Acute limb ischemia requires prompt diagnosis and expeditious restoration of arterial inflow to minimize the risk of limb loss and reperfusion-related injury. The two general causes of nontraumatic acute limb ischemia are in situ thrombosis and embolic occlusion. Abrupt in situ thrombosis of a native artery typically occurs due to a low flow state in an area of chronic, high-grade atherosclerotic stenosis. By contrast, thrombosis of a bypass graft typically occurs due to a low flow state within the graft caused by a reduction in arterial inflow and/or compromised outflow, in turn due to a technical problem (graft kinking or a missed lesion), intimal hyperplasia, or recurrent atherosclerotic lesion. Acute ischemia from embolization from a proximal source commonly occurs as the offending embolus lodges at a major bifurcation of an otherwise nondiseased peripheral artery. Regardless of the etiology, the severity of the ischemia is based on the location and the extent of arterial obstruction and the capacity of the existing collateral circulation to perfuse the distal tissues and may mitigate the severity of tissue hypoxia. Intravenous anticoagulation is initiated upon diagnosis to minimize clot propagation followed by urgent percutaneous or surgical intervention to restore arterial flow. Correction of the underlying etiology is necessary to prevent recurrence.

Thrombolytic agents currently available for the treatment of acute peripheral arterial thrombosis do not directly degrade fibrinogen, but act by converting plasminogen to its active form, plasmin, which then initiates thrombolysis by breaking down the fibrin and fibrinogen within the clot. No single thrombolytic agent has been clinically proven to be the most effective, and thus the choice of thrombolytic agent must be based on the results of ongoing clinical trials, specific patient characteristics, and the clinician’s experience and resources available.

There are two categories of thrombolytics: The fibrin-specific agents such as tPA activate fibrin-bound plasminogen found in thrombi but have minimal effect on the conversion of plasminogen to plasmin in the absence of fibrin; circulating plasminogen remains largely unaffected. By contrast, non-fibrin-specific agents such as streptokinase activate circulating plasminogen, result in systemic fibrinolysis, and are much less clot specific.

Streptokinase was the first pharmacological thrombolytic to be recognized and was initially put into clinical practice in the 1950s for the treatment of acute myocar-dial infarction. Produced by beta-hemolytic
streptococci, streptokinase binds with either free circulating plasmin or plasminogen to form a complex that can convert a second plasminogen molecule to plasmin. This characteristic of streptokinase results in a biphasic half-life. The first occurs at 16 minutes and represents the formation of the complex between the protein and antibodies, while the second occurs at 90 minutes and represents the true biological elimination of the protein. Due to the high antigenic potential of streptokinase, allergic reactions such as urticaria, periorbital edema, bronchospasm, and fever may occur and thus lessen its clinical value. Patients with prior exposure to streptokinase may develop high antibody titers, and thus a large initial bolus of streptokinase based on measurement of antibody titers may be necessary in these patients. Streptokinase use in the United States has declined due to the emergence of modern thrombolytics, but its use in developing countries remains widespread due to its low cost of production.

Urokinase was first isolated from human urine but is now currently manufactured using recombinant techniques from murine hybridoma or human neonatal renal parenchyma cells. Because of its nonantigenic nature, prior exposure does not result in preformed antibodies to urokinase, and allergic reactions are generally not observed. Urokinase is not fibrin specific and directly converts plasminogen to plasmin, and has a half-life of approximately 15 minutes. Urokinase played an important role as a pharmacologic thrombolytic in the major prospective randomized trials, but its production was halted by the Food and Drug Administration (FDA) in 1999 because of concerns of potential transmission of infectious agents stemming from manufacturing issues. Urokinase was reintroduced back into the U.S. market 3 years later, but with the FDA restriction that it be used in the treatment of pulmonary embolism only.

tPA is an enzyme produced by vascular endothelial cells that catalyzes the conversion of plasminogen to plasmin. The main advantage of tPA over the previously mentioned thrombolytics is its high specificity and affinity for fibrin, which results in minimal plasminogen activation by tPA in the plasma. Within thrombus the binding of fibrin to the tPA and plasminogen compound results in a conformational change to both molecules and leads to enzymatic conversion of plasminogen to plasmin. tPA has a half-life of 4 to 7 minutes, and is metabolized primarily via the liver (accounting for the profound primary fibrinolysis seen in the anhepatic phase of liver transplant and supraceliac aortic clamping).

Recombinant DNA technology is currently used to manufacture tPA (Activase, Alteplase, Genentech, South San Francisco, CA). In order to increase the duration of bioavailability of tPA, modern bioengineered versions have resulted in the creation of reteplase (Retavase, PDL BioPharma, Inc., Fremont, CA; half-life 13 to 16 minutes), and tenecteplase (TNKase, Genentech, South San Francisco, CA; half-life approximately 20 minutes). The increased half-life allows for successful administration as a single bolus rather than the continuous infusion with tPA. Tenecteplase and reteplase have demonstrated similar efficacy as alteplase.

Due to the difference in vessel caliber, the volume of the acute thrombus burden in the peripheral vasculature is greater than that seen in acute thrombosis of the vessels of the cerebral or coronary circulation. Because of the sheer volume of thrombus involved in a peripheral artery, systemic thrombolysis for peripheral vessels has been shown to be less effective and inferior than intraclot, catheter-directed thrombolysis.

The decision to pursue thrombolytic therapy should be individualized for each patient based on several factors. In general, catheter-directed thrombolysis is most effective the fresher the clot. In most major trials establishing the efficacy of this technique, the best results were seen if intervention was initiated within 14 days of symptom onset. However, in each trial successful outcomes were seen in vessels with occlusions much older than this, demonstrating that the degree and severity of the ischemia were more critical than chronicity in predicting outcome and that no absolute limits to the utility of intervention can be assigned.

The expected duration of treatment and the ability of the limb to tolerate the length of the chosen procedure also need to be taken in consideration—it is critical to remember that it is the time to reperfusion, not the time to initiation of therapy, that matters. Reperfusion injury may be decreased if arterial flow can be restored within 4 to 6 hours after the onset of symptoms. In other words, if the ischemia is profound and the limb is unlikely to physiologically tolerate a further prolonged course of thrombolytic infusion, urgent surgical thromboembolectomy is preferable as ischemic time is usually much less.

Absolute contraindications for thrombolysis include active internal bleeding, a recent cerebrovascular accident (within 2 months), or preexisting intracranial pathology at risk of hemorrhage. Relative contraindications include recent major trauma (or cardiopulmonary resuscitation), uncontrolled hypertension, active peptic ulcer disease, recent major surgery, obstetric delivery, or organ biopsy. Thrombolysis may not be effective, and therefore not strongly indicated, in patients with irreversible limb ischemia, mild to moderate ischemia with tolerable claudication, early postoperative bypass graft thrombosis (because of the very high rethrombosis rate), and large vessel thrombi easily accessible to surgery. Anecdotally a very high rate of massive distal embolization in patients with a thrombosed aortofemoral bypass limb has been observed, although mechanical thrombolysis may prevent this problem, and these patients should primarily be treated with open surgical intervention.