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Tissue Plasminogen Activator Coagulopathy Reversal

Recombinant tissue plasminogen activator (rtPA) has been approved to treat ischemic stroke in the first three hours following the onset of symptoms. If given promptly, 1 in 3 patients who receive rtPA have major improvement in their stroke symptoms.

Recombinant tPA produces local thrombolysis by converting plasminogen into plasmin, which then degrades fibrin into fibrin split products. More than 50% of rtPA is cleared 5 minutes after cessation of the infusion and approximately 80% is cleared after 10 minutes. Despite this rapid clearance, rtPA prolongs the prothrombin and activated partial thromboplastin times and decreases fibrinogen levels for as long as 24 hours or more from the time of infusion.

An important complication after treatment of acute stroke with rtPA is symptomatic intracerebral hemorrhage (sICH). Studies suggest that between 3.5% and 6% of stroke patients treated with rtPA develop sICH, and the hemorrhagic complication leads to death in about 50% of patients. Older patients, patients with very severe strokes, and patients who used aspirin before their strokes are all at increased risk for sICH (Yaghi S et al. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator. JAMA Neurol 2014; DOI: 10.1001/jamaneurol.2014.1210).

Because coagulopathy related to rtPA lasts up to 24 hours, both early and sustained reversal is necessary to avoid hematoma expansion and neurologic deterioration. The American Heart Association/American Stroke Association treatment guidelines for symptomatic ICH management recommend replacement of coagulation factors and platelets, acknowledging that there is limited evidence to support the strategy. Specifically, the guidelines call for the use of 10 bags of cryoprecipitate to reverse coagulopathy and one bag of single donor platelets or 6 to 8 bags of random donor platelets.

Each bag of cryoprecipitate contains 200 to 250 mg of fibrinogen and will increase the plasma fibrinogen level of a 70-kg adult by 6 to 8 mg/dL. Generally, 10 bags of cryoprecipitate are given if the fibrinogen level is between 50 and100 mg/dL and 20 bags are given if it is less than 50 mg/dL. A fibrinogen level should be measured at 30 to 60 minutes after completion of the transfusion to determine if additional doses are needed. The therapeutic goal is to keep the plasma fibrinogen level above 100 mg/dL. Circulating half life of fibrinogen is 3 to 5 days.

The potential benefits of aggressive approaches to managing sICH must be weighed against the potential for worsening thrombosis.

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