin

Rega‐Kaun

Kaun

Ebenbauer

et al. 2018

J Thromb Thrombolysis

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Obesity is associated with a prothrombotic milieu and an increased risk for thrombotic events. Bariatric surgery is the most effective treatment for obesity resulting in dramatic weight loss and reduced inflammation and extrinsic coagulation pathway activation. Blood samples were drawn from 60 patients undergoing Roux-en-Y gastric bypass surgery before and 1 year after the intervention. Protein C (PC), activated PC (APC), soluble thrombomodulin (TM), soluble E-selectin (E-Sel), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were evaluated. Both PC (187.4 ± 64.5% before surgery to 118.1 ± 48% 1 year after surgery, p < 0.001) and APC (138.7 ± 64.4% before surgery to 69.1 ± 65.7% after surgery, p < 0.001) were reduced following surgical intervention. TM showed a similar behavior with a reduction of soluble TM after the procedure from 5.7 ± 2.6 to 3.2 ± 1.4 ng/ml (p < 0.001). Similarly, soluble E-Sel was reduced after surgery from 26.6 ± 12.7 to 5.5 ± 4.1 ng/ml (p < 0.001). In contrast, aPTT was not shortened but slightly increased from 29.1 ± 4.8 s. before surgery to 31 ± 4.4 s. (p = 0.001) after surgery and levels of PT were reduced after surgery to 89.6 ± 15.5% from an initial 97.5 ± 13.5% (p < 0.001). In conclusion, we demonstrate a reduction of PC and APC 1 year after bariatric surgery accompanied by a reduction in soluble TM and soluble E-Sel. The reduction of PC and APC is not paralleled by a reduction but in contrast by a prolongation of aPTT suggesting a compensatory upregulation of PC during obesity. The reduction of TM and E-Sel might hint towards an improved endothelial function in this cohort of patients.

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Coagulation factor and protease pathways in thrombosis and cardiovascular disease

Cited by 66 publications

References 70 publications

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Construction of a Bivalent Thrombin Binding Aptamer and Its Antidote with Improved Properties

Bariatric surgery in morbidly obese individuals affects plasma levels of protein C and thrombomodulin

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