thromboplastin and Urticaria

Chronic urticaria (CU) is a widespread skin disease, characterized by the recurrence of transient wheals and itch for more than 6 weeks. Besides autoimmune mechanisms, coagulation factors, in particular tissue factor and thrombin, might also participate in the disease pathophysiology. Tissue factor expressed by eosinophils can induce activation of blood coagulation generating thrombin which in turn can increase vascular permeability both directly, acting on endothelial cells, and indirectly, inducing degranulation of mast cells with release of histamine, as demonstrated in experimental models. D-dimer, a fibrin degradation product, generated following activation of the coagulation cascade and fibrinolysis, has been found to be increased during urticaria exacerbations; moreover, it has been proposed as a biomarker of severity and resistance to H1-antihistamines in CU patients. The possible role of coagulation in CU is also supported by case reports, case series and a small controlled study showing the efficacy of anticoagulant therapy in this disease. The purpose of this review was to summarize the available data on the possible contribution of coagulation to the pathophysiology of CU focusing on clinical aspects and possible future therapeutic developments.

Topics: Animals; Autoantibodies; Biomarkers; Blood Coagulation; Blood Coagulation Factors; Chronic Disease; Complement System Proteins; Eosinophils; Humans; Thrombin; Thromboplastin; Urticaria

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 FcepsilonRI 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.

Topics: Autoimmunity; Blood Coagulation; Chronic Disease; Eosinophils; Humans; Immunoglobulin E; Mast Cells; Platelet Activation; Thromboplastin; Urticaria

Topics: Basophils; Chronic Urticaria; Complement C5a; Endothelial Cells; Histamine; Humans; Lipopolysaccharides; Receptor, Anaphylatoxin C5a; Receptors, IgE; Thromboplastin; Urticaria

Topics: Blood Coagulation; Chronic Disease; Gene Expression Regulation; Histamine; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Lipopolysaccharides; Mast Cells; Thromboplastin; Toll-Like Receptors; Urticaria

Topics: Anti-Allergic Agents; Chronic Disease; Humans; Immunoglobulin E; Omalizumab; Thromboplastin; Thyroglobulin; Urticaria

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.

Topics: Adult; Autoimmune Diseases; Blood Coagulation; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Pemphigoid, Bullous; Peptide Fragments; Prothrombin; Skin; Skin Diseases; Skin Tests; Thromboplastin; Thrombosis; Urticaria; Young Adult

Although several cases of chronic urticaria (CU) are currently regarded as autoimmune in origin, associated with histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils, which are involved in CU skin lesions, have recently been demonstrated as the major source of TF in human blood. We assessed whether eosinophils are the cellular source of TF in CU skin lesions.. Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals. The control group consisted of specimens of perilesional normal skin from different types of skin tumours (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores.. All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p = 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p = 0.001-0.0001). The double-staining experiments for TF and eosinophil cationic protein clearly showed that the TF-positive cells were eosinophils.. Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells in the pathophysiology of CU and might pave the way for new therapeutic strategies.

Topics: Adolescent; Adult; Aged; Chronic Disease; Eosinophils; Female; Humans; Male; Middle Aged; Thromboplastin; Urticaria; Young Adult

In patients with chronic urticaria (CU), plasma shows signs of thrombin generation and autologous plasma skin tests score positive in as many as 95% of cases.. To evaluate the initiators of blood coagulation that lead to thrombin generation and fibrinolysis in CU.. Activated factor VII, activated factor XII, fragment F(1+2), and D-dimer plasma levels were measured in 37 patients with CU and 37 controls. Skin specimens from 10 patients with CU and 10 controls were tested for tissue factor immunohistochemically.. Mean F(1+2) levels were higher in patients than controls (2.54 [SD 2.57] nmol/L vs 0.87 [0.26] nmol/L; P < .001); disease activity was moderate or severe in 9 of 11 (82%) and 9 of 26 (35%) patients showing high or normal F(1+2) levels, respectively (P < .025). Mean D-dimer plasma levels were higher in patients than controls (329 [188] ng/mL vs 236 [81] ng/mL; P < .01); disease activity was moderate or severe in 6 of 8 (75%) and 11 of 29 (38%) showing elevated or normal plasma D-dimer levels (P = NS). Factor VIIa levels were higher in patients than controls (2.86 ng/mL [0.66] vs 1.97 ng/mL [0.65]; P < .001). Activated factor VII and F(1+2) levels were correlated (r = 0.529; P = .008). Tissue factor reactivity was observed only in CU skin specimens.. The extrinsic pathway of clotting cascade is activated in CU. Disease severity is associated with the activation of the coagulation cascade.. The involvement of the coagulation pathway in CU opens new perspectives for a better understanding of the pathogenesis and, possibly, for the treatment of this disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Blood Coagulation Factors; Chronic Disease; Factor VIIa; Factor XII; Female; Fibrin Fibrinogen Degradation Products; Humans; Immunohistochemistry; Male; Middle Aged; Peptide Fragments; Prothrombin; Skin; Thromboplastin; Urticaria

Topics: Arteriosclerosis Obliterans; Aspergillus; Blood Coagulation; Blood Coagulation Tests; Electrocardiography; Fibrinogen; Fibrinolysis; Humans; Immunoelectrophoresis; In Vitro Techniques; Injections, Intravenous; Pelvis; Peptide Hydrolases; Retinal Artery; Thromboangiitis Obliterans; Thrombophlebitis; Thromboplastin; Urticaria