Elevation of circulating thrombin–antithrombin III complex and fibrin degradation products in urticaria: A laboratory finding unrelated to intravascular coagulopathy

Abstract

Dear Editor, Voluminous exudation of plasma components into the dermis through the hyperpermeable cutaneous vasculature marks a pathophysiological feature of urticaria. When skin mast cells are stimulated to degranulate by injection of recombinant human stem cell factor, fibrin is shown to be deposited in the perivascular area at the injected sites.1 Fibrin formation, therefore, originating from extravasated plasma fibrinogen could likewise occur in urticarial skin lesion. Massive fibrin formation in the dermis may well affect the plasma levels of coagulation/fibrinolysis parameters. As shown in Table 1, a large proportion of urticaria patients showed elevated circulating thrombin–antithrombin III complex (TAT) and/or D-dimer. Nobody showed a drop in plasma antithrombin III (AT III) activity, or a detectable level of plasma soluble fibrin monomer complex (SFMC). All the patients showed normal levels or ranges of platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma protein C and S activities, serum compliment C3 and C4, plasma fibrinogen and prothrombin (Factor II). The extent of skin rash was roughly correlated with circulating TAT or D-dimer. Some moderate and severe urticaria patients showed plasma levels of TAT and/or D-dimer comparable to those seen in thromboembolic disorders (TAT, >10 ng/mL; D-dimer, >10 µg/mL). Patients with higher plasma TAT levels tended to have higher D-dimer levels, but there was apparent disproportion between the two values in some cases. After the subsidence of urticaria, the elevated TAT levels returned within the normal range in all cases, so did the elevated D-dimer levels in all cases but two. In contrast, none of eight non-pruritic plaque psoriasis patients in stable clinical courses showed the elevation (data not shown). All the urticaria patients recovered without any sequel, not to mention thromboembolic complications. The observation suggests that the transient elevation of circulating D-dimer and/or TAT is relevant to skin mast cell degranulation, and that thrombin generation and subsequent activation of coagulation/fibrinolysis cascade occur in urticaria. The absence of signs and symptoms of intravascular coagulation in addition to the normal laboratory data including platelet counts, PT, APTT, plasma fibrinogen and prothrombin levels, and AT III activities indicates that activation of coagulation/fibrinolysis cascade occurs extravascularly, as demonstrated by abundant fibrinogen deposit in the dermis of biopsy specimens from urticaria (Fig. 1). Once the plasma coagulation factors extravasate into the dermis, coagulation/fibrinolysis cascade is instantly activated. Thrombin is inactivated by tissue AT III, thus not affecting plasma AT III activity. The TAT and fibrin degradation products then flow backwards into the systemic circulation through the hyperpermeable vasculature. Therefore, plasma TAT and/or D-dimer elevation should not be mistaken for evidence of impending or ongoing intravascular coagulopathy in urticaria. The absence of circulating SFMC, a sensitive indicator of fibrinolysis, is also accountable when fibrinolysis proceeds at the extravascular locus. The much larger Mr of SFMC than that of TAT or D-dimer prevents the molecule from reentering the circulation. There is a remote possibility that the normal constituents of the skin, including epidermal keratinocytes,2 eccrine duct epithelial cells or vascular endothelial cells,3 may be the source of thrombin under certain inflammatory conditions, triggering the activation of coagulation cascade in the skin. Thrombin and fibrin degradation products have such pleiotropic immunomodulatory or pro-inflammatory properties as enhancement of vascular permeability and provocation of mast cell degranulation.4,5 Whatever the mechanism of elevated circulating TAT and D-dimer might be, our observation suggests a potential role of coagulation/fibrinolysis cascade activation in the skin in mast cell-mediated inflammatory dermatoses, as implicated by the report of effective anticoagulation therapy for recalcitrant urticaria.6 Fibrinogen deposit in the dermis of biopsy specimens from (a) the lesional skin of psoriasis (b) and urticaria (case 3). Paraffin-embedded biopsy specimens were deparaffinized and incubated with polyclonal anti-fibrinogen antibody (DAKO Japan, Kyoto, Japan). Color development was achieved using diaminobenzidine as substrate (original magnification, ×40). Note the abundant fibrinogen deposit in the perivascular and interstitial areas in the dermis of urticarial skin. The immunohistochemical staining of the biopsy specimens from three psoriasis and four urticaria patients showed similar findings.