Thrombolytic Agents

Plasminogen Activators These drugs act by converting the inactive proenzyme, plasminogen, into the active enzyme, plasmin. Plasmin can digest fibrinogen, fibrin monomers, and cross-linked fibrin (as found in a thrombus) into fibrin degradation products. These agents vary in stability, half-life, and fibrin selectivity. The thrombolytics that have been reported for use in stroke IAT include urokinase (UK), alte-plase, reteplase, pro-urokinase, and streptokinase (SK).19,54 In general, the nonfibrin-selective drugs (e.g., UK and SK) can result in systemic hypofibrinogen-emia, whereas the fibrin-selective agents (e.g., rt-PA and r-pro-UK) are mostly active at the site of thrombosis.

First-Generation Agents: Streptokinase, a protein derived from group C b-hemoly-tic streptococci, has a half-life of 16-90 minutes and low fibrin specificity. This drug proved to have a very narrow therapeutic window and significant rates of intracerebral and systemic hemorrhage55; it is no longer used for stroke IAT. Urokinase is a serine protease with a plasma half-life of 14 minutes and low fibrin specificity. The UK dose used in cerebral IAT has ranged from 0.02 to 2 x 106 units (Figure 4.1).19

Second-Generation Agents: Alteplase (rt-PA) is a serine protease with a plasma half-life of 3.5 minutes and a high degree of fibrin affinity and specificity. The rt-PA dose used in cerebral IAT has ranged between 20 and 60 mg.19 The theoretical disadvantages of Alteplase include its relative short half-life and limited penetration into the clot matrix because of strong binding with surface fibrin, which could delay recanalization and increase the risk of recurrent occlusion. Additionally, rt-PA appears to have some neurotoxic properties, including activation of metalloprotei-nases, which may result in increased blood-brain barrier permeability leading to cerebral hemorrhage and edema, as well as amplification of calcium currents through the NMDA receptor leading to excitotoxicity and neuronal death.56 Prourokinase (r-pro-UK) is the proenzyme precursor of UK. It has a plasma half-life of 7 minutes and high fibrin specificity. Despite the favorable results of the PROACT-I and -II trials,22,23 the FDA did not approve r-pro-UK for use in stroke IAT.

Third-Generation Agents: Reteplase is a structurally modified form of alteplase, with a longer half-life (15-18 minutes). In addition, it does not bind as highly to fibrin; thus, unbound reteplase can theoretically better penetrate the clot and potentially improve in vivo fibrinolytic activity. Qureshi et al. have reported the use of low-dose IA reteplase (up to 4 units) in conjunction with mechanical thrombolysis.54 TIMI 2 and 3 recanalization was achieved in 16 out of 19 patients, with no symptomatic ICHs. Tenecteplase is another modified form of rt-PA with a longer half-life (17 minutes), greater fibrin specificity, and greater resistance to PAI-1. Pilot clinical trial data of IV tenecteplase in acute ischemic stroke suggest the drug is safe and promising.57

New-Generation Agents: Desmoteplase is a genetically engineered version of the clot-dissolving factor found in the saliva of the vampire bat Desmodus rotundus.

Fibrolase Cleaving Fibrin

FIGURE 4.1 Eighty-four-year-old man found unresponsive, nonverbal to stimulation, with right hemiparesis, facial droop, and left gaze deviation. He was last seen normal approximately 4 hours before his presentation to the Emergency Department (ED). A CTA was performed in the ED demonstrating occlusion of the left M1 segment (a and b). A cerebral angiogram was then performed. Left internal carotid artery (LICA) angiogram confirmed the CTA findings (c). LICA angiogram after 150,000 units of urokinase was infused through a microcatheter within the clot demonstrating successful recanalization of the left M1 segment (d and e). Note a distal M2 clot that did not recanalize after IA urokinase treatment (circle—e and arrow—f).

FIGURE 4.1 Eighty-four-year-old man found unresponsive, nonverbal to stimulation, with right hemiparesis, facial droop, and left gaze deviation. He was last seen normal approximately 4 hours before his presentation to the Emergency Department (ED). A CTA was performed in the ED demonstrating occlusion of the left M1 segment (a and b). A cerebral angiogram was then performed. Left internal carotid artery (LICA) angiogram confirmed the CTA findings (c). LICA angiogram after 150,000 units of urokinase was infused through a microcatheter within the clot demonstrating successful recanalization of the left M1 segment (d and e). Note a distal M2 clot that did not recanalize after IA urokinase treatment (circle—e and arrow—f).

This drug is more potent and more selective for fibrin-bound plasminogen than any other known plasminogen activator. Unlike t-PA, desmoteplase is not activated by fibrinogen or b-amyloid proteins, factors that may exacerbate the risk for ICH. Moreover, desmoteplase inhibits t-PA-induced potentiation of excitotoxic injury. The effect of IV administration of desmoteplase 3-9 hours after symptom onset in stroke patients who demonstrate a mismatch on PWI/DWI MRI is currently being investigated.7

No direct comparison trials have been reported between the different thrombolytic agents in acute ischemic stroke. In a retrospective review of the results for acute stroke IAT performed at our center, we have found significantly higher rates of recanalization and good clinical outcome in the era in which IA UK was used versus the era in which UK was not available and IAT with rt-PA was the primary treatment.58 Conversely, in another retrospective study, Eckert et al.59 found no major difference between the recanalization rates of UK and rt-PA.

Alternatives to Plasminogen Activation: Other Thrombolytics Thrombolytics currently in the market are plasminogen activators. Therefore, their activity is impacted by the amount of plasminogen in the thrombus. New drugs that do not depend on the availably of plasminogen are currently being evaluated for stroke therapy.

Direct Fibrinolytics: Alfimeprase is a recombinant truncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising,60 but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for IAT in acute stroke (CARNEROS-1) is planned to begin soon.

Microplasmin is a truncated form of plasmin that is more resistant to the effects of antiplasmin. In a rabbit stroke model, intravenous microplasmin infusion resulted in a high rate of clot lysis without increasing the rate of ICH. In addition, there was significant improvement in the behavioral rating scores, suggesting a neu-roprotective effect.61 The ongoing MITI-IV trial is a 40-patient multicenter, doubleblind, placebo-controlled trial using three different intravenous doses of microplas-min to treat acute ischemic stroke (NIHSS >6 and <22) within 12 hours of symptom onset.

Defibrinogenating Agents Ancrod is the purified fraction of Malayan pit viper venom. It acts by directly cleaving and thus inactivating fibrinogen, and therefore indirectly inducing anticoagulation. In the Stroke Treatment with Ancrod Trial, 500 stroke patients presenting within 3 hours of symptom onset were randomized to receive ancrod (n = 248) or placebo (n = 252). Good outcome (BI > 95-100 at 3 months) was achieved in 42.21% and 34.4% of the patients, respectively (p = 0.04). There was no significant difference in mortality but a trend toward more symptomatic ICH with ancrod (5.2% vs. 2%, p = 0.06).62 The ASP-II Trial is currently enrolling patients with an NIHSS score between 5 and 25 who present within 6 hours of stroke onset for treatment with ancrod or placebo.

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