In 2005, Merkel et al. [2] reported an increased incidence of VTEs in AAV among 180 people with Wegener’s granulomatosis enrolled in the Wegener’s Granulomatosis Etanercept Trial (WGET) in the United States [6]. All subjects were enrolled during a period of active disease and were assigned to either etanercept or placebo in addition to treatment with glucocorticoids and either cyclophosphamide or methotrexate. Subjects were evaluated every three months, which included determination of disease activity as measured by the Birmingham Vasculitis Activity Score for WG (BVAS/WG) [6] and full interim medical history. Information on VTEs prior to the study onset was obtained, and there was continuous surveillance for VTEs during the trial [7]. All VTEs were clinically apparent and confirmed with diagnostic studies. Thirteen individuals had had VTEs prior to enrollment in the trial. Among the 167 individuals without a history of VTE, 16 experienced events during 228 person-years of observation, an incidence of 7.0 VTEs per 100 person-years. The VTEs were either deep venous thrombosis (DVT) of lower extremities or pulmonary embolism. Most VTEs occurred during or closely following periods of active disease. No difference was found in use of acetylsalicylic acid (ASA) or hospitalization length among those who suffered from VTE versus those who did not.

In 2006, Weidner et al. [3] retrospectively reviewed all patients who were treated for AAV at a single nephrology clinic (University of Erlangen-Nürnberg, Germany) during a 16-year period. This patient population is different from the WGET cohort as it included patients with microscopic polyangiitis and renal-limited vasculitis; moreover, all patients had kidney involvement. Thirteen of 105 patients had VTEs during the 367.5 person-years of observation, yielding an incidence of 4.3 events per 100 person-years. Twelve of the 13 events occurred during periods of active vasculitis. No patients with VTEs in this cohort were found to have protein C, protein S, or antithrombin deficiencies, antiphospholipid antibodies, the factor V Leiden mutation, or the nephrotic syndrome.

In a report from the Netherlands in 2008, Stassen et al. [4•] looked at VTE in a cohort of 198 patients with AAV, including Wegener’s granulomatosisG, microscopic polyangiitis, and renal-limited vasculitis. During a median follow-up period of 6.1 years, 25 VTEs occurred in 25 patients, an incidence of 1.8 events per 100 person years. Similar to what was found in the two above-outlined studies, a much higher incidence of VTE (6.7 per 100 person years) was observed during periods of active disease. VTEs were more common among the subset of patients with microscopic polyangiitis and renal-limited vasculitis than among patients with Wegener’s granulomaotsis (24 vs. 7.0%, P < 0.01).

A recent study from France [8] (so far only published as an abstract) also addressed thrombosis in AAV (Churg Strauss syndrome, Wegener’s granulomatosis and microscopic polyangiitis). These investigators found that 7.6% of 845 patients with AAV had VTEs during a mean follow up of 58 months. Most of the VTEs occurred in close temporal proximity to the time of diagnosis of vasculitis.

The importance of established hypercoagulable risk factors in the development of VTE in AAV remains to be fully determined. The prevalences of antiphospholipid antibodies and common genetic mutations associated with hypercoagulability were recently determined among individuals in the WGET study [9•]. Although there was a slightly increased prevalence of antiphospholipid antibodies among persons with Wegener’s granulomatosis compared with the general population (confirming prior reports), there was no association found between the presence of anticardiolipin antibodies and VTE. Additionally, the same study reported that the prevalences of mutations in factor V Leiden, prothrombin G20210A, and methylentetrahydrofolate reductase were not different among patients with Wegener’s granulomatosis and VTE compared with rates in the general population [9•].

The clinical presentation of thrombosis in Behçet’s disease is different from what is observed in AAV and other hypercoagulable states. Superficial subcutaneous thrombophlebitis and DVTs are the most common thrombotic events in Behçet’s disease. Thromboses at unusual sites such as cerebral sinuses or hepatic veins are often described, as are intracardiac thrombi [10,14,18–20]. Despite the increased prevalence of DVT in Behçet’s disease, pulmonary embolism appears to be rare. In a study of 137 patients from Turkey, two had pulmonary embolism [14] and in a report of 170 Japanese patients with Behçet’s disease who underwent postmortem examinations, pulmonary thrombi were found in only one case [21]. Similarly, in a large series of 5095 patients with Behçet’s disease from Iran, with a median observation period of 3 years, only six patients had pulmonary embolism [17]. In a systematic review focusing on pulmonary involvement in Behçet’s disease it was found that when thrombi are located within the pulmonary vasculature, pulmonary vasculitis or an aneurysm is almost always present [22].

In Behçet’s disease there appears to be a spatial relationship between thrombosis and inflammation. Superficial thrombophlebitis is characterized by clinical features of inflammation surrounding the thrombus. In a study of 13 patients with Behçet’s disease and pulmonary artery aneurysms, all individuals either had thrombi in the affected vessels at initial evaluation or subsequently developed such thrombi [23]. Intracardiac thrombi in Behçet’s disease are associated with heavy inflammatory infiltrates both in the thrombus itself and sometimes also in the underlying myocardium [19]. A recent report assessed the usefulness of anticoagulation in addition to immunosuppressive agents for thrombosis in Behçet’s disease. In this small retrospective study, no decrease in recurrent VTEs was observed among those treated with anticoagulation compared with those who received immunosuppressive therapy alone [24•].

Several studies have examined the prevalence of thrombophillic factors among patients with Behçet’s disease [25–31]. A meta-analysis reported no difference in the prevalence of factor V Leiden, prothrombin mutation (G20210A), or methylenetetrahydrofolate reductase mutation among patients with Behçet’s disease versus controls. However, considering only patients with Behçet’s disease, there was a statistically significant association between prothrombin mutation (G20210A) and thrombotic events. In a subanalysis restricted to studies from Turkey, an association between factor V Leiden and thrombosis also was observed [32].

In a small study from the UK, a significantly increased prevalence of VTEs was found among 28 people with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR) compared with healthy controls: 8/28 (29%) patients with GCA/PMR vs. 1/28 (4%) controls [33]. Among patients with GCA, anticardiolipin antibodies and increased levels of lipoprotein were associated with VTE [33]. In another study of 34 patients with GCA from Italy, 8 ischemic cerebral or cardiac events occurred and 12 patients had optic neuropathy. No VTEs were reported. Seventeen of the 34 patients had anticardiolipin antibodies, but no association with ischemic events was found [34].

Large artery stenosis is a well known complication of GCA [35], but to what extent these occlusive events are mediated by thrombosis is unclear. Microthrombosis could also play role in anterior ischemic optic neuropathy, which is the main cause for blindness in GCA. Aspirin has been shown to decrease the rate of ischemic events in GCA [36,37], potentially through its antiplatelet properties. Larger studies on the occurrence of thrombotic events in GCA are needed.

Takayasu’s arteritis (TAK) is characterized by stenoses and occlusion of large arteries, and less commonly by aneurysms. As in GCA, it remains unclear to what extent occlusion of large arteries is preceded by a thrombotic event in TAK. One study found the presence of thrombus in a large artery in seven of 24 patients with TAK who underwent imaging with CT scans [38] but additional confirmatory research is needed. Case reports have also described thrombotic events in TAK where suction thrombectomy and urokinase have restored flow through large-vital arteries [39,40].

In a recent study from France of patients with several types of vasculitis (so far only published as an abstract), those with polyarteritis nodosa (PAN) had fewer VTEs than did patients with AAV [8]. Several arterial thrombotic events have been described in PAN in the setting of positive antiphospholipid antibodies [41–43]. Thrombotic thrombocytopenia purpura has also been described in PAN [44].

In Kawasaki’s disease, thrombosis is a well known sequela of structural changes in coronary arteries [45]. The association between markers of platelet activation and coronary artery lesions [46,47] and the utility of aspirin in Kawasaki’s disease supports the possible importance of thrombosis in this disease.

In AAV, fibrinoid necrosis is a prominent feature on histologic examination. The term `fibrinoid’ refers to material that looks like fibrin under light microscopy. Although the exact chemical composition of the lesion is not known, immunohistochemical analysis has confirmed the presence of fibrin in the lesion [55], linking this end product of the coagulation cascade to the scene of inflammation and structural vessel damage in AAV.

It is generally agreed that an initiating event in activation of the coagulation cascade in vivo is expression of active tissue factor (TF), which sets off repeated iterations of activation of individual coagulation factors that ultimately lead to build-up of fibrin and formation of a thrombus [56•]. Active TF comes in contact with other major components of the coagulation cascade through two main pathways. First, disruption of the endothelial layer exposes active TF on the underlying connective tissue. In vasculitis, this is a conceptually attractive mechanism for thrombosis in Behçet’s disease and vasculitis affecting large and medium sized arteries, where thrombosis is seen in spatial association with vessel destruction and inflammation [19,23,38]. In AAV, there is necrosis of endothelial cells, which become detached from their underlying basement membrane. This injury could set off activation of the coagulation cascade.

A second mechanism by which active TF interacts with the coagulation system involves several inflammatory cytokines that can induce TF expression on endothelial cells and circulating monocytes [57]. In AAV, endothelial cells become detached from their underlying basement membrane, and the quantity of circulating endothelial cells in peripheral blood has been found to correlate with vasculitis disease activity [58]. It is, therefore, possible that circulating endothelial cells expressing TF play a key role in clinical thrombosis in AAV occurring at sites distant from areas of active vasculitis. It is also possible that circulating cytokines induce TF expression on endothelial cells and monocytes in the setting of intact endothelium. Other potential mechanisms of association between AAV and thrombosis have been proposed; including that widespread endothelial dysfunction occurs in vasculitis and results in a decreased production of thrombomodulin and other anticoagulant factors [7•].

Treating physicians should have a low threshold for evaluating patients with vasculitis for thrombosis, especially in AAV and Behçet’s disease, and particularly during periods of active disease. Currently, it is not recommended to screen for thrombosis among asymptomatic individuals, and the role, if any, of prophylactic treatment with antiplatelet agents and anticoagulants remains to be defined. There are no data to inform physicians on the appropriate duration of anticoagulant treatment for VTE in vasculitis.