The link between coagulation and inflammation

Circumstantial evidence suggests that innate immunity and coagulation share a common evolutionary origin, which explains the extensive crosstalk between inflammatory cytokines and coagulation factors, with many components being important for both systems. The inflammatory cytokine network, when activated, induces several prothrombotic conditions such as endothelial dysfunction, tissue factor (TF) expression and coagulation activation, inhibition of fibrinolysis and the protein C system.6 Also, indirectly, there may be a link between adiposity, insulin resistance, inflammation and coagulation, since cytokines like tumour necrosis factor α (TNFα) and interleukin 6 (IL-6) are released in adipose tissue and play a large part in all the above phenomena.7 Activation of coagulation and fibrin deposition can be viewed as a part of the host defence of the body against infectious agents in an attempt to contain the invading entity, and the consequent inflammatory response, to a limited area. In addition, activation of the extrinsic coagulation system and impairment of the fibrinolytic pathway may help to perpetuate and amplify the inflammatory response.8

Other factors that also contribute to a hypercoagulable state are activated platelets and microparticles.9 ,10 All these factors together can contribute to prothrombotic conditions which enhance the thromboembolic risk in several autoimmune diseases, such as RA.

How inflammation triggers coagulation and impairs fibrinolysis

As mentioned before, inflammation modulates thrombotic responses by upregulating procoagulants, and downregulating anticoagulants and fibrinolysis. These mechanisms have been extensively investigated in cases of sepsis.8 In chronic inflammatory diseases, such as RA, these mechanisms are less clear, but also seem to have an important role in the link with venous or arterial thrombosis (figure 1).

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Figure 1

Overview of the interactions between the systemic inflammatory state in rheumatoid arthritis and the haemostatic system as possible explanations for the increased venous or arterial thrombosis risk. F1+F2, prothrombin fragments 1+2; FVIII, factor VIII; FXII, activated factor XII; ICAM, intracellular adhesion molecule; IL, interleukin; PAI-1, plasminogen activator inhibitor-1; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TNFα, tumour necrosis factor α; t-PA, tissue plasminogen activator antigen, vWF, von Willebrand factor.

The most important inducer of the coagulation response is TF, which is found on extravascular cells. Inflammatory mediators, like C-reactive protein (CRP), TNFα, IL-6 and complement activation can trigger TF synthesis in intravascular cells, such as monocytes and endothelial cells.11 Indeed, high TF plasma levels have been detected in studies of patients with RA, particularly in patients with active disease.12 Furthermore, raised plasma levels of coagulation factors like fibrinogen, von Willebrand factor (vWF), factor (F) VIII, activated factor (F) XIIa, thrombin generation markers such as prothrombin fragments 1+2 (F1+2) and thrombin–antithrombin complexes have been demonstrated in patients with RA.13–17 Many of these markers are associated with endothelial dysfunction—for example, FXIIa and vWF, or cardiovascular events, like fibrinogen and FVII. Endothelial dysfunction is the first step in the pathogenesis of atherosclerosis, and progression of endothelial dysfunction is closely linked to inflammation. During inflammation endothelial cells undergo changes and start to express higher levels of adhesion molecules and TF but lower levels of nitric oxide and thrombomodulin, thereby losing their antithrombotic properties.12

Some factors of the fibrinolytic pathway, such as fibrinogen, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 (PAI-1) and D-dimer, have been associated with an increased risk of coronary events or stroke.13 ,18 All of these factors have been found to be raised in patients with RA.13 Peters et al15 found that thrombin-activatable fibrinolysis inhibitor levels were significantly higher in patients with RA with a high inflammatory state (CRP >10 mg/L) than in patients with RA with less inflammation (CRP <10 mg/L). TNFα seems to be involved in modulating the expression of all the major components of the fibrinolytic system.19 All these findings suggest that inflammation shifts the haemostatic balance to a prothrombotic state, and this process is probably also present in a chronic inflammatory disease such as RA.

Several anticoagulant mechanisms, such as the antithrombin–heparin mechanism, the TF pathway inhibitor (TFPI) mechanism and the protein C anticoagulant system, prevent unwanted clot formation. Evidence shows that these pathways are downregulated by inflammation. Both TFPI and the protein C pathway seem to have a protective effect on endothelial dysfunction and atherosclerosis.20 However, the role of these pathways and the link between RA and thromboembolic events is not clear. Only one prospective follow-up study has looked at the association between coagulation or fibrinolysis markers and the onset of cardiovascular events in an RA population. They found that although the levels of vWF, PAI-1, haptoglobin and erythrocyte sedimentation rate were all significantly higher in the group with cardiovascular (CV) events, only PAI-1 and t-PA significantly predicted CV events.21

The role of platelet function

There is a growing awareness that platelets can modulate immune responses. When activated, platelets facilitate leucocyte recruitment to sites of vascular injury and inflammation, express complement and other inflammatory receptors and release a collection of cytokines, chemokines and antibacterial proteins. Platelets play an active role in atherothrombosis, and high platelet reactivity is associated with a higher risk of CV events.9 Several studies have shown an increased platelet count, together with elevated platelet activation markers, like CD62P (P-selectin), CD63 and their subsequent expression in RA.22

Medication

Most patients with RA today are treated with a variety of drugs, including non-steroidal anti- inflammatory drugs (NSAIDs), corticosteroids, disease modifying antirheumatic drugs (DMARDs) and biological agents, to relieve symptoms and stop disease progression. NSAIDs are known to increase the risk of hypertension and myocardial infarction. Moreover, in a population-based Danish case–control study it was found that the use of NSAIDs was associated with a twofold increased risk of VTE.23 ,24 Although there are conflicting results for corticosteroids and thromboembolism, numerous studies have shown unfavourable effects of glucocorticoids on cardiovascular risk and risk factors, such as diabetes, adiposity and blood pressure.25 However, there is no evidence linking low-dose glucocorticoid treatment and cardiovascular disease (CVD) in RA. The explanation might be that the anti-inflammatory effects during active disease balance possible adverse effects on coagulation and fibrinolysis23 ,26 (table 1).

Data for CVD or VTE risk and DMARD use in RA are scarce except for methotrexate and hydroxychloroquine. All the meta-analyses and larger observational studies suggest that methotrexate and hydroxychloroquine have a beneficial effect, reducing the risk of CVD,23 ,27 ,28 though definitive studies are lacking.

TNFα and IL-6 are pivotal mediators of the inflammatory cascade in RA, and both cytokines seem to be risk determinants for VTE and CVD.29 It is therefore very likely that TNF inhibitors and IL-6 inhibitors have a beneficial effect on the haemostatic status in RA, resulting in a decreased thromboembolic risk. One study showed an improvement of clinical and laboratory parameters, as well as a reduction in the activation of coagulation and endothelial dysfunction, in patients with RA treated with the anti-TNFα chimeric monoclonal antibody, infliximab.30 Moreover, a recently conducted randomised trial (MEASURE) found that IL-6 receptor blockade reduced fibrinogen and D-dimer by more than 40% compared with placebo.31

Concluding remarks

RA and many other autoimmune diseases can be considered as a prothrombotic state and a risk factor for VTE and CVD. Inflammation is probably the link between these illnesses. However, other genetic and acquired risk factors, such as smoking and physical inactivity, might also play a role. Furthermore, the contribution of autoantibodies, such as antiphospholipid antibodies or antibodies against biological agents, to the link between autoimmune diseases and VTE and CVD is not yet clear and requires further study.

Unfortunately, except for the recent MEASURE trial, most of the studies that looked at haemostatic markers in RA were conducted with small numbers of patients with active and longstanding RA. These studies cannot explain which pathophysiological mechanism causes an increase in these markers, or the nature of their specific contribution to the relation between chronic inflammation and (athero)thrombotic risk.

To date not a single study has properly investigated whether or not the prothrombotic state in inflammatory autoimmune diseases is a causal factor for the increased risk of developing cardiovascular or venous thromboembolic events.. Therefore, more large prospective cohort and case–control studies relating VTE and CVD to inflammatory and haemostatic markers are needed. If randomised controlled trials with biological agents, DMARDs and other potentially anti-inflammatory and anticoagulant drugs also measured haemostatic markers in patients with RA, the pathophysiological pathways might be discovered, and also potential ways to decrease CVD and VTE risk. If, when and what kind of anticoagulant prophylaxis should be given to patients with RA is also largely unknown. All these questions and more need to be answered to improve our strategies for diagnosing, monitoring and treating patients with RA with a high thromboembolic risk.