tissue plasminogen activator

**Physiology:** Endogenous tPA is released by endothelial cells. It cleaves plasminogen to plasmin, and plasmin cleaves fibrin and fibrinogen, producing fibrin degradation products including D-dimer. tPA is fibrin-selective, so it activates plasminogen mainly on the clot surface. Inhibitors: PAI-1 (inhibits tPA) and alpha-2-antiplasmin (inhibits plasmin).

**Pharmacology:** - Recombinant agents: alteplase (tPA), reteplase, and tenecteplase (TNK-tPA). Tenecteplase is a single-bolus agent and is increasingly used for stroke and MI. - Streptokinase and urokinase are other fibrinolytics. Streptokinase is non-fibrin-specific and antigenic. - Lab effects: increased PT and PTT, decreased fibrinogen, and normal platelet count. Bleeding time is usually unchanged.

**Clinical uses:** - Acute ischemic stroke: give within 3–4.5 h of symptom onset or last known well, after CT excludes hemorrhage. Blood pressure must be below 185/110 mm Hg. Check glucose, because hypoglycemia mimics stroke. - STEMI: use if PCI cannot be done within about 120 min of first medical contact. Primary PCI is preferred. - Massive or high-risk PE with hemodynamic instability. - Also used for catheter occlusion and, in selected cases, peripheral arterial thrombosis.

**Contraindications (high-yield):** - Active internal bleeding. - Prior intracranial hemorrhage. - Recent intracranial or spinal surgery, or serious head trauma, within 3 months. - Ischemic stroke within 3 months. - Intracranial neoplasm, AVM, or aneurysm. - Suspected aortic dissection. - Uncontrolled severe hypertension. - Bleeding diathesis, with platelets <100,000, INR >1.7, or therapeutic anticoagulation (e.g., a DOAC taken within 48 h). - Blood glucose <50 mg/dL. - Extensive hypodensity on CT.

**Adverse effects:** Bleeding is the main one, especially intracranial hemorrhage (about 6% in stroke trials) and GI bleeding. Angioedema, especially with ACE inhibitor use, and reperfusion arrhythmias after MI also occur.

**Management of bleeding:** - Stop the infusion. - Give aminocaproic acid or tranexamic acid, which are antifibrinolytics that inhibit plasmin(ogen). - Give cryoprecipitate (replaces fibrinogen), fresh frozen plasma, and platelets as needed.

**Board pearls:** - Fibrinolysis in stroke cannot be given if CT shows hemorrhage. Hemorrhagic stroke is a contraindication. - For large-vessel occlusion, mechanical thrombectomy can be done up to 24 h in selected patients, with or without tPA. - Excess fibrinolysis, as in DIC, liver disease, or prostate cancer, is treated with aminocaproic acid. - Streptokinase is derived from group C beta-hemolytic streptococci. - Fibrinolytics do not prevent new clot formation, so give heparin and antiplatelets afterward as appropriate. In stroke, hold these for 24 h after tPA.