Activation of Blood Coagulation in Two Prototypic Autoimmune Skin Diseases: A Possible Link with Thrombotic Risk.

Massimo Cugno,Alessandro Borghi,Samantha Griffini,Luigia Venegoni,Emilio Berti,Alberto Tedeschi,Angelo Valerio Marzano,Paolo Bucciarelli,Elena Grovetti,Riccardo Asero

doi:10.1371/journal.pone.0129456

Abstract

Coagulation activation has been demonstrated in two prototypic autoimmune skin diseases, chronic autoimmune urticaria and bullous pemphigoid, but only the latter is associated with increased thrombotic risk. Two markers of coagulation activation (prothrombin fragment F1+2 and fibrin fragment D-dimer) were measured by immunoenzymatic methods in plasma samples from 30 patients with active chronic autoimmune urticaria, positive for autologous serum skin test, 30 patients with active bullous pemphigoid and 30 healthy subjects. In skin biopsies, tissue factor expression was evaluated by both immunohistochemistry and in situ hybridization. F1+2 and D-dimer levels were higher in active chronic autoimmune urticaria (276.5±89.8 pmol/L and 5.56±4.40 nmol/L, respectively) than in controls (145.2±38.0 pmol/L and 1.06±0.25 nmol/L; P=0.029 and P=0.011) and were much higher in active bullous pemphigoid (691.7±318.7 pmol/L and 15.24±9.09 nmol/L, respectively) (P<0.0001). Tissue factor positivity was evident in skin biopsies of both disorders with higher intensity in bullous pemphigoid. F1+2 and D-dimer, during remission, were markedly reduced in both disorders. These findings support the involvement of coagulation activation in the pathophysiology of both diseases. The strong systemic activation of coagulation in bullous pemphigoid may contribute to increase the thrombotic risk and provides the rationale for clinical trials on anticoagulant treatments in this disease.

Highlights

Evidence exists on the close link among the immune response, inflammation and coagulation [1,2]
In subsequent studies we found that Chronic urticaria (CU) patients show an activation of the tissue factor (TF) pathway of coagulation cascade [17], and that in patients with severe disease such activation can be so pronounced as to produce an elevation of plasma levels of D-dimer, the last being regarded as a sign of fibrinolysis [18]
In this study for the first time two autoimmune skin diseases have been compared in terms of degree of blood coagulation activation and expression of TF in lesional skin

Summary

Introduction

Evidence exists on the close link among the immune response, inflammation and coagulation [1,2]. Proinflammatory mediators induce the expression of tissue factor (TF), the main initiator of blood coagulation, while activated proteases of coagulation trigger inflammation [3] Such a cross-talk amplifies and maintains the activation of both systems, and is potentially involved in the pathophysiology of autoimmune skin diseases, such as chronic autoimmune urticaria (CAU) and bullous pemphigoid (BP). Considering spontaneous CU, experimental and clinical findings have supported an autoimmune origin in about 40% of cases [6,7] In these chronic autoimmune urticaria (CAU) patients, circulating histamine-releasing autoantibodies directed against IgE (anti-IgE) or against the α subunit of the high—affinity IgE receptor (anti-FcεRI) have been demonstrated in-vitro by immunoblotting, enzyme immunoassay and basophil histamine-release assay [8,9,10,11] and are associated with positivity of autologous serum skin test (ASST) in-vivo [12]. The activation of the TF pathway of coagulation results in turn in the generation of thrombin which, in experimental models, has been shown to induce edema [20,21] and release of inflammatory mediators [15]

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