Kevin S. Attenhofer, MD
Over the past 20 years, use of intravenous recombinant tissue-type plasminogen activator (IV-rtPA; Actiplase) has become ubiquitous as the first-line treatment for acute ischemic stroke. Despite recent exciting advances in endovascular therapy, as well as emerging optimism about tenecteplase (TNK), IV-rtPA remains king.
IV-rtPA binds to fibrin on the surface of clot and cleaves plasminogen into plasmin. Fibrin molecules are then broken apart by the plasmin, and the clot dissolves. It is important to note that although IV-rtPA is relatively selective for clot-bound plasminogen, it still activates circulating plasminogen, thereby releasing plasmin. This can lead to the breakdown of circulating fibrinogen and cause an unwanted systemic hyperfibrinolysis. (Side note: Streptokinase and urokinase lack this specificity for clot-associated fibrin, and this is likely why they failed as therapeutic options.) I often hear practitioners cite the short half-life of IV-rtPA itself; however, they overlook the downstream effects of coagulopathy (decreased fibrinogen; increased PT, aPTT) which may persist for at least 24 hours.1
Since IV-rtPA does carry this risk of systemic coagulopathy (of which the most feared complication is symptomatic intracranial hemorrhage (sICH)), patients treated with IV-rtPA have traditionally been monitored in an intensive care setting for 24 hours following the administration of IV-rtPA. In this paper, Chang et al. postulate that the highest risk for hemorrhage occurs within 12 hours based on the pharmacodynamics of IV-rtPA (maximal coagulopathy at 1-4 hours after administration).1
Figure. Timing of symptomatic hemorrhage
after intravenous tPA (tissue-type plasminogen
activator).
Chang et al. conducted a prospective observational study at Johns Hopkins Bayview Medical Center of 385 patients treated with IV-rtPA between 2004 and 2017. They reviewed all neuroimaging within 48 hours of IV-rtPA for hemorrhage, and defined sICH in accordance with the ECASS (European Cooperative Acute Stroke Study) definition. sICH was attributed to IV-rtPA if it occurred within 36 hours of IV-rtPA administration. 21 of 385 patients (5.5%) had sICH. The mean length of time from IV-rtPA administration to diagnosis of sICH was 8.5 hours. Only 4 of 21 patients had sICH after 12 hours (2 of which had unknown time of neurological change).
One critical aspect of this study to be aware of is that they did not exclude patients who received a combination of IV-rtPA and endovascular therapy. This was the only reported baseline characteristic that was of statistical note, and likely carries clinical significance as well. Combination
therapy may increase the risk of early hemorrhage due to direct endovascular irritation. Further, since this study dates back to 2004, we cannot know how standardized endovascular practices were in this cohort, nor do we know how these practices match today’s standard of care. Inclusion of endovascular therapy may have also led to over-estimated numbers of early hemorrhage because of contrast extravasation post-procedure.
The authors conclude that since most post IV-rtPA sICHs occur within 12 hours, monitoring to 24 hours is not necessary in most cases. This would be a significant departure from current practice, which has large implications for resource utilization and availability. I think their data is convincing: 4 of 385 (1%) of patients treated with IV-rtPA had sICH diagnosed after 12 hours. It would be interesting to know if these 4 are patients in whom management would have been changed as a result of this study, or if they were comorbidly sick with other ICU needs.
Another interesting point to keep in mind is the rise of tenecteplase. TNK may be even more clot-specific than IV-rtPA, and length of post-treatment ICU monitoring for each drug may impact usage trends.
References:
- Ho CH, Wang SP. Serial thrombolysis-related changes after thrombolytic therapy with TPA in patients with acute myocardial infarction. Thromb Res. 1990;58:331–341.
