Introduction – vasculitis, thrombo-embolic disease and Virchow’s triad

In the early nineteenth century, the prevailing view on the origin of thrombo-embolic disease was the one held by the influential French pathologist Jean Cruveilhier. His theory was that the thrombotic process was a consequence of blood vessel inflammation, as he had seen clots develop in areas where pus was present. The central dogma of his work was that inflammation was a basic process for the development of thrombosis, as expressed in the aphorism he coined: ‘La phlebite domine toute la pathologie’ (Phlebitis dominates all pathology). In 1856 Rudolph Virchow, widely regarded as one of the seminal figures in anatomical pathology and to whom the ‘Virchow triad’ of thrombosis (hypercoagulability, blood vessel damage and blood stasis) is attributed, published an extensive essay (‘Gesammelte Abhandlungen zur Wissenschaftlichen Medicine’ (Collective treatises on Scientific Medicine)) refuting and discrediting Cruveilhier’s view of an association between thrombosis and blood vessel inflammation . For Virchow, inflammation was a consequence of blood vessel thrombosis and not a cause. Virchow’s theory prevailed and the association between thrombosis and inflammation was subsequently minimised. Within the field of vasculitis, this theory is now being challenged.

Similar to other inflammatory processes such as infections and sepsis, which can be pro-thrombotic, many vasculitides are currently being recognised as conditions that have an association with thrombosis ( Table 1 ). The prevailing model for the development of thrombosis depends on a disruption in the endothelial layer of the blood vessel, with either exposure of subendothelial collagen or release of tissue factor . Within the family of vasculitides, it is unclear how the pro-thrombotic environment is generated, but it has been a repeated observation that episodes of thrombosis cluster around periods of increased disease activity or shortly after diagnosis or disease onset . As a potential correlate, recent studies have linked periods of active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides in children with higher concentrations of tissue-factor containing microparticles , providing a compelling hypothesis for an association between inflammation associated with active vasculitis and thrombosis.

The objective of this article is to provide an overview of the clinical evidence exploring associations between different vasculitides and thrombo-embolic disease.

Venous thrombo-embolic disease in ANCA-associated vasculitides

Four studies from different patient populations have described an increased risk of venous thrombo-embolism (VTE) in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) ( Table 2 ) . In 2005 the Wegener’s granulomatosis (now renamed granulomatosis with polyangiitis, GPA) Etanercept Trial (WGET) was published. This study investigated whether etanercept was a useful therapy for remission maintenance after successful treatment induction in patients with GPA, with negative results . The study followed a total of 180 GPA patients for an average of 27 months, and during the course of the study it was observed that the participants had a higher than expected incidence of VTE (7.0 events per 100- patient-years), even when compared with individuals treated with etanercept for other indications, patients with lupus, rheumatoid arthritis or the general population . The incidence of VTE was comparable to that of individuals who have had a previous VTE. A total of 29 GPA patients out of 180 (16.1%) had VTE at some point and 16 of these episodes occurred after study enrolment. Eleven out of the 29 prevalent VTE episodes were pulmonary embolisms (PEs) with or without deep venous thrombosis (DVT). It was also noted that incident VTE episodes were usually associated with periods of active disease (within 2 months of enrolment). In a subsequent study performed with stored samples from the WGET study participants, the presence of known pro-thrombotic factors was studied and compared with the general population and correlated with the presence of VTE . Only a higher frequency of anti-cardiolipin antibodies was noted (12% in WGET vs. 1–5% in healthy controls). Other pro-thrombotic markers (e.g., beta 2 glycoprotein-1 antibodies and genetic pro-thrombotic factors) were not different compared to those in controls. No factors studied were correlated with the presence of VTE among WGET study participants.

In 2006, Weidner and colleagues published a retrospective analysis after reviewing records from 105 patients diagnosed with AAV at the University of Erlangen-Nürnberg, Germany, between 1986 and 2001 . They confirmed 13 cases of VTE, seven in patients with GPA, three in patients with microscopic polyangiitis (MPA) and three in patients with renal-limited vasculitis. The calculated incidence was 4.3 events per 100-patient-years, with 81% of episodes occurring during periods of reported active disease; however, no disease activity tool was used in the study. In 2008, Stassen and colleagues published their retrospectively reviewed data from 198 patients diagnosed with AAV between 1990 and 2005 at the University Medical Center Groningen in the Netherlands . A total of 25 VTE episodes were identified after an average of 6.1 years of follow-up. The overall incidence of VTE was lower than in previous reports (1.8 events per 100 person-years). However, in this longer follow-up study with fewer periods of active disease the estimated incidence increased to 6.7 events/100-person-years when only periods of active disease were considered. In this report, 52% of VTE events occurred during the 3 months before or after the initial diagnosis or a relapse and events associated with GPA were a relative minority (46%). Eight cases were PEs with or without DVT.

In 2009, the French Vasculitis Study Group published the results of their retrospective analysis of the frequency of VTE among 1130 patients with four different forms of systemic necrotising vasculitides . The diagnoses were GPA ( n = 377), MPA ( n = 236), Churg–Strauss syndrome (CSS) ( n = 232) and polyarteritis nodosa (PAN) ( n = 285). The mean follow-up was 58 months, and a total of 83 VTE episodes occurred, on average 5.8 months after the initial diagnosis. The frequencies of VTE per disease category within the AAV were 30/377 (8%) for GPA, 18/236 (7.6%) for MPA and 19/232 (8.2%) for CSS. This was the first report identifying the frequency of VTE in CSS. These frequencies were significantly higher than that seen in PAN (2.5%). The overall incidence of VTE during the follow-up period was 1.58/100-person-years, but increased significantly during periods in which the disease was considered to be active (3 months before and 6 months after an initial diagnosis or relapse) for an incidence during these periods of 7.26 events/100 person-years during active disease. After a multivariable analysis, older age at diagnosis, male sex, history of prior VTE and history of stroke with motor deficit were factors positively associated with the diagnosis of VTE.

In summary, frequencies of VTEs are increased in all forms of AAV, mainly during periods of active disease. PEs comprise a significant proportion of VTE events. Currently recognised pro-thrombotic factors do not explain the increased frequencies of VTE in patients with AAV. The clinical and therapeutic implications of these findings are still unclear. At the very least, these observations should lead to an increased awareness about the potential risk of DVT and PE. Patients with AAV presenting with increased dyspnoea and/or haemoptysis could be suffering from a vasculitis relapse, an infection or a PE.

Venous thrombo-embolic disease in ANCA-associated vasculitides

Four studies from different patient populations have described an increased risk of venous thrombo-embolism (VTE) in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) ( Table 2 ) . In 2005 the Wegener’s granulomatosis (now renamed granulomatosis with polyangiitis, GPA) Etanercept Trial (WGET) was published. This study investigated whether etanercept was a useful therapy for remission maintenance after successful treatment induction in patients with GPA, with negative results . The study followed a total of 180 GPA patients for an average of 27 months, and during the course of the study it was observed that the participants had a higher than expected incidence of VTE (7.0 events per 100- patient-years), even when compared with individuals treated with etanercept for other indications, patients with lupus, rheumatoid arthritis or the general population . The incidence of VTE was comparable to that of individuals who have had a previous VTE. A total of 29 GPA patients out of 180 (16.1%) had VTE at some point and 16 of these episodes occurred after study enrolment. Eleven out of the 29 prevalent VTE episodes were pulmonary embolisms (PEs) with or without deep venous thrombosis (DVT). It was also noted that incident VTE episodes were usually associated with periods of active disease (within 2 months of enrolment). In a subsequent study performed with stored samples from the WGET study participants, the presence of known pro-thrombotic factors was studied and compared with the general population and correlated with the presence of VTE . Only a higher frequency of anti-cardiolipin antibodies was noted (12% in WGET vs. 1–5% in healthy controls). Other pro-thrombotic markers (e.g., beta 2 glycoprotein-1 antibodies and genetic pro-thrombotic factors) were not different compared to those in controls. No factors studied were correlated with the presence of VTE among WGET study participants.

Table 2

Clinical studies on the association between ANCA vasculitides and venous thrombo-embolic disease.

Study	Study type	Patient population	Main result	Comment
Merkel et al., 2005	Ancillary study from RCT	180 patients with GPA enrolled to a clinical trial between 2000 and 2002	Incidence rate of 7.0 VTE events per 100-patient-years	Incidence rate higher than SLE, RA, and normal population
Weidner et al., 2006	Uncontrolled retrospective cohort analysis	105 patients with AAV followed between 1986 and 2001	Incidence rate of 4.3 VTE events per 100-patient-years
Stassen et al., 2008	Uncontrolled retrospective cohort analysis	198 patients with AAV followed between 1990 and 2005	Incidence rate of 1.8 VTE events per 100 person-years	Incidence rate was 6.7 events per 100-person-years during periods of active disease
Allenbach et al., 2009	Uncontrolled retrospective cohort analysis	377 patients with GPA, 236 patients with MPA, 232 patients with CSS followed between 1985 and 2006	Overall incidence rate 1.58 VTE events per 100-person-years. Absolute frequencies of 8% for GPA, 7.6% for MPA, 8.2% for CSS	Incidence rate was 7.26 events per 100 person-years during periods of active disease

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