Coagulation proteases and cardiovascular disease

There is increasing interest in the many possible mechanisms through which co-agulation proteases may promote arterial cardiovascular disease (CVD). Athero-sclerosis and thrombosis are the principal pathologies underlying coronary heart dis-ease (CHD), ischaemic stroke, and periph-eral arterial disease (PAD) (1). Circulating coagulation proteases (as well as their final substrate, fibrinogen) may be biomarkers for risk of arterial thrombosis and throm-bo-embolism; and may also influence the structure of fibrin clots and thrombi (2). Both coagulant and anticoagulant pro-teases can influence multiple cells in the vessel wall and in vital organs; and hence can influence processes including haemo-stasis, atherosclerosis, ischaemia and reper-fusion injury, inflammation, organ and vessel remodelling, and fibrosis (3) (Figure 1). Selective anticoagulation with new agents which target specific proteases has increased knowledge of this multitude of physiological and pathological actions; and clinical trials of NOACs (non-vitamin K-dependent oral anticoagulants; also re-ferred to as DOACs, for direct oral antico-agulants) have shown reduction in risk of major bleeding compared to traditional vit-amin K antagonists (VKAs), especially in intracranial bleeding; but in some trials in-creased risk of gastro-intestinal bleeding (4). These results require explanation of the possible mechanisms for organ-specific haemostasis.For this theme issue of the journal, we invited experts in several of these areas to provide brief reviews.Lowe and Rumley review evidence from prospective epidemiological studies for as-sociations of circulating levels of coagu-lation proteases, fibrinogen, and activation markers of coagulation and fibrinolysis with risk of CVD (5). To date, plasma fibri-nogen shows the strongest and most con-sistent associations with CVD; however, genetic studies do not support causality, and there is limited evidence that lowering fibrinogen levels reduces CVD risk. These associations may result from up-regulation of pro-inflammatory cytokines such as in-terleukin-6. In contrast, the common gen-etic polymorphisms for factors II, V and the von Willebrand factor:FVIII complex (non-O blood group) show associations with CHD risk, consistent with potential causal roles in arterial thrombosis, as with venous thrombosis. The associations of fi-brin D-dimer and tissue plasminogen acti-vator (t-PA) antigen levels with CHD risk are consistent with potential roles for acti-vation of coagulation, fibrinolysis and en-dothelial cells.Bjorkqvist et al. review in vivo activation and functions of the protease factor XII (FXII), the principal initiator of the contact system of coagulation, and an initiator of fibrinolysis and the classic complement system pathway of inflammation (6). They conclude that FXII influences thrombotic risk without altering haemostasis, and also plays a role in inflammation, sepsis and hereditary angioedema. These properties have renewed interest in FXII inhibition as a therapeutic strategy to treat aberrant vas-cular leakage and thrombotic disorders.Rezaie reviews protease-activated recep-tor (PAR) signalling by coagulation pro-teases in endothelial cells. PAR 1–4 are G-protein coupled receptors which can be specifically activated by thrombin and all vitamin K-dependent coagulation pro-teases (except FIXa) (7). While activation of PAR1 by thrombin induces pro-inflam-matory signaling responses, its activation by activated protein C (APC) elicits anti-inflammatory responses in cultured en-dothelial cells. Recombinant APC has been used as a therapeutic drug for treatment of adults with severe sepsis.Mosnier et al. review cytoprotective APC therapy for ischaemic stroke. APC is not only a natural anticoagulant, but also conveys multiple cytoprotective effects on many different cell types that involve multiple receptors including PAR1, PAR3, and the endothelial protein C receptor (EPRC) (7). Application of molecular en-gineered APC variants to rodent stroke models demonstrated that the beneficial ef-fects of APC require its cytoprotective ac-tivities but not its anticoagulant activities. The cytoprotective selective APC variant, 3K3A-APC is currently undergoing clinical trials in ischaemic stroke.Antoniak et al. review the role of tissue factor (TF)-FVII(a) activation of PARs in pathologic heart remodeling associated with myocardial infarction, viral myocardi-tis and hypertension (8). Cardiomyocyte TF is essential to maintain heart haemo-stasis. TF-dependent activation of coagu-lation and activation of PARs contribute to initial size of myocardial infarction, as well as pathologic heart remodelling including hypertrophic growth of cardiomyocytes and fibrosis.Bridge et al. review the associations of clot properties and CVD. Fibrin clot struc-ture is altered by levels of fibrinogen, thrombin, but also by metabolic disturb-ances including diabetes mellitus and hy-perhomocystinaemia; as well as treatment with aspirin, anticoagulants, statins and fi-brates (9). Change in fibrin clot structure in vitro, to a denser clot with smaller pores, which is more resistant to lysis, is strongly