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Cugno et al. [1] reviewing the topic of chronic urticaria (CU) highlight the role of blood coagulation in the pathophysiology of this disease. This is an innovative view that represents the major breakthrough of the last few years to unravel the poorly understood mechanisms underlying the pathogenesis of urticaria lesions. Previous important discovers in this field are depicted in a figure of the paper that reports the chronology of the key events of CU pathophysiology investigation in the last two decades. The first important discover dates back to the 1980s, when Grattan et al. described the possible autoimmune origin of the disease in about half of CU patients in whom the intradermal injection of autologous serum caused a wheal and flare reaction. Subsequently, the presence of histamine-releasing autoantibodies directed against IgE or the alpha-subunit of the high-affinity IgE receptor (FceRI) was found in about 30–35% of CU patients. The skin reaction to autologous serum was ascribed to the presence of functionally active autoantibodies to FceRI and to other less-characterized histamine-releasing factors as activation of the complement system by IgG autoantibodies against the alpha-subunit of the FceRI that has been shown to enhance histamine release. The autoimmune background, in a consistent proportion of CU patients, is further supported by the frequent association with autoimmune thyroiditis [2] and by anecdotal reports of the association between CU and other autoimmune disorders, such as Graves disease, type 1 diabetes and celiac disease. Although the presence of histamine-releasing autoantibodies accounts for CU pathomechanism in almost half of the patients, the pathomechanisms involved in the other half of patients remain not determined. The studies on blood coagulation can partially fill this gap. Hence, it is known that activation of the coagulation cascade leads to generation of vasoactive substances such as thrombin which stimulate endothelium to increase vascular permeability [3, 4]. CU patients show an activation of coagulation cascade through the tissue factor expressed by eosinophils infiltrating CU lesional skin. Thus, it is possible to hypothesize that the eosinophil is a leading actor in the CU scenario. The activation of coagulation has been described also in other diseases characterized by inflammation, including other cutaneous disorders, such as bullous pemphigoid and angioedema due to C1 inhibitor deficiency [5–8], and a wide spectrum of systemic inflammatory diseases, such as rheumatoid arthritis [9] inflammatory bowel diseases [10] and sepsis [11]. This should not necessarily lead to consider activation of the coagulation as a nonspecific phenomenon, but rather to think that different diseases share, at different sites, a common intermediate step in their pathophysiology. Thus, in the skin microenvironment of CU and bullous pemphigoid, eosinophils express TF which activate coagulation and generate vascular permeability mediators. In angioedema due to C1-inhibitor deficiency, another skin disease characterized by increase in vascular permeability, there is an activation of blood coagulation [7, 8], but edema is mediated by bradykinin generated upon activation of the contact system. An obvious concern with these views comes from the observation that markers of thrombin generation like F1 ? 2 are increased in several prothrombotic conditions, such as disseminated intravascular coagulation [12], deep venous thrombosis [13] and endotoxinemia [14] that are not characterized by urticaria or edema. Therefore, we can conclude that thrombin M. Cicardi (&) Dipartimento di Scienze Cliniche ‘‘Luigi Sacco’’, Universita di Milano, Ospedale L. Sacco Milano, Milan, Italy e-mail: marco.cicardi@unimi.it

Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications by Dr. Massimo Cugno et al.