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Clinical Trial
. 2019 Dec;144(6):1566-1574.e6.
doi: 10.1016/j.jaci.2019.08.040. Epub 2019 Sep 25.

Increased thrombin-activatable fibrinolysis inhibitor levels in patients with chronic rhinosinusitis with nasal polyps

Yoshimasa Imoto  1 , Atsushi Kato  2 , Tetsuji Takabayashi  3 , Whitney Stevens  4 , James E Norton  4 , Lydia A Suh  4 , Roderick G Carter  4 , Ava R Weibman  4 , Kathryn E Hulse  4 , Kathleen E Harris  4 , Anju T Peters  4 , Leslie C Grammer  4 , Bruce K Tan  5 , Kevin Welch  5 , Stephanie Shintani-Smith  5 , David B Conley  5 , Robert C Kern  5 , Shigeharu Fujieda  3 , Robert P Schleimer  4
Affiliations
Clinical Trial

Increased thrombin-activatable fibrinolysis inhibitor levels in patients with chronic rhinosinusitis with nasal polyps

Yoshimasa Imoto et al. J Allergy Clin Immunol. 2019 Dec.

Abstract

Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease subdivided based on the presence or absence of nasal polyps (NPs). Histologic features of chronic rhinosinusitis with nasal polyps (CRSwNP) include inflammatory cell infiltration and excessive fibrin deposition in NPs. Thrombin-activatable fibrinolysis inhibitor (TAFI) is an enzyme that plays an antifibrinolytic role in the body. The significance of TAFI has been documented in patients with chronic inflammatory diseases, including chronic lung disease; however, it has not been evaluated in the pathogenesis of NPs.

Objective: The objective of this study was to evaluate the potential role of TAFI in the pathogenesis of NPs.

Methods: Nasal lavage fluid was collected from control subjects and patients with CRS. We measured levels of thrombin/anti-thrombin complex (TATc) and TAFI protein using an ELISA.

Results: TATc levels in nasal lavage fluid were significantly increased in patients with CRSwNP and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with control subjects, and TAFI levels in nasal lavage fluid were also significantly increased in patients with CRSwNP compared with those in control subjects and patients with CRSsNP. There was a significant correlation between TATc and TAFI levels in nasal lavage fluid. Interestingly, patients with CRS and asthma showed increased TATc and TAFI levels in nasal lavage fluid compared with those in patients with CRS without asthma, especially patients with CRSwNP.

Conclusions: Increased TATc and TAFI levels in nasal passages of patients with CRSwNP might participate in fibrin deposition in NPs and might play a role in the pathogenesis of CRSwNP and asthma.

Keywords: Chronic rhinosinusitis; asthma; coagulation; fibrin; fibrinolysis; thrombin; thrombin-activatable fibrinolysis inhibitor.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflicts of interest associated with this manuscript.

Figures

Figure 1.
Figure 1.
Levels of TATc and TAFI in nasal lavage fluids and nasal tissue. (A) Increased TATc in nasal lavage fluids in patients with CRS compared to controls (●; control, ■; CRSsNP, ▲; CRSwNP in nasal lavage fluids, n = 15–21). (B) The level of TATc in nasal polyp tissue is increased compared to all UT (●; control UT, ■; CRSsNP UT, ▲; CRSwNP UT, △; CRSwNP NP tissue, n = 7 − 15). (C)) Increased TAFI in nasal lavage fluids in CRSwNP (n = 15–21). (D) Increased TAFI levels were observed in nasal polyp tissue compared to all UT tissue (n = 7 − 15). The levels of TATc and TAFI protein in nasal lavage fluids and nasal tissue extract were measured by ELISA. The concentrations of TATc and TAFI were normalized to the concentration of total protein. *P < .05, **P < .01, and ***P < .001.
Figure 2.
Figure 2.
Levels of TAFI in serum. The levels of TAFI protein in serum were measured by ELISA and normalized to total protein in serum (●; control, ■; CRSsNP, ▲; CRSwNP, n = 912). NS, not significant.
Figure 3.
Figure 3.
Levels of albumin in nasal lavage fluids. Increased albumin in nasal lavage fluids among CRSsNP and CRSwNP subjects (n = 15–21). The levels of albumin in nasal lavage fluids were measured by ELISA. *P < .05, **P < .01, and ***P < .001.
Figure 4.
Figure 4.
Evaluation of TATc and TAFI levels in nasal lavage fluids according to clinical background. (A) TATc levels subdivided by comorbidity of asthma in all subjects including control subjects, (B) TAFI levels subdivided by comorbidity of asthma in all subjects including control subjects (▲; non-asthmatic subjects, ♦; asthmatic subjects, n = 15–36), (C) TATc levels subdivided by comorbidity of asthma in CRSwNP subjects, (D) TAFI levels subdivided by comorbidity of asthma in CRSwNP subjects (▼; non-asthmatic subjects, ●; asthmatic subjects, n = 9–12). *P < .05, **P < .01, and ***P < .001.
Figure 5.
Figure 5.
Proposed hypothetical model for elevated TAFI and its role in the pathogenesis of NPs. In NPs, down regulation of tPA and elevated FXIIIA enhance fibrin formation in the presence of a Th2 milieu. Inflammatory cells produce inflammatory mediators that lead to vascular leakage, which also increases TAFI levels in NPs. In addition, thrombin (TATc) activates TAFI, which contributes to the down regulation of fibrinolysis further by attenuating the fibrinolysis cascade.
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