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Severe frostbite can have devastating consequences with loss of limbs and digits. One of the mechanisms of cold injury to human tissue is vascular thrombosis. The effect of tissue plasminogen activator (tPA) and heparin in limb and digit preservation in severe frostbite patients has not been previously studied.Intra-arterial (6 patients) or intravenous (i.v., 13 patients) tPA and IV heparin were used in patients with severe frostbite. All patients between January 1, 1989 and February 1, 2003 with severe frostbite not improved by rapid rewarming, with absent Doppler pulses in distal limb or digits, without perfusion by Technetium (Tc) 99m three-phase bone scan, and no contraindication to tPA use were eligible. Efficacy was assessed on the basis of predicted digit amputation before therapy, given the clinical and Tc-99m scan results, versus partial or complete digits removed.There were no complications with i.v. tPA. Two patients with intra-arterial TPA had bleeding complications. We know from historical Tc-99m scan data which digits were at risk for amputation. In this study, there were 174 digits at risk in 18 patients and only 33 were amputated.Intravenous tPA and heparin after rapid rewarming is safe and reduced predicted digit amputations considerably. Patients with no response to thrombolytic therapy were those with more than 24 hours of cold exposure, warm ischemia times greater than 6 hours, or evidence of multiple freeze–thaw cycles. Our algorithm for treatment of severe frostbite now includes use of i.v. tPA for patients without contraindications.