Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants

Spronk, Henri M. H.; Jong, Anne Margreet De; Crijns, Harry J.; Schotten, Ulrich; Gelder, Isabelle C. Van; Cate, Hugo Ten

doi:10.1093/cvr/cvt343

Cited by 126 publications

(90 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, the direct cellular effects of thrombin and factor Xa are responsible for several proatherogenic processes and these additional actions of thrombin and the other coagulation proteins open opportunities for therapeutic modulation. In particular, the potential to attenuate thrombo‐inflammation by direct anticoagulants in the setting of secondary prevention of atherothrombotic events (see below), seems of interest …”

Section: Pathophysiologymentioning

confidence: 99%

See 1 more Smart Citation

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

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.

show abstract

Section: Pathophysiologymentioning

confidence: 99%

“…In particular, the potential to attenuate thrombo-inflammation by direct anticoagulants in the setting of secondary prevention of atherothrombotic events (see below), seems of interest. 28…”

Section: Par Activationmentioning

confidence: 99%

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…To demonstrate the use of protease activity as probabilistic bbits to solve inference problems, we designed probabilistic circuits by leveraging protease promiscuity. Protease promiscuity occurs under multi-target (i.e., a single protease cutting multiple substrates) and common-target (i.e., multiple proteases cutting the same substrate) settings, and is a fundamental feature that allows proteases to carry out distinct physiological functions 26 (e.g., coagulation proteases control the formation of fibrin clots as well as the expression of adhesion molecules and cytokines 40 ) ( Fig S9E ). To create two-state probabilistic bbits, we considered the superposed activity of a single protease cleaving two distinct substrates, and defined the probability of the protease to be found in state 0 (cleaving substrate 1) or state 1 (cleaving substrate 2) by the relative cleavage velocity for either substrate 41 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteases as Biological Bits for Programmable Medicine

Holt

Kwong

2019

Preprint

View full text Add to dashboard Cite

12Engineered biocircuits that interface with living systems as plug-and-play constructs may enable 13 new applications for programmable therapies and diagnostics. We create biological bits (bbits) 14 using proteasesa family of pleiotropic, promiscuous enzymesto construct the biological 15 equivalent of Boolean logic gates, comparators and analog-to-digital converters. We use these 16 modules to write a cell-free bioprogram that can combine with bacteria-infected blood, quantify 17 infection burden, and then calculate and unlock a selective drug dose. Inspired by probabilistic 18 computing, we leverage multi-and common-target protease promiscuity as the biological analog 19 of superposition to program three probabilistic bbits that solve all implementations of the two-bit 20 oracle problem, Learning Parity with Noise. Treating a network of dysregulated proteases in a 21 living animal as an oracle, we use this algorithm to resolve the probability distribution of 22 coagulation proteases in vivo, allowing diagnosis of pulmonary embolism with high sensitivity and 23 specificity (AUROC = 0.92) in a mouse model of thrombosis. Our results demonstrate that 24 protease activity can be programmed in cell-free systems to carry out classical and probabilistic 25

show abstract

“…In addition to their pro-coagulation properties, factor Xa and thrombin have pleiotropic effects on inflammatory processes, tissue remodelling and development of atherosclerosis [9,10]. Both factors bind and activate protease-activated receptors (PARs).…”

Section: Coagulation Linked To Inflammationmentioning

confidence: 99%