The most significant complications of fibrinolytic therapy are hemorrhagic, and the most catastrophic complication is intracranial hemorrhage, seen in at least 1 to 3 percent of patients.42 In the GUSTO trial, the incidence of "moderate or worse" bleeding was highest in the front-loaded tPA plus heparin arm. 21 Fibrinolytics should not be given to any patient with an absolute contraindication (T§ble...216z3. and T§.bie 216.-.4). In patients with a relative contraindication, careful weighing of potential risks and benefits of fibrinolysis in consultation with the physician who will assume in-hospital care of the patient is indicated.

Allergic reactions and anaphylaxis from SK and anistreplase should be treated with 50 mg diphenhydramine and 125 mg methylprednisolone intravenously. Hypotension occurs in up to 10 percent of patients treated with either SK or tPA, and is treated by slowing the fibrinolytic infusion rate and administering intravenous crystalloid, paying close attention to the patient's volume status.

To minimize the bleeding risks associated with fibrinolytic therapy, the following precautions should be observed: (1) avoid all unnecessary needle sticks, (2) avoid any arterial punctures, (3) limit venous access to easily compressible sites (e.g., avoid central lines, especially the jugular or subclavian veins), and (4) avoid both nasogastric tubes and nasotracheal intubation.

Careful monitoring of the patient is crucial. The hematocrit should be checked every 4 to 6 h after fibrinolytic therapy is initiated. A fall in hematocrit of greater than 2 percent should prompt a search for the source of blood loss. Most bleeding episodes (more than 70 percent) occur at vascular puncture sites, but intracranial, intrathoracic, retroperitoneal, gastrointestinal, genitourinary, or soft-tissue extremity hemorrhage may occur.

External bleeding at any site should be controlled with prolonged manual pressure. Significant bleeding, especially from an internal site, mandates discontinuation of the fibrinolytic agent, aspirin, and heparin. Volume replacement using normal saline or lactated Ringer's solution should be provided as necessary and supplemented with red blood cell transfusions if clinically indicated. The thrombin time, aPTT, platelet count, and fibrinogen level should be checked. Heparin administered within 4 h of the onset of bleeding can be reversed with protamine (1 mg of protamine for every 100 U heparin).

Massive bleeding with hemodynamic compromise necessitates coagulation factor replacement in addition to the interventions recommended above. Ten units of cryoprecipitate (rich in fibrogen) should be administered and the fibrinogen level rechecked. If the fibrinogen level is less than 100 mg/dL, the dose of cryoprecipitate should be repeated. If bleeding continues after cryoprecipitate or if bleeding persists despite a fibrinogen level above 100 mg/dL, 2 U of FFP should be given. If bleeding persists after appropriate cryoprecipitate and FFP treatments, a BT should be checked. If it is less than 9 min, 10 U of platelets should be administered, followed by an antifibrinolytic agent (e.g., e-aminocaproic acid or tranexamic acid); if the BT time is less than 9 min, platelets are not necessary, but an antifibrinolytic agent should still be administered for continuing hemorrhage. The dose of e-aminocaproic acid is 5 g intravenously over 60 min, followed by a continuous infusion of 1.0 g/h for 8 h or until bleeding stops. The dose of tranexamic acid is 10 mg/kg intravenously every 6 to 8 h.

Fibrinolytic-associated intracranial hemorrhage requires an aggressive and rapid approach. Immediately discontinue the fibrinolytic agent, aspirin, and heparin. Administer protamine in the dose outlined above if the patient received heparin. The patient should also receive cryoprecipitate, FFP, platelet transfusion, and an antifibrinolytic agent (e.g., e-aminocaproic acid or tranexamic acid). A neurosurgeon should be consulted immediately.

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