Tenecteplase is given as a single intravenous bolus ranging from 30 to 50 mg depending on body weight. Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset. In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better outcomes in several randomized clinical trials. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1-hour infusion. Streptokinase has been associated with increased bleeding risk in acute ischemic stroke when given at a dose of 1.5 million units, and its use is not recommended in this setting.
Platelet function is regulated by three categories of substances. The first group consists of agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines, collagen, thrombin, and prostacyclin. The second category contains agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D2, prostaglandin E2, and serotonin. A third group comprises agents generated within the platelet that act within the platelet, eg, prostaglandin endoperoxides and thromboxane A2, the cyclic nucleotides cAMP and cGMP, and calcium ion. From this list of agents, several targets for platelet inhibitory drugs have been identified (Figure 34–1): inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-induced platelet aggregation (clopidogrel, prasugrel, ticlopidine), and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole and cilostazol are additional antiplatelet drugs.
The prostaglandin thromboxane A2 is an arachidonate product that causes platelets to change shape, release their granules, and aggregate (see Chapter 18). Drugs that antagonize this pathway interfere with platelet aggregation in vitro and prolong the bleeding time in vivo. Aspirin is the prototype of this class of drugs.
As described in Chapter 18, aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. Other salicylates and nonsteroidal anti-inflammatory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase; that is, their action is reversible.
In 2014, following a review of the available data, the FDA reversed course and concluded that aspirin for primary prophylaxis (patients without a history of myocardial infarction or stroke) was not supported by the available data but did carry significant bleeding risk. In contrast, meta-analysis of many published trials of aspirin and other antiplatelet agents have demonstrated the utility of aspirin in the secondary prevention of vascular events among patients with a history of vascular events.
THIENOPYRIDINES: TICLOPIDINE, CLOPIDOGREL, & PRASUGREL
Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation by inhibiting the ADP pathway of platelets. These drugs irreversibly block the ADP P2Y12 receptor on platelets. Unlike aspirin, these drugs have no effect on prostaglandin metabolism. Use of ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now considered standard practice in patients undergoing placement of a coronary stent. As the indications and adverse effects of these drugs are different, they will be considered individually.