Therapeutic angiogenesis improves fibrinolytic imbalance in patients with critical limb ischemia

The mechanisms of fibrinolysis have been suggested to be linked to the pathogenesis of peripheral artery disease. The impact of therapeutic angiogenesis on the parameters of fibrinolysis was studied in critical limb ischemia (CLI). CLI patients (N = 29) and blood donors as controls (N = 29) were enrolled. Bone marrow (600 ± 50 ml) was centrifuged (3200g, 20 min, 22°C), bone marrow-derived mononuclear cells (100-120 ml) were separated by Optipress I and implanted into the ischemic limb using intramuscular injections. ELISA was employed for the assessment of plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) levels. Patients were followed-up prior to the procedure and after 1, 3 and 6 months. All stage-IV patients (N = 22) had ischemic lesions. The lesions resolved in 10 patients. Five patients underwent major amputation; they all were stage-IV. Ischemic lesions persisted in seven patients beyond 6 months. The t-PA levels were higher in patients compared with the healthy controls both at baseline (P < 0.01) and after 6 months (P < 0.05). No significant changes were observed in the t-PA levels during the follow-up. PAI-1 was higher in patients than in the healthy individuals at baseline (P < 0.001) and at month 1 (P < 0.05). However, no difference in PAI-1 levels between the patients and the healthy individuals was found after 3 and 6 months. The PAI-1 levels were significantly downregulated during the follow-up compared with the baseline (P < 0.0001). Therapeutic angiogenesis for the CLI downregulates PAI-1 levels, thus having a systemic effect on fibrinolysis.