Diabetic skin microangiopathy : studies on pathogenesis and treatment

Abstract

Background: Most of late diabetic complications have their basis in a disturbed microcirculation, i.e. diabetic microangiopathy. This along with peripheral arterial occlusive disease (PAOD) and neuropathy contribute to the development of chronic diabetic foot ulcers, a severe and expensive complication often leading to lower-limb amputations and an increased death rate. Hypercoagulation and impaired fibrinolysis associated with diabetes mellitus might contribute to the pathogenesis of diabetic microangiopathy.

Aims: 1. To study the effects of the low molecular weight heparin compound dalteparin (Fragmin®, Pharmacia Corporation/Pfizer) on a) ulcer outcome, b) peripheral macro- and microcirculation, and c) haemostatic function, in patients with diabetes, PAOD and chronic foot ulcers; 2. To evaluate the predictive values of macro- (toe blood pressure, TBP) and microcirculatory (transcutaneous oxygen tension, TcP02) measurements for ulcer outcome in patients with diabetes.

Methods: 1. Prospective, randomised, double-blind and placebo-controlled multicenter study. The patients were randomised to treatment with daily injections of 5000 U dalteparin or placebo, until ulcer healing or for a maximum of six months. Ulcer healing was evaluated every fourth week, and peripheral circulation and haemostatic function at baseline, after 3 and 6 months, or earlier in case of discontinuation of treatment. Foot skin microcirculation was evaluated by TcP02 and laser Doppler fluxmetry (LDF), and haemostatic function by analysis of plasma fibrinogen concentration, fibrin gel structure (permeability coefficient, Ks; fiber mass/length ratio, µ), prothrombin fragment 1+2 (F 1+2), plasminogen activator inhibitor-1 (PAI-1) activity, von Willebrand factor (vWF) and tissue plasminogen activator (tPA) antigen; 2. Prospective study enrolling 50 patients with diabetes and chronic foot ulcers. TBP and TcP02 were measured at baseline, and the ulcer outcome was evaluated every 4-6 weeks during 12 months.

Results: 85 out of 87 patients completed the study protocol, of which 43 were randomised to dalteparin and 42 to placebo. Ulcer outcome was significantly (p=0.042) better in the dalteparin group, as compared to the placebo group. More patients healed with intact skin or decreased the ulcer area >=50%, and the amputation rate was reduced to 25% in the dalteparin group.

Skin microcirculation: TcPO2 improved significantly (p=0.01 5) during treatment with dalteparin. Skin vasodilatory response to local heating measured by LDF improved significantly in dalteparin treated patients who showed an improved ulcer outcome.

Haemostatic function: Ks and µ increased significantly during treatment with dalteparin, while plasma fibrinogen concentration was unchanged. High plasma fibrinogen and a tight fibrin gel structure were associated with impaired skin microcirculation. Plasma tPA antigen and vWF increased during treatment with dalteparin, while F 1 +2 and PAI-1 activity increased significantly in patients on placebo.

Prediction of ulcer outcome: Measurement of TcP02 provided a higher positive predictive value (79%; cut-off 25 mmHg) than TBP (67%; cut-off 30 mmHg).

Conclusions: Treatment with a daily dose of 5000 U dalteparin, as an adjunct to a multidisciplinary treatment programme, improves ulcer outcome and skin microcirculation in patients with diabetes and neuro-ischaemic foot ulcers. Impaired local skin microcirculation in these patients is associated with hyperfibrinogenaemia and a tight and rigid fibrin gel structure. Treatment with dalteparin exerts an inhibitory effect on thrombin generation, improves fibrinolytic function and increases fibrin gel porosity, which most probably conduce to the beneficial effects of dalteparin on the local foot skin microcirculation and the outcome of neuro-ischaemic foot ulcers in patients with diabetes.