Behçet’s disease: new insight into the relationship between procoagulant state, endothelial activation/damage and disease activity

Abstract

BackgroundBehçet disease (BD) is associated with a prothrombotic state of unknown origin that may lead to life-threatening events. Calibrated Automated Thrombogram (CAT) and Rotational Thromboelastometry (ROTEM) are two global haemostasis assays that may reveal new insights into the physiopathological mechanisms of the disease and its procoagulant condition.Methods23 BD patients who had no signs or symptoms of current thrombosis and 33 age- and sex-matched controls were included in the study. We performed ROTEM and CAT tests and assessed erythrocyte count, platelet count, platelet contribution to clot formation and plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor type 1 (PAI-1), fibrinogen, C-reactive protein (CRP), thrombin-antithrombin III complex (TAT), D-dimer and E-selectin (ES).ResultsBoth ROTEM and CAT tests showed a hypercoagulable state in the BD patients. Plasma levels of PAI-1, fibrinogen, TAT, CRP and ES were significantly increased in this group compared to controls. The disease activity (DA) was significantly correlated with levels of ES and the maximum clot firmness, and this last one, in turn, correlated with rising levels of ES, PAI-1, CRP and fibrinogen. CAT parameters did not correlate with DA or ES.ConclusionsBoth ROTEM and CAT tests reveal that patients with BD have a procoagulant state even in the absence of thrombosis. ROTEM test indicates that increased levels of fibrinogen and PAI-1 may be involved in the prothrombotic state of this pathology, while platelets do not significantly contribute. Moreover, CAT assay demonstrate that plasma from BD patients is able to generate more thrombin than controls in response to the same stimulus and that this effect is independent of the DA and the endothelial impairment suggesting the involvement of another factor in the hypercoagulable state observed in BD patients. This study also shows that endothelium activation/damage may be a contributing factor in both the procoagulant and clinical conditions of BD, as shown by the direct correlation between ES levels, ROTEM parameters and DA.

Rotational thromboelastometry (ROTEM) in Behçet's disease

“…Bilge et al reported a significant increase in maximum clot firmness (MCF) in a cohort of patients with BD, which may indicate a prothrombotic state in this disease. This report is in line with a study we recently published [2] highlighting the usefulness of ROTEM and of the calibrated automated thrombogram for studying the hypercoagulable state in BD patients.…”

Endothelial Dysfunction and Altered Coagulation As Mediators of Thromboembolism in Behçet Disease

“…Since endothelial dysfunction and vascular involvement in BD play important roles in disease pathogenesis, measurement of parameters related to endothelial function have been proposed for evaluating disease progression in BD patients. Endothelial dysfunction can be assessed by flow-mediated dilatation of the brachial artery by ultrasonography 22 and by measuring high-sensitivity C-reactive protein, 22 homocysteine, 22 ADMA, 22 activated protein C, 41 soluble TM, 41 von Willebrand factor, 41 soluble CD62E (s-CD62E), 42 vascular endothelial growth factor, 43 and endocan levels. 44…”

“…An alteration in the fibrinolytic system is suggested by a correlation between the increase in activity and antigen levels of PAI-1 with disease activity. 42 Increased plasma levels of PAI-1 in patients with BD can be explained by the systemic activation of coagulation which increases thrombin production in response to a stimulus. This induces platelet synthesis, release of active PAI-1, 51,52 and release of TGF β, which therefore may increase PAI-1 synthesis by endothelial cells.…”

“…55 Recently, our group has successfully used two global coagulation tests to evaluate the hypercoagulable condition in BD. 42 One test was rotational thromboelastometry (ROTEM), a viscoelastometric clotting test that measures the kinetics of clot formation and fibrinolysis, providing global information on the cellular and soluble procoagulant/anticoagulant protein interactions. We recorded the clot formation time (CFT, time to 20-mm amplitude, which reflects the speed of the clotting process), α angle (α, tangent to the curve at 2-mm amplitude [in degrees], which reflects the rate of fibrin polymerization), and maximum clot firmness (MCF, which reflects the maximum tensile strength of the thrombus).…”

Thrombosis in vasculitic disorders−clinical manifestations, pathogenesis and management

“…In this study, the changes in coagulation detected by ROTEM showed a tendency to the hypercoagulable state in patients with BD, as demonstrated by accelerated clot formation and increased clot strength. In another study, the ROTEM test showed that elevated levels of fibrinogen and PAI-1 could be associated with the prothrombotic state in patients with BD, and the calibrated automated thrombogram (CAT) assay demonstrated that the plasma obtained from BD patients was capable of generating more thrombin in response to the same stimulus than the plasma drawn from controls [64].…”