Potential Value of Anti-inflammatory in the Prevention and Treatment of Deep Vein Thrombosis

There is increasing evidence of functional interdependence of inflammation and thrombosis in vascular diseases [1,2]. The interaction between the two processes of thrombosis and inflammation, in which inflammation promotes thrombosis and thrombosis amplifies inflammation, is mediated by endothelial cells, leukocytes and platelets in a process known as immuno-thrombosis [2,3]. Currently, the commonly used clinical treatments for DVT, including anticoagulation and thrombolysis, etc., have the risk of bleeding. Therefore, there is potential value that target inflammation for prevention and treatment of DVT.

Involvement of inflammation in the pathophysiology of DVT

Inflammation plays a key role in the occurrence and development of DVT. On the one hand, inflammation promotes DVT formation and progression, and on the other hand, DVT further amplifies the inflammatory response.

Formation of DVT

Under normal physiological conditions, endothelial cells are in a resting state, and adhesion factor intercellular adhesion molecule-1 is mainly distributed in the junctions between endothelial cells, which has anti-inflammatory, anticoagulant and antithrombotic effects [4]. It is first mechanically activated and, due to inflammation, increases the expression of P-selectin on its surface, thus promoting the adhesion of leukocytes and platelets [5,6]. Intriguingly, anti-P-selectin antibodies have been reported to reduce inflammation, thereby decreasing venous thrombus formation, without increasing the risk of bleeding [7]. Pro-inflammatory cytokines promote the procoagulant state mainly by inducing the expression of tissue factors, thus accelerating the formation of venous thrombosis [8]. To be sure, anti-inflammatory is effective in reducing the risk of DVT formation.

Development of DVT

Fibrinolysis and matrix remodeling are major events in the development of venous thrombosis, affecting the mechanical recanalization of venous thrombosis and the occurrence of postthrombotic syndrome. In the late stage of DVT, inflammation, particularly through leukocyte recruitment in the vessel wall and thrombus, accelerating its fibrosis, making the vascular wall less compliant, thicker and more conducive to the recurrence of DVT. Polymorphonuclear neutrophils promote DVT resolution and vascular remodeling through NETosis, urokinase release, collagenase and matrix metalloproteases-9 (MMP-9) [9,10]. Interestingly, MMP9 inactivation causes more macrophages infiltration into the thrombus and a relative decrease in the hardness of collagen and elastin fibers during resolution of vein thrombus, which has a significant effect on thrombus resolution and the recovery of vessel wall elasticity but does not affect thrombus formation [11]. Additionally, inflammation has a significant impact on post-DVT vessel recanalization, vessel scarring, fibrosis, compliance, and eventual valve damage. To some extent, anti-inflammatory therapy affects resolution of vein thrombosis and vascular remodeling, as well as the incidence of post-thrombotic syndrome.

At present, the commonly used clinical treatments for DVT include anticoagulation and thrombolysis, which increase the risk of bleeding. Inflammation plays a different role in the occurrence and progression of DVT through different molecular mechanisms. Anti-inflammatory therapy is a potentially effective treatment for DVT, which reduces the interference to the normal clotting system and to some extent decreases the occurrence of bleeding related complications. However, the targets of anti-inflammatory therapy may differ at different stages in the progression of DVT. Further research on safe and effective targets for prevention and treatment of DVT in different stages of DVT progression is still needed.

This work was supported by grants from the National Natural Science Foundation of China (No. 82070496).

The authors declare no conflict of interest.

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