Fibrinolysis (Blood Clot Dissolution)

Endothelial cells release tPA in response to thrombin, bradykinin, venous occlusion, and exercise. tPA has a particular affinity for fibrin — bound to fibrin, it is a potent activator of plasminogen; in solution, it is far less active. This fibrin-targeted mechanism concentrates plasmin generation at the clot surface, minimizing systemic fibrinogen consumption. Urokinase plasminogen activator (uPA), a second activator, is more active in tissue beds and contributes to extracellular matrix remodeling and inflammation.

Plasminogen activator inhibitor 1 (PAI-1) is the dominant inhibitor of tPA and uPA, released by endothelium and platelets. Alpha-2 antiplasmin neutralizes free plasmin in solution. Thrombin-activatable fibrinolysis inhibitor (TAFI), generated during clotting, removes C-terminal lysines from fibrin that plasmin needs for binding — slowing fibrinolysis on dense clots. Together these systems balance hemostasis: enough plasmin to dissolve obsolete clots, not so much as to bleed.

IV alteplase is indicated for acute ischemic stroke within 4.5 hours of symptom onset, with strict exclusion criteria (recent surgery, recent stroke, active bleeding, severe hypertension, INR > 1.7, glucose < 50 or > 400). Earlier treatment is dramatically better — number needed to treat under 90 minutes is 4-5, rising to 14 at 4.5 hours. Mechanical thrombectomy extends the window to 24 hours for large vessel occlusions in selected patients. Tenecteplase, given as a single bolus, has comparable efficacy and is replacing alteplase in many centers.

Fibrinolysis was the first effective therapy for ST-elevation MI, opening the infarct artery in roughly 70% of cases. Primary PCI is now preferred where available — door-to-balloon under 90 minutes outperforms fibrinolysis. Where PCI is more than 120 minutes away, fibrinolysis remains first-line, ideally within 30 minutes door-to-needle. Tenecteplase is the standard agent for prehospital and small-hospital use because of its single-bolus dosing.

D-dimer is a fibrin degradation product released when plasmin cleaves cross-linked fibrin. It is sensitive but not specific for venous thromboembolism — elevated in pregnancy, age, infection, malignancy, and post-surgery. A negative d-dimer in a low-pretest-probability patient effectively rules out PE or DVT. A positive d-dimer requires imaging. Age-adjusted thresholds (age × 10 µg/L over 50) improve specificity in older patients without sacrificing sensitivity.

For acute massive or submassive PE, ileofemoral DVT, and arterial thrombosis, catheter-directed delivery of lower-dose tPA achieves local lysis with reduced systemic bleeding. Pharmacomechanical approaches combine drug with mechanical fragmentation or aspiration. Trials in PE show similar efficacy to systemic with lower bleeding rates. Limb-threatening arterial occlusion is managed with combined catheter thrombolysis, thrombectomy, and definitive revascularization.

Plasminogen deficiency is rare but causes ligneous conjunctivitis and impaired wound healing. PAI-1 excess promotes thrombosis. Tranexamic acid blocks plasminogen binding to fibrin and is an antifibrinolytic — used in trauma (CRASH-2 showed 1.5% mortality reduction if given within 3 hours), postpartum hemorrhage (WOMAN trial), and surgical bleeding. Aprotinin, a plasmin inhibitor once used in cardiac surgery, was withdrawn after concerns about renal and cardiovascular adverse events.