The fibrin-stabilizing factor as a topical means for leg ulcer healing: Biochemical and experimental properties and clinical results

Abstract

The topical application of factor XIII (Fibrogammin HS) is a new concept in the treatment of ulcerative leg disease. In addition to the mode of application, the utilization of a fibrin-stabilizing effect in ulcer treatment is a completely different strategy, since many other medications used for local wound treatment contain a fibrinolytic component. Of the 29 inpatients treated topically during the last 3 years, 17, 12 female and 5 male averaging 60.8±13.6 years, suffered ulcerative leg disease due to a postthrombotic syndrome. The average period since first clinical manifestation of venous ulcer was 3.5±2.1 years. Thirteen patients (76.4%) with chronic ulceration showed such a distinct improvement of topical site after an average period of 3.02±1.05 weeks with topically applied factor XIII (Fibrogammin HS) combined with compression bandaging that they were discharged for further ambulant treatment. Apart from a wound surface reduction and a clinical improvement of granulation, we observed a marked reduction of bleeding and secretion tendency within the ulcus area, especially in patients with severe venous insufficiency. Our hypothesis was that high doses of topically applied factor XIII could improve barrier function of endothelial cells in the wound area. For experimental investigation, porcine aortic endothelial cells were cultured on filter membranes to confluent monolayers. To monitor the barrier function, permeability of the monolayer was continuously measured as flux of trypan blue-labeled albumin. Confluent endothelial monolayers exposed to factor XIII (Fibrogammin HS) showed a significant (n=8,p<0.05) reduction of albumin flux compared with controls. After induction of hyperpermeability in endothelial monolayers by incubation with potassium cyanide (KCN) and 2-deoxyglucose (2-DG), we found a significant increase (up to 250%) in albumin flux compared with controls (n=8,p<0.05). This hyperpermeability was significantly reduced to 50% (n=8,p<0.05) in monolayers that had been preincubated with Fibrogammin HS. We conclude that F XIII reduces permeability of endothelial monolayers. This effect is due to the stabilization of the endothelial barrier function and likely caused by cross-linking of suitable substrates from endothelial cell membrane or extracellular matrix. Because of our good clinical results in improvement of granulation and reduction of secretion during topical treatment of venous ulcer and the demonstrable effect on endothelial permeability, F XIII may play an important role in wound healing of chronic ulcerative leg disease.