Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications
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- Cugno, M., Marzano, A.V., Asero, R. et al. Intern Emerg Med (2010) 5: 97. doi:10.1007/s11739-009-0333-5
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Chronic urticaria (CU) is a skin disorder characterized by the recurrent eruption of short-lived wheals accompanied by redness and itching for at least 6 weeks. The wheals can be associated with angioedema. CU is considered an autoimmune disease in about 50% of cases with the presence of circulating histamine releasing autoantibodies mainly directed against the high affinity IgE receptor FcεRI on mast cells and basophils or against IgE. In several CU cases regarded as idiopathic; the actual pathophysiological mechanisms are still unknown. Some patients with CU do not respond to antihistamines and require the use of systemic steroids or cyclosporin, which are, however, not always effective. In CU, several investigators have demonstrated the activation of coagulation that is due to the involvement of eosinophils and a tissue factor pathway with generation of thrombin potentially contributing to an increased vascular permeability. CU patients often present with elevation of coagulation and fibrinolysis markers, such as prothrombin fragment F1+2 and d-dimer, which correlate with the disease severity. Preliminary data indicate that anticoagulant treatment with heparin and warfarin may be effective in reducing the symptoms of this disorder. Taken together, all these findings provide the rationale for proposing clinical trials on the use of anticoagulant drugs as adjuvant treatment in CU patients.
KeywordsChronic urticariaCoagulationEosinophilTissue factorAutoimmunity
CU is a rather frequent disease with an estimated prevalence of 0.5–1% [3, 4] and a female predominance (female/male ratio: 2/1) . CU has a heavy impact on the quality of life; in fact, health status scores in patients with CU are comparable to those reported from patients with coronary artery disease, particularly in terms of work performance, sleep disruption, emotional reactions and social interactions .
Classification of chronic urticaria
Clinical classification of chronic urticaria
Ordinary urticaria (the most common form, generally without a defined triggering stimulus)
Physical urticaria (triggered by different physical stimuli)
Cholinergic urticaria (heat, physical exercise)
Delayed pressure urticaria
Contact urticaria (skin contact with biologic or chemical agents)
Urticarial vasculitis (small vessel vasculitis)
Pathogenesis of chronic urticaria
Several factors have been advocated as causes of the disease, including emotional disorders [6, 7], food allergy, intolerance to food additives  and chronic infections like Helicobacter pylori . More recently, experimental and clinical findings have supported the autoimmune origin in several cases of CU . CU is thought to have an autoimmune basis in approximately 45% of patients. In a variable proportion (30–60%) of patients with active disease, the intradermal injection of autologous serum (autologous serum skin test, ASST) causes a wheal-and-flare reaction, and the serum from some CU patients is able to induce histamine release from cultured basophils of healthy subjects. Both phenomena have been ascribed to circulating IgG specific for the high affinity IgE receptor FcεRI present on mast cells and basophils or for IgE [10–12]. The IgG antibodies activate the classical complement cascade [13, 14], and purification of IgG subclasses demonstrate histamine-releasing activity predominantly within subclasses 1 and 3 . Other autoantibodies may also contribute to CU. A recent large in vitro study identifies autoantibodies to CD23 (the low-affinity IgE receptor) in 65% of patients with CU . This autoantibody is able to cause mast cell degranulation in vitro indirectly through the release of the major basic protein from eosinophils. The quite frequent association of CU with antithyroid antibodies [17–19], markers of autoimmunity , further supports the autoimmune nature of the disease.
Although autoimmunity explains some aspects of CU pathogenesis, several points remain unclear. It is generally accepted that autoantibodies to IgE or to the high-affinity IgE receptor, FcεRI, which are commonly regarded as the most relevant pathogenic factors in this disease, can be detected in sera of only 25–50% of patients with CU [11, 12, 21–23]. Another important problem is the discrepancy between skin response to autologous serum and the histamine release from cultured basophils. The ASST elicits a wheal-and-flare reaction in about 50% of CU patients [1, 24], and sera from only half of those who score positive on ASST are positive for in vitro histamine release assay (HRA) . Moreover, Fagiolo et al.  find that sera from CU patients containing anti-FcɛRI autoantibodies retain the ability to induce a wheal-and-flare reaction upon intradermal injection of autologous serum even after depletion of IgG. These findings suggest the possible involvement of other factors both in the autoreactive state detected by ASST and in the pathogenesis of CU.
Involvement of blood coagulation in chronic urticaria
CU patients show a marked increase in plasma markers of thrombin generation and fibrinolysis during severe exacerbations of the disease . The activation of coagulation and fibrinolysis decreases till complete normalization during remission of CU [33, 40], and, as far as we know, is not associated with an increased risk of thrombosis. Whether this phenomenon (activation of coagulation/fibrinolysis) is relevant to the disease pathophysiology, or simply acts as an amplification system is still to be defined; however, the fact that it parallels the activity of CU may provide the rationale for the evaluation of anticoagulant and antifibrinolytic therapy in patients with CU. Heparin is an anticoagulant that potentiates the effect of antithrombin, a plasma protein that binds irreversibly to some serine protease enzymes (mainly factor Xa and thrombin) and blocks their activity. Scattered reports indicate that heparin can be effective in the treatment of CU [42, 43]. Meyer-De Schmid and Neuman  observe a persistent remission in four CU patients (complete in 3 and partial in 1) treated with intravenous unfractioned heparin at dosage of 50–100 mg twice a day corresponding to 5,000–10,000 U. Chua and Gibbs  observe a complete remission in a CU patient refractory to antihistamine and immunosuppressive treatments during administration of subcutaneous unfractioned heparin (5,000 U twice a day) with a relapse when heparin was discontinued. Moreover, oral anticoagulant drugs improve clinical symptoms in patients with CU unresponsive to antihistamines in a small but double-blind, placebo-controlled trial in which six of eight CU patients responded to warfarin . In a recent uncontrolled study, Mahesh et al.  obtain remission with warfarin at a therapeutic dose in four out of five CU patients (complete in 2 and partial in 2). The antifibrinolytic agent tranexamic acid, which is very effective in angioedema patients , has been proposed also in the treatment of CU with a good clinical response in two CU patients , but its effectiveness was not confirmed in a double-blind study . Taken together, all these findings provide the rationale for proposing clinical trials on the use of anticoagulant drugs as adjuvant treatment in CU patients.
Conflict of interest statement
The authors declare that they have no conflict of interest related to the publication of this manuscript.