Risk of Intracranial Hemorrhage After tPA: 5 Important Facts

Welcome to Neurology Update. I’m Dr. Andrew Wilner, and today I’m going to review some important facts about intracranial hemorrhage after the use of intravenous alterpase.

FDA approved in 1996, intravenous alteplase (ie, tissue plasminogen activator; tPA) is the standard of care for acute ischemic stroke, when given within 3 to 4.5 hours after the onset of a stroke. Although the risk of intracerebral hemorrhage limits the use of tPA, the actual risk depends on the patient profile and the type of intracerebral hemorrhage, but ranges from 2% to 7%.¹

Hemorrhage classification

Hemorrhages may be classified radiologically as: hemorrhagic infarction type 1 (small petechiae); hemorrhagic infarction type 2 (confluent petechiae); parenchymal hematoma type 1 (< 30% of the infarcted area); parenchymal hematoma type 2 (> 30% of the infarcted area with significant mass effect); and extra-ischemic hematoma (distant hematoma from infarcted zone).

Risk factors for symptomatic intracranial hemorrhage based on a systematic review and meta-analysis of 55 studies include: older age, greater stroke severity, higher baseline glucose, hypertension, congestive heart failure, renal impairment, diabetes mellitus, ischemic heart disease, atrial fibrillation, baseline antiplatelet use, leukoaraiosis, acute infarct on imaging, microhemorrhages on MRI.

Clinical practice

In general, tPA treatment is likely to outweigh the harm of hemorrhage, despite its risk. If a patient otherwise fits inclusion and exclusion criteria, tPA should not be withheld.

The risk of hemorrhage is increased because tPA triggers plasmin activation, which degrades cross-linked fibrin into fibrin split products and reversal agents. Reperfusion injury and breakdown of the blood-brain barrier may also contribute to the risk of symptomatic intracranial hemorrhage.

Approximately half of symptomatic intracranial hemorrhages occur by 10 hours after treatment, with the rest occurring by 36 hours. Intracranial hemorrhage occurring after 36 hours is not likely due to tPA.

Current protocols that include ICU monitoring for 24 hours followed by intracranial imaging aid in the detection of intracranial hemorrhage. Any neurological deterioration should also trigger neuroimaging to look for the development of intracranial hemorrhage. Treatment of post-thrombolytic hemorrhage includes cardiovascular and respiratory support, blood pressure management, neurological monitoring, prevention of hematoma expansion, control of elevated intracranial pressure, and seizure control.

Reversal of alteplase-induced coagulopathy should be considered in the setting of symptomatic intracranial hemorrhage, particularly in the presence of an ongoing coagulopathy, but the precise indications and choice of agents are unclear. Various reversal agents may be considered. These include activated Factor VII, antifibrinolytic agents (epsilon-aminocaproic acid and tranexamic acid), cryoprecipitate, fresh frozen plasma, platelets, prothrombin complex concentrate, and vitamin K. Of these, cryoprecipitate is probably the first choice. After a fibrinogen level is drawn, 10 units should be administered. The treatment goal is a fibrinogen level of at least 150 mg/dL. Neurosurgical intervention may also be considered if clinically indicated.

Five Key Points

1. Symptomatic intracranial hemorrhage after IV tPA for ischemic stroke occurs in 2% to 7% of patients.

2. Hemorrhages can be graded according to their radiologic appearance.

3. Certain patients are more susceptible, such as those with larger strokes, diabetes, and older age.

4. If symptomatic intracranial hemorrhage occurs, reversal of the alteplase-induced coagulopathy may be necessary. Cryoprecipitate is probably the first choice, but clear superiority has not been shown for any of the multiple available agents.

5. Neurosurgical intervention may be considered.

Disclosures:

Dr Wilner is Associate Professor of Neurology at the University of Tennessee Health Science Center and a staff physician at Regional One Health in Memphis, TN. Dr. Wilner's latest book, Bullets and Brains, is a collection of over 100 essays that focus on the intersection of neurology and society. Twitter: @drwilner.

References:

1. Yaghi S, Willey JZ, Cucchiara B et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: a scientific statement for health care professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48:e343-e361.