Haemorrhage and thrombosis: tackling two sides of a single vasculitic disease

Abstract

Venous thrombotic events (VTE) are well recognized as being associated with systemic inflammation, infection and malignancies. Their early diagnosis and timely treatment are important in preventing disease morbidity and improving outcomes. Numerous autoimmune diseases have been linked with VTE, for example, there is a 2-fold increased risk of venous thrombosis in rheumatoid arthritis, coeliac disease and inflammatory bowel disease compared with the general population, which is further increased during disease flares [1]. In anti-neutrophil cytoplasm antibody (ANCA)-associated small vessel vasculitis (AAV), VTE have been reported from small cohort series and from larger randomized clinical trials, with rates of up to 18 times that found in the general population [2–4]. Increased risk of VTE occurs mostly in the context of acute AAV disease (where it is 5-fold commoner than during remission) [4], and may precede or follow AAV presentation; however, even patients in remission remain pro-thrombotic. Both deep-vein thrombosis and pulmonary emboli are common, although the former appear to predominate in many series. An incidence of between 1.8 and 7 cases per 100 patient-years has been reported from cohort studies and clinical trials, with predominance in patients with PR3-ANCA in some series, but not others [2–4]. Classic risk factors are not always present in those patients with VTE and when present do not differ in incidence between those AAV patients with or without VTE, suggesting that the other factors, such as inflammatory disease itself predisposes to VTE [4]. What specifically drives the propensity for thombotic events in systemic vasculitis? Virchow's triad, described over 150 years ago, defines contributing factors to thrombogenesis, which may also be applied to systemic vasculitis; (i) abnormal blood constituents, (ii) abnormal blood flow and (iii) abnormal blood vessel walls. Circulating inflammatory factors have been shown to be important in provoking VTE with C-reactive protein (CRP), IL-6, tumour necrosis factor and factor VIII, all known to be elevated in acute AAV, stimulating endothelial production of procoagulant factors such as tissue factor, von Willebrand factor, prothrombin fragments 1 and 2, D-dimer and plasminogen activator inhibitor type 1 (PAI-1), while also activating factor X in the coagulation cascade [5–8]. Abnormal blood flow may result from hyperviscosity and platelet aggregation in the context of systemic inflammation with elevated levels of fibrinogen [8], or loss of anti-thrombogenic factors in association with nephrotic range proteinuric renal injury [9]. Finally, the activated vascular endothelium, found in AAV, plays a critical role in orchestrating several contributing abnormalities promoting thrombosis. Activation of primed polymorphonuclear cells by ANCA results in endothelial cytotoxicity and generates procoagulant apoptotic bodies and loss of anti-thrombogenic capacity. Moreover, recent reports of anti-plasminogen and anti-tissue plasminogen activator antibodies, in a proportion of patients with AAV, suggest that these antibodies may directly interfere with the coagulation pathway and promote VTE [10, 11].