Chronic Rhinosinusitis and the Coagulation System

Abstract

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases in adults and severely affects quality of life in patients. Although various etiologic and pathogenic mechanisms of CRS have been proposed, the causes of CRS remain uncertain. Abnormalities in the coagulation cascade may play an etiologic role in many diseases, such as asthma and other inflammatory conditions. While studies on the relationship between asthma and dysregulated coagulation have been reported, the role of the coagulation system in the pathogenesis of CRS has only been considered following recent reports. Excessive fibrin deposition is seen in nasal polyp (NP) tissue from patients with chronic rhinosinusitis with nasal polyp (CRSwNP) and is associated with activation of thrombin, reduction of tissue plasminogen activator (t-PA) and upregulation of coagulation factor XIII-A (FXIII-A), all events that can contribute to fibrin deposition and crosslinking. These findings were reproduced in a murine model of NP that was recently established. Elucidation of the mechanisms of fibrin deposition may enhance our understanding of tissue remodeling in the pathophysiology of NP and provide new targets for the treatment of CRSwNP.

Keywords: Rhinosinusitis; coagulation; factor XIIIa; fibrinolysis; nasal polyps; tissue plasminogen activator.

Fig. 1. Summary of the coagulation and fibrinolysis cascades. (A) The coagulation cascade, which favors clot formation, is initiated in vivo by tissue factor (TF) and factor VIIa (FVIIa) and leads to the conversion of prothrombin to thrombin by the prothrombinase complex (FXa and FVa). Subsequent cleavage of fibrinogen by thrombin, along with the aggregation of platelets, can result in formation of a thrombus. The fibrin clot is further stabilized by FXIII, which is also activated by thrombin, and the clotting process is magnified by other positive-feedback loops (not shown). (B) Plasmin-mediated fibrinolysis, resulting in fibrin degradation products and clot lysis, occurs following the conversion of plasminogen to plasmin by tissue-type plasminogen activator (tPA). Plasminogen activator inhibitor 1 (PAI-1) rapidly inhibits tPA. Alpha-2-antiplasmin (α-2-AP) inactivates plasmin by forming a 1:1 inhibitory complex with circulating plasmin. Thrombin-activatable fibrinolysis inhibitor (TAFI) cleaves the C-terminal lysine residues of fibrin, preventing the co-activation of plasminogen by fibrin.

Fig. 2. Activation of bronchoalveolar coagulation in asthma. Plasma (containing clotting factors, such as FVII and FX) leaks from lung capillaries as a consequence of the inflammatory response. Tissue factor expression on epithelial cells, eosinophils, and macrophages initiates intra-alveolar coagulation by activation of FVII (which can also be produced by epithelial cells), which then activates factor X. The activated prothrombinase complex, factors Xa and Va activate thrombin, which acts on fibrinogen to produce the fibrin of the clot. Interventions with the anticoagulants fondaparinux (FXa inhibitor) and hirudin (thrombin inhibitor) and the plasminogen activators t-PA and u-PA improve the disturbed pulmonary hemostatic balance and concurrently diminish allergic inflammation and asthma parameters in experimental settings.

Fig. 3. Hypothetical model to explain the role of tissue plasminogen activator (t-PA) in excessive fibrin deposition in nasal polyps. (A) As a protease, t-PA converts plasminogen to plasmin, which promotes fibrin degradation into FDPs. (B) In the presence of Th2 cytokines, t-PA levels are reduced, promoting fibrinogenesis. Reduced tissue levels of t-PA facilitate abnormal fibrin deposition in NP.

Fig. 4. Hypothetical model in which the Th2 milieu facilitates excessive fibrin deposition in NP tissue. Th2 inflammation leads to the recruitment of M2 macrophages and the subsequent production of FXIII-A, which induces excessive fibrin deposition by cross-linking of fibrin and via the anti-fibrinolytic effect through binding α₂-plasmin inhibitor (α₂PI) to fibrin. In the presence of Th2 cytokines, t-PA levels are reduced, causing impaired plasmin generation, which, in turn, decreases fibrinolysis.