Thrombolytics

The body already has a clot-dissolving system. Its key enzyme is plasmin, made from the inactive protein plasminogen; plasmin breaks down fibrin, the mesh that holds a clot together. The natural switch is tissue plasminogen activator (tPA), a serine protease found in the cells lining blood vessels.

Alteplase is tPA made by recombinant DNA technology, and tenecteplase is a modified form of it. Both bind to the fibrin in a thrombus and convert the plasminogen trapped there into plasmin, so the clot dissolves and blood flow returns. That is the key difference from anticoagulants: they prevent clots from forming, but heparin has no fibrinolytic activity and will not break down an existing clot.

Alteplase’s conversion of plasminogen is enhanced by fibrin and limited without it, so at the clot it starts local fibrinolysis with limited systemic proteolysis. Tenecteplase was engineered with higher fibrin specificity, more resistance to plasminogen activator inhibitor-1 (PAI-1) and a longer half-life than native tPA.

Half-life decides how each drug is given. Alteplase is cleared from plasma with an initial half-life of less than 5 minutes, so it runs as a bolus plus an infusion. Tenecteplase has a terminal half-life of 90–130 minutes and is given as one IV bolus over 5 seconds. Both are cleared mainly by the liver.

Fibrin specificity is not complete: plasmin lyses circulating fibrinogen as well as fibrin, and circulating fibrinogen falls after both drugs (16–36% after 100 mg of alteplase; 4–15% after tenecteplase). The tenecteplase label adds that the clinical effect of fibrin specificity on bleeding has not been established. Bleeding is the most frequent adverse reaction of both drugs.

In acute ischemic stroke, intracranial hemorrhage must be excluded before treatment — a head CT is done first, because hemorrhagic stroke and brain tumors are contraindications. Treatment then starts as soon as possible and within 3 hours of symptom onset. During and after treatment, blood pressure is monitored and controlled frequently, and neurologic status is checked serially.

Intracranial bleeding is the feared complication. In the alteplase stroke trials, symptomatic intracranial hemorrhage within 36 hours occurred in 6.4% of treated patients versus 0.6% with placebo, without an increase in 90-day mortality. Because of this risk, stroke treatment is limited to facilities that can promptly evaluate and manage intracranial hemorrhage.

In heart attack the trade-off is weighed too: alteplase’s label notes the risk of stroke may outweigh the benefit when the MI puts the patient at low risk of death or heart failure, and in a large STEMI the tenecteplase label says to choose either thrombolysis or PCI as the primary reperfusion strategy.