C-reactive protein, immunothrombosis and venous thromboembolism

Abstract

C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP). with the latter two being destabilized isoforms possessing highly pro-inflammatory features. pCRP* and mCRP have significant biological effects in regulating many of the aspects central to pathogenesis of atherothrombosis and venous thromboembolism (VTE), by directly activating platelets and triggering the classical complement pathway. Importantly, it is now well appreciated that VTE is a consequence of thromboinflammation. Accordingly, acute VTE is known to be associated with classical inflammatory responses and elevations of CRP, and indeed VTE risk is elevated in conditions associated with inflammation, such as inflammatory bowel disease, COVID-19 and sepsis. Although the clinical data regarding the utility of CRP as a biomarker in predicting VTE remains modest, and in some cases conflicting, the clinical utility of CRP appears to be improved in subsets of the population such as in predicting VTE recurrence, in cancer-associated thrombosis and in those with COVID-19. Therefore, given the known biological function of CRP in amplifying inflammation and tissue damage, this raises the prospect that CRP may play a role in promoting VTE formation in the context of concurrent inflammation. However, further investigation is required to unravel whether CRP plays a direct role in the pathogenesis of VTE, the utility of which will be in developing novel prophylactic or therapeutic strategies to target thromboinflammation.

Keywords: C-reactive protein; COVID-19; Thromboinflammation; immunothrombosis; venous thromboembolism.

Figure 1

The proposed role of CRP in immunothrombosis and VTE pathogenesis. The inciting events leading to VTE formation are endothelial inflammation with the subsequent recruitment of platelets and leukocytes. Leukocytes provide a source of tissue factor (TF) and highly activated neutrophils undergo NETosis, thereby resulting in thrombin formation and the generation of fibrin. Circulating CRP levels rapidly increase in the setting of inflammation and pCRP binds to disturbed cell surfaces, such as inflamed endothelial cells (EC) and activated platelets where it dissociates into the pro-inflammatory and pro-thrombotic isoforms pCRP* and mCRP. These pro-inflammatory isoforms amplify further activation of the endothelium, platelets and bind to complement C1q, thereby initiating complement activation. These changes result in further recruitment and activation of leukocytes ultimately leading to increased tissue TF and NET formation, thus resulting in enhanced thrombus formation. CAMs, cell adhesion molecules; EC, endothelial cells; MV, microvesicles; RBC, red blood cells; CRP, C-reactive protein; pCRP, pentameric CRP; pCRP*, neoepitope expressing pCRP; mCRP, monomeric CRP; NETs, neutrophil extracellular traps; TF, tissue factor.