Endothelial cell activation and hypercoagulability in ocular behçet’s disease

doi:10.1016/j.ajo.2003.12.010

American Journal of Ophthalmology

Volume 137, Issue 5, May 2004, Pages 850-857

https://doi.org/10.1016/j.ajo.2003.12.010 Get rights and content

Abstract

Purpose

To investigate the presence of a hypercoagulable state and vascular endothelial dysfunction in patients with ocular Behçet’s disease and relate the results to the activity of ocular and systemic involvement.

Design

Cross-sectional laboratory and clinical study.

Methods

Prospective study of blood samples of 24 patients diagnosed with ocular Behçet’s disease, which were analyzed for factor VIII, factor XI, von Willebrand factor antigen and ristocetin (vWF ag and risto), antithrombin III (ATIII), protein C and S, fibrinogen and activated protein C (APC) resistance. The results were compared with 40 healthy controls and analyzed for association with ocular and systemic clinical features.

Results

The mean values of factor VIII, factor XI, vWF ag, vWF risto, ATIII, and fibrinogen were significantly raised compared to healthy population (for all: P < .001). Most striking were factor VIII activity levels above 130% in 79% (19 of 24) of our patients. 67% (16 of 24) had levels of factor VIII above 150%, which correlates with a fivefold increase in risk of thrombosis. Other prothrombogenic factors were negative in all but 2 patients (1 protein C deficiency, 1 factor V Leiden mutation). Endothelial cell activation, measured by vWF activity, revealed elevated levels in 42% (10/24). Complete/incomplete Behçet’s disease patients with present or previous macular edema had significantly higher FVIII levels than complete/incomplete Behçet’s disease patients who had never shown any signs of macular edema (P = .04). Further correlations between the laboratory results and clinical symptoms were not found.

Conclusions

We found a generalized hypercoagulable state with endothelial cell activation in ocular Behçet’s disease, irrespectively of current ocular disease activity.

Section snippets

Methods

We studied 24 patients diagnosed with ocular Behçet’s disease who came to the F.C. Donders Institute of Ophthalmology, University Medical Center Utrecht; the demographic characteristics are given in Table 1. The patients were classified according to the criteria of the Behçet’s Research Committee3, 4, 16 and were divided into two groups: complete/incomplete Behçet’s disease (n = 18) and suspect/possible type Behçet’s disease (n = 6; Table 2).

Diverse clinical data were registered, including

Results

All patients had either signs of endothelial activation, increased levels of coagulation factors, or both (Table 4, FIGURE 2, FIGURE 3); however, no unique anomaly common to all Behçet’s disease patients was identified.

The incidence of systemic vascular disease in our patients was 8% (2 of 24). The incidence of vascular involvement in the eye, vasculo-Behçet’s disease of the eye, was 80% (19 of 24 patients) at the time of sampling (vasculitis n = 13; retinal thrombosis, ischemia, or

Discussion

Evidence for a hypercoagulable state or generalized vascular endothelial dysfunction was found in all patients with ocular Behçet’s disease, irrespective of their current ocular or systemic disease activity. The nature or levels of the prothrombotic abnormalities differed from individual to individual.

In literature, multiple, but not uniform, findings of hypercoagulation and endothelial cell activation were previously reported.20, 21, 22, 23, 24, 25 Several studies attempted to correlate

References (38)

S. Kiraz et al.
Pathological haemostasis and “prothrombotic state” in Behçet's disease
Thromb Res
(2002)
J.C. Chambers et al.
Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome
J Am Coll Cardiol
(2001)
T. Matsuo et al.
Choroidal abnormalities in Behçet’s disease observed by simultaneous indocyanine green and fluorescein angiography with scanning laser ophthalmoscopy
Ophthalmology
(1999)
H. Demiroglu et al.
Risk factor assessment and prognosis of eye involvement in Behçet's disease in Turkey
Ophthalmology
(1997)
T. Lisman et al.
Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis
Gastroenterology
(2001)
Y.J. Lee et al.
Coagulation parameters and plasma total homocysteine levels in Behçet's Disease
Thromb Res
(2002)
S. Kiraz et al.
Pathological haemostasis and “prothrombotic state” in Behcet's disease
Thromb Res
(2002)
S. Demirer et al.
Haemostasis in patients with Behçet's Disease
Eur J Vasc Endovasc Surg
(2000)
E. Dupuy et al.
Parameters of hemostasis in Behçet's disease
Rev Med Interne
(1983)
D.H. Verity et al.
Factor V Leiden mutation is associated with ocular involvement in Behçet’s disease
Am J Ophthalmol
(1999)

T. Sakane et al.

Behçet’s disease

N Engl J Med

(1999)

Behcet's disease. Lancet...

P. Zafirakis et al.

Adamantiades-Behçet’s disease

Nussenblatt RB, Whitcup SM, Palestine AG. Behçet’s disease. In: Nussenblatt RB, Craven L, Buckwater, editors. Uveitis:...

E. Kural-Seyahi et al.

The long-term mortality and morbidity of Behçet’s syndromea 2-decade outcome survey of 387 patients followed at a dedicated center

Medicine (Baltimore)

(2003)

L.A. Lee

Behçet’s disease

Semin Cutan Med Surg

(2001)

B. Wechsler et al.

Deep venous thrombosis in Behçet's disease106 localizations in a series of 177 patients

Presse Med

(1987)

B.D. Golden et al.

Behçet’s-type vasculopathy in a patient without the diagnostic features of Behçet's disease

Arthritis Rheum

(1996)

P.R. Ames et al.

Thrombosis in Behcet's diseasea retrospective survey from a single UK centre

Rheumatology (Oxford)

(2001)

Cited by (44)

Assessment of endothelial function in autoimmune diseases
2014, Revue de Medecine Interne
De nombreuses maladies inflammatoires auto-immunes ont été associées à l’apparition d’une athérosclérose accélérée ou à d’autres types de vasculopathies conduisant à une augmentation de l’incidence des maladies cardiovasculaires. Parallèlement aux facteurs de risque cardiovasculaires traditionnels, la dysfonction endothéliale est un élément précoce important dans la pathogenèse de l’athérosclérose, et contribue à l’initiation de la plaque et à sa progression. La dysfonction endothéliale est caractérisée par un changement du phénotype vasculaire qui aboutit à un état pro-inflammatoire, pro-adhésif et pro-coagulant. Par conséquent, l’évaluation de la dysfonction endothéliale s’articule autour de ces différents changements. Ainsi, plusieurs marqueurs biologiques sont utilisés comme indicateurs de la dysfonction endothéliale : les molécules d’adhésion solubles (ICAM-1, VCAM-1, E-sélectine), les facteurs pro-thrombotiques (thrombomoduline, facteur de von Willebrand, inhibiteur de l’activateur du plasminogène-1) et les cytokines inflammatoires. Concernant l’évaluation fonctionnelle de l’endothélium, la dilatation des grosses artères en réponse à l’augmentation du débit sanguin régional constitue une méthode non invasive largement utilisée dans les études physiopathologiques mais également dans des études d’intervention. Dans cette mise au point, nous détaillerons le rôle de l’endothélium, les mécanismes de sa dysfonction et les explorations dont nous disposons pour son évaluation en pratique clinique. Enfin, nous résumerons les différentes données concernant l’attente endothéliale au cours des principales maladies auto-immunes.
Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.
Association of allelic variants of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase with thrombosis or ocular involvement in Behçet's disease: A systematic review and meta-analysis
2013, Autoimmunity Reviews
Citation Excerpt :
In summary, our search strategy yielded a total of 259 potentially relevant studies and 31 of them were selected for further analysis. Four of these 31 papers [23–26] were excluded because of different causes, such as lack of clearly defined diagnostic criteria of BD [25], lack of a case–control design [23] and because they did not analyze the distribution of these SNPs in cases with BD and in a control group eligible for inclusion (healthy controls or BD patients without thrombosis) [24,26]. Therefore, 27 studies [11–13,15,16,27–47] were finally selected to be included in our meta-analysis and genotype frequencies among patients (n = 1844) and cases (n = 2478) are summarized in Table 1.
Thrombosis is frequent in patients with Behçet's disease (BD), although the exact cause remains uncertain. Some single nucleotide polymorphism (SNP) (G1691A in factor V gene, also called factor V Leiden [FVL], G20210A in prothrombin gene and C677T in methyltetrahydrofolate reductase [MTHFR] gene) have been associated with thrombosis and ocular involvement in BD with controversial results.
To assess the effects of FVL, prothrombin and MTHFR SNP variants in patients with BD and thrombosis and ocular involvement by means of a systematic review and meta-analysis.
We retrieved studies analyzing the genotype of the above-mentioned polymorphism among patients with BD. A meta-analysis was conducted in a random effects model and calculations of odds ratio (OR) and confidence intervals (CI) were done. Sensitivity analysis and tests for heterogeneity of the results were performed.
27 previous studies analyzed the association of BD and thrombosis with the FVL, prothrombin and MTHFR polymorphisms. A significant association was found between the possession of the AA or GA genotypes of FVL polymorphism among patients with BD and the presence of any thrombosis (OR = 2.51; 95% CI: 1.68, 3.74; P < 0.00001). In addition, a significant association was found between the possession of the GA or AA genotypes and the presence of BD (OR = 2.67; 95% CI: 1.93. 3.72; P < 0.00001) when cases with BD and healthy controls were compared. This association was not found when studies from Turkey were excluded. No association was found between prothrombin and MTHFR SNPs and thrombosis in BD, and no association between any SNP and ocular involvement was shown either.
Factor V Leiden could be responsible for some thrombotic events in at least Turkish patients. However, this relationship has to be demonstrated from a pathogenic point of view.
Update of Behçet disease. A presentation of 2 cases in Primary Care
2012, Semergen
La enfermedad de Behçet es una enfermedad inflamatoria multisistémica crónica que evoluciona por brotes. Es más común en Asia y en los países de la cuenca mediterránea oriental (Ruta de la Seda). En España la prevalencia es de 5 a 10 casos por 100.000 habitantes. Es una enfermedad de difícil diagnóstico por las numerosas y variadas manifestaciones clínicas y porque no se dispone de pruebas de laboratorio patognomónicas. El retraso en el diagnóstico, frecuente en países de baja prevalencia como España, aumenta la morbilidad y la mortalidad de los pacientes con enfermedad de Behçet.
Behçet's disease is an inflammatory multisystemic chronic disease that progresses by outbreaks. It is more common in Asia and countries in the eastern Mediterranean basin (Silk Route). In Spain the prevalence is between 5 and 10 cases per 100,000 inhabitants. It is a difficult disease to diagnose because of the multiple and varied clinical manifestations, and because there are not pathognomonic laboratory tests available. The delay in the diagnosis, which is frequent in countries of low prevalence like Spain, increases the morbidity and the mortality of patients with Behçet́s disease.
IL-10 plus the EASIX score predict bleeding events after anti-CD19 CAR T-cell therapy
2023, Annals of Hematology
Replication Study of the Association of GAS6 and PROS1 Polymorphisms with Behçet’s Disease in a Japanese Population
2023, Ocular Immunology and Inflammation
Retinal microvasculature features in patients with Behcet’s disease: a systematic review and meta-analysis
2022, Scientific Reports

View all citing articles on Scopus

^☆: This study was supported in part by the Dr F. P. Fischer Foundation, Utrecht, The Netherlands.

View full text

Endothelial cell activation and hypercoagulability in ocular behçet’s disease☆

Abstract

Purpose

Design

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Thromb Res

J Am Coll Cardiol

Ophthalmology

Ophthalmology

Gastroenterology

Thromb Res

Thromb Res

Eur J Vasc Endovasc Surg

Rev Med Interne

Am J Ophthalmol

Behçet’s disease

N Engl J Med

Adamantiades-Behçet’s disease

The long-term mortality and morbidity of Behçet’s syndromea 2-decade outcome survey of 387 patients followed at a dedicated center

Medicine (Baltimore)

Behçet’s disease

Semin Cutan Med Surg

Deep venous thrombosis in Behçet's disease106 localizations in a series of 177 patients

Presse Med

Behçet’s-type vasculopathy in a patient without the diagnostic features of Behçet's disease

Arthritis Rheum

Thrombosis in Behcet's diseasea retrospective survey from a single UK centre

Rheumatology (Oxford)