Increasing evidence has linked various forms of systemic inflammatory diseases with both arterial and venous thrombosis [1▪–4▪]. Systemic inflammation plays a major role in this process as extensive cross-links exist between inflammation and hemostasis. The high risk of acute venous thrombosis in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis was initially recognized in the pediatric population  and confirmed in a large randomized trial conducted by the Wegener's Granulomatosis Etanercept Trial Research Group . This risk is especially important during active disease, further supporting the role of inflammation in thrombosis. Some forms of systemic vasculitis have also been linked with a high risk of arterial events as well. A better understanding of these risks and the underlying pathophysiology is essential in developing preventive and therapeutic strategies.
The aim of this review is to discuss the association between thrombosis and systemic vasculitis.
INFLAMMATION AND THROMBOSIS
A close relationship exists between the inflammatory immune response and hemostasis [7▪,8▪]. There is generally a tight balance between procoagulant and anticoagulant factors in the blood. Inflammation can shift the balance promoting a prothrombotic state. Key cytokines in this process include tumor necrosis factor α, interleukin (IL) 1, and IL-6 (Fig. 1). Mouse models have demonstrated elevated gene expression of IL-6 during venous thrombogenesis, and blockade of IL-6 reduces chemokine ligand 2 (important in the recruitment of monocytes to the site of thrombosis) and fibrosis of the vein wall that can lead to postthrombotic syndrome [9▪]. In addition, thrombotic events promote a proinflammatory environment through effects on leukocyte trafficking and generation of cytokines as well as chemokines. For instance, thrombin is generated from the coagulation cascade, and it has an important role in increased expression of P-selectin, an adhesive molecule involved in leukocyte trafficking. Soluble P-selectin levels have been shown to be significantly elevated in acute deep vein thrombosis (DVT) and are reduced with anticoagulation [10▪,11▪]. Furthermore, in primate models, inhibition of P-selectin has been shown to effectively promote thrombus resolution similar to the effect of enoxaparin . Key interfaces that link inflammation to coagulation include the tissue factor pathway, thrombin, the protein C system, and the fibrinolytic system (Table 1).
Vascular involvement is common in Behçet's disease, affecting up to 40% of patients with a male predominance . Both arterial and venous vessels of any size can be affected in Behçet's disease. The majority of thrombotic events are venous in origin with the most common being DVT in the extremities and superficial thrombophlebitis. The vast majority of venous thrombosis events are found in patients who are symptomatic. The rate of asymptomatic DVT of the extremities in those patients with no history of vascular thrombosis is reported to be 6% which is higher then seen in healthy or disease controls [14▪]. It is generally believed that there is a low rate of embolic phenomenon to the lungs because of tight adhesions of the peripheral thrombosis to the venous walls. Indeed, the rate of pulmonary thrombosis has remained low in Behçet's disease (between 4 and 10%) [13,15▪▪,16]. However, it is difficult to distinguish in-situ pulmonary thrombosis from pulmonary embolisms, making the true rate of pulmonary embolic disease unknown. Less common locations of venous thrombosis described in Behçet's disease include vena cava thrombosis, Budd–Chiari syndrome, and cerebral venous sinus thrombosis [13,17▪]. Budd–Chiari syndrome, estimated to occur in 1–3% in Behçet's disease, often coexists with inferior vena cava and portal vein thrombosis. The presence of Budd–Chiari syndrome in Behçet's disease carries a poor prognosis with a mean survival of 10 months compared with 16 months in those with Budd–Chiari syndrome without Behçet's disease [13,18,19]. Central venous thrombosis is estimated to occur in 8% of Behçet's disease and in about 13% of Behçet's disease with neurologic involvement. Central venous thrombosis most commonly presents as intracranial hypertension. Compared with non-Behçet's disease patients, those with Behçet's disease and central venous thrombosis are more likely to be male, present at a younger age, and less likely to develop venous infarcts. In general, outcomes in treated Behçet's disease patients with central venous thrombosis remain good; however, severe visual loss due to optic atrophy can occur [17▪,20,21].
The cause of thrombosis in Behçet's disease remains incompletely understood, and multiple factors in the coagulation cascade have been studied with conflicting results. Recent data have suggested the role of nitric oxide, protein C pathway, and microparticles in pathogenesis [22▪–25▪,26,27▪▪]. Endothelial cell dysfunction is thought to play a major role especially at sites of vasculitis. Nitric oxide, produced by endothelial cells, induces vasodilation and inhibition of platelet aggregation that help prevent thrombosis. Nitric oxide is diminished in patients with active Behçet's disease compared with inactive disease and healthy controls [22▪]. This may be related to the oxidative stress generated by inflammatory cells or genetic polymorphisms found in endothelial nitric oxide synthase, possibly explaining some genetic differences in the risk of thrombosis [23▪]. The protein C pathway has an important role in anticoagulation through inactivation of factor V and also anti-inflammatory properties. Behçet's disease patients have significantly lower levels of activated protein C, lower endothelial protein c receptor levels, and increased resistance to activated protein C. In addition, those with a history of venous thrombosis (VTE) have lower levels of activated protein C compared with those without a VTE history [24▪,25▪]. Microparticles are small membrane particles derived from platelets, monocytes, and leukocytes that can trigger the coagulation cascade through expression of surface tissue factor and anionic phospholipids, particularly phosphatidylserine . In Behçet's disease, both activated platelets and platelet microparticles have been shown to be elevated compared with healthy controls [27▪▪].
The management of venous thrombosis in Behçet's disease has remained controversial. Early evidence for the role of immunosuppression came from a randomized control trial, demonstrating a decreased rate of DVT in those randomized to receive azathioprine 2.5 mg/kg per day . Later, a South Korean cohort reported an increased recurrence of DVT with long-term anticoagulation (>6 months) alone versus immunosuppression with or without long-term anticoagulation . Recently, a French study [15▪▪] including a large number of patients (807) found that immunosuppressives and glucocorticoids significantly decreased the risk of recurrent DVT. In 2008, the European League Against Rheumatism published recommendations that endorsed the use of immunosuppressants (glucocorticoids, azathioprine, cyclophosphamide, and cyclosporine A) in the management of acute deep venous thrombosis in Behçet's disease, while discouraging antiplatelet, anticoagulant and antifibrinolytic agents because of lack of clear benefit and a low incidence of pulmonary embolisms. Anticoagulation, when used in Behçet's disease, should be carefully monitored because of the risk of hemorrhage in this population. Pulmonary artery aneurysms (PAA) may coexist in Behçet's disease patients with thrombosis, and hemorrhage from such aneurysms can have devastating consequences. Screening for PAA should be conducted prior to starting anticoagulation.
SMALL VESSEL VASCULITIS
The increased incidence of VTE in granulomatosis with polyangiitis (formerly Wegener's) (GPA) has been well recognized. Analysis of 167 patients demonstrated an incidence of seven VTE per 100 person-years of follow-up in those patients with no prior history of VTE . The risk of VTE in GPA was seven times the risk of VTE in systemic lupus erythematosus, which is also known to have a high incidence of venous thrombosis, largely because of its association with antiphospholipid syndrome. The risk in GPA was similar to that seen in those in the general population with recurrent DVT. Similarly, retrospective data from a French cohort support a similar risk in patients with microscopic polyangiitis (MPA) and Churg–Strauss as in GPA . However, all of these studies have evaluated the risk of symptomatic VTE. There is no data regarding the rate of asymptomatic DVT and the role of screening for DVT in this population of patients. In addition, few data exist regarding preventive strategies of VTE in these patients. Statins, known for their anti-inflammatory effects, have recently been recognized to have antithrombotic effects as well. In a large randomized trial, rosuvastatin was shown to significantly reduce the occurrence of symptomatic venous thromboemolism [31,32]. The role of statins in VTE prevention in small vessel vasculitis may be an important question for future studies.
The risk of arterial thrombotic disease is also increased in GPA, MPA, and Churg–Strauss [33,34]. Retrospective data demonstrated the risk of ischemic heart disease to be biphasic, with the highest risk appearing either within 4 years of diagnosis or after 10 years of diagnosis . Prospective data from four European Vasculitis Study Group trials found that 14% of patients with GPA and MPA will have a cardiovascular event within 5 years of diagnosis [35▪▪]. The age-standardized annual cardiovascular mortality rate was found to be 3.7 [95% confidence interval (CI) 3.2–4.3] times higher than expected in the general population. Interestingly, the presence of proteinase 3 (PR3) ANCA was protective, whereas a positive myeloperoxidase ANCA test was associated with an increased risk of cardiovascular events. There was no evidence to suggest an increased risk of ischemic stroke in GPA, MPA, or Churg–Strauss [2▪,33]. The high prevalence of cardiovascular events soon after diagnosis suggests that active disease may play a role in triggering arterial thrombosis. Aggressive cardiovascular risk factor reduction should be considered in patients with small vessel vasculitis; however, future studies are needed to determine whether such measures are effective in this population of patients.
As in Behçet's disease, the cause and mechanisms resulting in an increased incidence of thrombosis are unclear. Several studies [29,36] have confirmed the observation that the majority of VTE events associated with GPA, MPA, or Churg–Strauss occur during active disease. Because these small vessel vasculitides are associated with the presence of ANCA, it was postulated that the oxidative burst arising from ANCA-primed neutrophils cause endothelial dysfunction, which could promote thrombosis. However, no clear causal relationship between ANCA positivity and thromboembolic disease has been established . Antibodies to the antisense part of PR3 DNA were found in PR3-ANCA-positive patients. These anticomplementary PR3 (cPR3) antibodies were found to block the conversion of plasminogen into plasmin, interfering with the dissolution of fibrin clot. AnticPR3 antibodies were predictive of DVT formation [37,38]. However, these results await further confirmation by other laboratories. An increased incidence of anticardiolipin antibodies was found in GPA; however, this was not associated with the presence of thrombosis. No association has been found between GPA and antiβ2-glycoprotein antibodies or common genetic prothrombotic disorders (factor V Leiden, prothrombin gene mutation or methylenetretrahydrofolate reductase) .
In addition to Churg–Strauss, thrombophilia is also associated with other diseases marked by eosinophilia such as hypereosinophilic syndrome and parasitic disease. Eosinophils contain preformed protein-containing granules that are released when activated. Some of these proteins have known prothrombotic effects including tissue factor, membrane basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPOx). Tissue factor released by eosinophils has been shown to activate factor X and has a role in early transendothelial migration of eosinophils . Both MBP and ECP inhibit factor XII activation, leading to decreased fibrinolysis via decreased plasmin generation, block the anticoagulant effects of endothelial-bound and exogenous heparin, stimulate platelets to produce platelet factor 4 that can also block heparin; and inhibit thrombomodulin-mediated activation of the protein C system (an important anticoagulant). EPOx can also stimulate endothelial cells to express tissue factor [40,41▪▪,42].
Multiple studies have documented an increased risk of both arterial (coronary artery disease) as well as venous thrombosis and pulmonary embolism associated with polyarteritis nodosa (PAN) [1▪,3▪,4▪]. This risk has been reported as markedly high in comparison to other systemic autoimmune diseases. However, it should be noted that prior to 1994, MPA was considered a microscopic form of PAN. A direct comparison between PAN and systemic small vessel vasculitis (GPA, MPA, and Churg–Strauss) suggests that that the risk of VTE in PAN is lower (0.58 versus 1.84 events per person-year, respectively). However, the risk remains highest during active disease in PAN as compared with inactive disease (3.27 versus 0.58 events per person-year, respectively). The risk is independent of hepatitis B status . There is no clear association between PAN and ischemic strokes [2▪].
LARGE VESSEL VASCULITIS
Although there is no clear increased risk of venous thrombosis in either Takayasu's (TAK) or giant cell arteritis (GCA), there is an increased risk of arterial thrombosis. The rate of strokes and transient ischemic attacks is similar in both diseases, 5–20%, emphasizing the overlap of these two diseases . Atherosclerosis may explain the increased incidence in GCA, given the older age of these patients and related risk factors; however, TAK patients are young and not expected to have significant risk factors for atherosclerosis. In a retrospective study of 190 patients with TAK, 10% developed a stroke. The strongest risk factor for the development of a stroke was a history of transient monocular blindness. Large lobar type and cortical border-zone infarcts on MRI were common (33 and 29%, respectively) supporting embolic disease [44▪]. These findings are postulated to be related to premature atherosclerosis related to endothelial dysfunction.
In GCA there is clear evidence that low-dose aspirin (75–150 mg daily) prevents cerebrovascular events and vision loss . In TAK, a retrospective study of 48 patients showed that those patients who developed an acute ischemic event were significantly less likely to be taking antiplatelet therapy compared with TAK with no ischemic events (14 versus 82%, P < 0.0001). Antiplatelet therapy had a clear protective effect from ischemic events (hazard ratio of 0.055, 95% CI 0.006–0.514, p0.011), whereas no effects were seen with anticoagulants or immunosuppressive medications . Although most of the patients in this study were on doses of aspirin ranging from 100–200 mg per day, the optimal dose of aspirin for prevention of ischemic events in TAK merits further investigation. There is no evidence that statin therapy decreases the incidence of arterial thrombotic events in either GCA or TAK [46,47].
Accumulating data support the presence of an extensive cross-talk between the pathways of inflammation and hemostasis. Although the mechanisms underlying the hypercoagulable state seen in systemic vasculitis remain incompletely understood, common pathways likely exist. Vascular thrombosis in Behçet's disease is common, particularly venous thrombosis. Strong evidence supports the role of systemic immunosuppression with agents such as glucocorticoids, azathioprine, cyclophosphamide, and cyclosporine A in the treatment and prevention of DVT in Behçet's disease, although the role and length of anticoagulation remain controversial. As PAA can be associated with DVT in Behçet's disease, anticoagulation should be closely monitored and screening for PAA performed. In small vessel vasculitis, the occurrence of both venous and arterial thrombosis seems highly correlated with disease activity, which raises the question whether anti-inflammatory therapies used for systemic vasculitis have a direct effect in limiting the rate of thrombosis. Whereas traditional measures of ANCA do not correlate well with the risk of thrombosis, cPR3 antibodies, known to have antifibrinolytic activity, may promote thrombosis. This hypothesis however, remains to be confirmed. Stronger evidence now exists for the use of aspirin in primary prevention of arterial ischemic events in TAK.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 146).
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