Activation of blood coagulation in bullous pemphigoid: Role of eosinophils, and local and systemic implications

BACKGROUND: Bullous pemphigoid (BP) is a blistering skin disease caused by autoantibodies to hemidesmosomal proteins, with eosinophils participating in blister formation. Eosinophils are a source of tissue factor (TF), an initiator of blood coagulation. OBJECTIVES: To evaluate the local and systemic activation of coagulation in BP. METHODS: We studied 20 patients with active BP (eight re-evaluated during remission) and 40 controls. The coagulation markers prothrombin fragment F1+2 and d-dimer were measured in the plasma of all subjects and in both plasma and blister fluid of patients with BP. TF was evaluated immunohistochemically in skin specimens from the 20 patients and in 20 normal samples. RESULTS: F1+2 and d-dimer levels were higher in plasma of patients with BP (649 +/- 96 pmol L(-1) and 18.52 +/- 3.44 nmol L(-1), respectively) than in plasma of controls (157 +/- 7 pmol L(-1) and 1.42 +/- 0.06 nmol L(-1); P = 0.0001), and were very high in blister fluid (40 449 +/- 3491 pmol L(-1) and 1532.32 +/- 262.81 nmol L(-1); P = 0.0001). Plasma and blister fluid F1+2 and d-dimer levels paralleled blood and tissue eosinophilia and disease severity. In the eight patients re-evaluated during remission, there was a marked reduction in F1+2 (from 1127 +/- 144 to 287 +/- 52 pmol L(-1); P = 0.005) and d-dimer (from 24.03 +/- 4.08 to 4.69 +/- 1.51 nmol L(-1); P = 0.029). Immunohistochemistry revealed strong TF reactivity in BP skin (P = 0.0001), and colocalization studies confirmed eosinophils as a source of TF. CONCLUSIONS: The coagulation cascade is activated in BP and correlates with the severity of the disease and with eosinophilia, indicating that eosinophils play a role in coagulation activation via TF. The hypercoagulability may contribute to inflammation, tissue damage, blister formation and possibly thrombotic risk in BP.