Intracerebral hemorrhage due to thrombolytic therapy …

Adrian Marchidann MD

Stroke & Vascular Disorders

Updated 09.12.2024
Released 07.16.1996
Expires For CME 09.12.2027

Intracerebral hemorrhage due to thrombolytic therapy

Author: Adrian Marchidann MD

See Contributor Disclosures

Editor: Steven R Levine MD

Intracerebral hemorrhage due to thrombolytic therapy

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Introduction

Overview

Treatment of acute ischemic stroke by arterial recanalization with intravenous thrombolysis with or without endovascular thrombectomy leads to improved outcomes, as demonstrated by several randomized clinical trials. The main thrombolytics used in clinical practice are intravenous recombinant tissue plasminogen activator, a synthetic version of endogenous tissue plasminogen activator, and tenecteplase. Endovascular mechanical thrombectomy is used for the removal of large arterial blood clots. A small proportion of stroke patients undergoing these treatments experience intracerebral hemorrhage. One of the causes of neurologic deterioration after recanalization is symptomatic intracerebral hemorrhage, leading to increased disability or death. In this article, the author reviews the clinical presentation, risk factors, and management of recanalization-induced symptomatic intracerebral hemorrhage, the most dreaded complication of acute stroke therapy.

Key points

	• Thrombolysis is effective against selected cases of acute ischemic stroke.
	• The most feared risk of thrombolysis is symptomatic intracerebral hemorrhage.
	• Multiple definitions of symptomatic intracerebral hemorrhage have caused variability in reporting its frequency and risk factors.
	• The risk of symptomatic intracerebral hemorrhage after rtPA was given within 3 hours of stroke onset was 6.4% in the NINDS clinical trial and 5% to 6% in clinical practice.
	• Symptomatic intracerebral hemorrhage occurred in 2.4% of patients who received rtPA within 4.5 hours of stroke onset.
	• In strokes caused by large vessel occlusion, endovascular thrombectomy following rtPA is superior to rtPA alone but without an increased risk of symptomatic intracerebral hemorrhage.
	• Large stroke, early CT changes of ischemia, hyperglycemia, and a history of diabetes have been associated with post-thrombolysis symptomatic intracerebral hemorrhage.

Historical note and terminology

Sussman and Fitch were the first to use plasmin-mediated thrombolysis for acute ischemic stroke treatment (111). Before the advent of CT, which allows the exclusion of hemorrhagic stroke, thrombolysis was administered several hours or days after stroke onset. The high rates of symptomatic intracerebral hemorrhage and death led to the cessation of thrombolysis in clinical practice (09).

In the National Institute of Neurological Disorders and Stroke (NINDS) trial, rtPA administered within 3 hours of ischemic stroke onset resulted in a 30% likelihood of good outcome at 3 months compared to placebo. However, rtPA was associated with a 6.4% risk of symptomatic intracerebral hemorrhage (85). The United States Food and Drug Administration approved rtPA for selected patients with ischemic stroke within 3 hours from onset. Later, favorable outcomes with a rate of symptomatic intracerebral hemorrhage of 2.4% led the American Stroke Association to recommend extending the therapeutic window of rtPA up to 4.5 hours after stroke onset (47). However, the extended window has not yet been approved by the FDA (17). Several clinical trials demonstrated that endovascular thrombectomy, with or without rtPA, reduces disability after ischemic stroke due to large vessel occlusion when compared to rtPA alone, without an additional risk of symptomatic intracerebral hemorrhage (93).

Clinical manifestations

Presentation and course

	• Post-thrombolysis hemorrhagic transformation may be unnoticed until it is large enough to cause neurologic dysfunction.
	• Hemorrhagic transformation should be suspected if headache, vomiting, decreased level of consciousness, and neurologic deterioration occur soon after thrombolysis.
	• Symptomatic hemorrhagic transformation is more likely to complicate large acute ischemic strokes and is an independent predictor of increased morbidity and mortality.

Acute ischemic stroke manifests as sudden onset of focal neurologic deficits, including aphasia, hemiparesis, hemisensory loss, vision loss, neglect, or ataxia. Intracerebral hemorrhage after thrombolysis may go unnoticed until cerebral dysfunction is caused by increasing blood volume. Key signs of symptomatic hemorrhagic transformation include headache, decreased level of consciousness, nausea, vomiting, marked elevation in blood pressure, and worsening of focal neurologic deficits.

Prognosis and complications

The definition of symptomatic intracerebral hemorrhage impacts the reported rates and outcomes. In the NINDS rtPA stroke study, symptomatic intracerebral hemorrhage was defined as any clinical worsening thought to be caused by a simultaneously diagnosed hemorrhage by neuroimaging (85). In the ECASS III trial, symptomatic intracerebral hemorrhage was defined as responsible for the clinical deterioration of four or more points on the NIH Stroke Scale (NIHSS) within 72 hours or death at 90 days of rtPA (47). Additional reviews favor a similar definition of parenchymal hemorrhage within 24 to 36 hours of treatment or death within 7 to 90 days (122; 128).

Intracerebral hemorrhage may be classified based on radiographic criteria: (1) hemorrhagic infarction type 1 for small petechiae, (2) hemorrhagic infarction type 2 for confluent petechiae without mass effect within an infarct, (3) parenchymal hemorrhage type 1 for hematomas involving less than 30% of the infarct with mass effect, and (4) parenchymal hemorrhage type 2 for hematomas involving greater than 30% of the infarct with mass effect (48).

Only the parenchymal hemorrhage type 2 has been associated with poor prognosis (116). Symptomatic hemorrhage predicts severe disability and 50% or greater 30-day mortality (109).

Biological basis

	• Hemorrhagic transformation is due to blood-brain barrier disruption and reperfusion that occurs after cerebral ischemic lesion.
	• Post-thrombolysis hemorrhage is most often asymptomatic.
	• Symptomatic intracerebral hemorrhage after thrombolysis occurs mostly within large strokes and may lead to worse neurologic dysfunction, morbidity, or death.

Etiology and pathogenesis

Hemorrhagic transformation of an ischemic infarct may occur spontaneously. The mechanism is reperfusion injury of the occluded vessel. In the NINDS trial, the frequency of symptomatic intracerebral hemorrhage was 0.6% in the placebo arm (85). Parenchymal hematoma, seen in approximately 3% of all ischemic stroke patients, occurs with large lesions, hyperglycemia, and thrombolysis (89). Uncontrolled systolic blood pressure may increase hematoma volume and worsen prognosis (79).

While restoring cerebral perfusion, thrombolysis also aggravates the disruption of the neurovascular unit and blood-brain barrier caused by ischemia. tPA stimulates the production of plasmin, an enzyme with lytic characteristics. In addition to fibrin, plasmin activated in contact with the blood clot attacks other proteins like fibrinogen, complement, casein, and gelatin, leading to impaired hemostasis, tissue damage, and bleeding. Additionally, tPA stimulates the production of matrix metalloproteinases types 2, 3, and 9 by the astrocytes, endothelium, and leukocytes, respectively. The reactive oxygen species contribute to additional damage and inflammation, particularly after recanalization (53). The reperfusion injury to the blood vessels results in bleeding (57). The severity and degree of ischemic injury to vasculature determine the risk of intracerebral hemorrhage during thrombolysis (49).

Epidemiology

	• Intravenous thrombolysis increases the risk of hemorrhagic transformation compared to placebo.
	• Several factors increase the likelihood of post-thrombolysis intracerebral hemorrhage: coagulopathy, head CT findings, uncontrolled hypertension, hyperglycemia, delayed treatment, advanced age, severe stroke, and incomplete healing from trauma, surgery, or stroke.

Introduction

The rate of reported intracerebral hemorrhage after thrombolysis varies with its definition, patient population, type of agent, dose, timing, route of administration, and concomitant treatments. In studies of myocardial infarction treatment, rtPA was responsible for intracerebral hemorrhage in approximately 1% of patients (67; 42). A better appreciation for hemorrhagic conversion of ischemic stroke following thrombolysis can be achieved by reviewing selected trials (Table 1).

Intravenous thrombolytic therapy

Alteplase (rtPA). The NINDS trial led to FDA approval of rtPA for ischemic stroke treatment within 3 hours of onset (85). Symptomatic intracerebral hemorrhage was defined as intracerebral hemorrhage diagnosed by CT and responsible for clinical worsening within 36 hours from treatment onset. Of the 312 patients treated with rtPA, 6.4% had a symptomatic intracerebral hemorrhage compared to 0.6% in the placebo arm. An additional 4.2% of patients treated with rtPA had asymptomatic hemorrhage diagnosed by CT scan at 24 hours as compared to 2.8% of placebo patients. Severe baseline neurologic deficit and cerebral edema or mass effect on the baseline CT scan were independently associated with an increased risk of symptomatic intracerebral hemorrhage. Nevertheless, these patients still benefited from thrombolysis (87).

Table 1. Incidence of Symptomatic Intracerebral Hemorrhage in Selected Randomized Clinical Trials Using Intravenous Thrombolytic Therapy +/- Endovascular Treatment in Acute Ischemic Stroke

Studies	No. of patients	Time window	Drug and dose	Symptomatic hemorrhage in treatment group	Symptomatic hemorrhage in control group
NINDS*	624	3 hours	rtPA 0.9 mg/kg	6.4%	0.6%
2006 ECASS III**	821	3 to 4.5 hours	72-hour infusion	2.4%	0.2%
2013 IMS-3	656	3 hours	0.9 mg/kg in IV group vs. 0.6 mg/kg + EV	6.2%	5.9%
2013 MR-Rescue	118	8 hours	Standard treatment vs. merci	4%	4%
2015 MR CLEAN	500	6 hours	IV tPA alone vs IV tPA + EV	7.7%	8.4%
2015 ESCAPE	306		IV tPA alone vs IV tPA + EV	3.6%	2.7%
2015 EXTEND IA	70		IV tPA alone vs IV tPA + stentriever	0%	5.7%
2015 SWIFT PRIME	196		IV tPA alone vs IV tPA + stentriever	0%	3.1%
REVESCAT	206		IV tPA alone vs IV tPA + stentriever	1.9%	1.9%
* Symptomatic hemorrhage was defined as a CT-documented hemorrhage that was temporarily related to a change in the patient’s clinical condition in the judgment of the clinical investigator. ** Hemorrhagic transformation associated with neurologic deterioration of 4 or more points on the NIHSS at 72 hours or causing death by 90 days.

Table 2. Risk Factors for Intracerebral Hemorrhage in Patients with Acute Ischemic Stroke

• Use of a thrombolytic agent
• CT findings of early infarction before treatment
• Hyperglycemia or history of diabetes mellitus
• Seve stroke as determined by the NIHSS score
• Longer time to treatment
• Concomitant antithrombotic drug use
• Older age
• Deviation from established treatment protocols
• Elevated systolic blood pressure before treatment
• Recent stroke

Additional trials (ECASS, ECASS II, ATLANTIS-a, ATLANTIS-b) exploring the use of similar or higher doses of rtPA for acute stroke up to 5 to 6 hours from onset revealed high rates of hemorrhagic conversion without a clinical benefit. Symptomatic intracerebral hemorrhage is more likely to occur with large infarction volume, severe deficits, advanced age, congestive heart failure, and the use of aspirin before thrombolysis (48; 23; 22; 62).

A pooled analysis of 2775 patients enrolled in randomized placebo-controlled trials of rtPA suggested a clinical benefit up to 4.5 hours from onset (46). The ECASS III trial confirmed this benefit despite a risk of symptomatic intracerebral hemorrhage of 2.4% (47). Another observational study of rtPA within the 3- to 4.5-hour window reported a 2.2% rate of symptomatic intracerebral hemorrhage at 7 days using the ECASS III definition (123). This led the American Heart Association/American Stroke Association to recommend the extension of the therapeutic window of rtPA to 4.5 hours after onset (30). A meta-analysis summarizing 26 randomized controlled trials that enrolled 7152 acute stroke patients, most of whom received rtPA within the 0- to 6-hour time window, found a three-fold increase in symptomatic intracerebral hemorrhage. Despite this, there was a significantly reduced chance of poor outcomes (127).

Approximately one in six strokes have an unknown time of onset, mostly when the symptoms are noted on awakening from sleep. If a lesion is visible on diffusion-weighted imaging but not on fluid-attenuated inversion recovery sequence, the stroke likely occurred earlier than 4.5 hours. This observation led to the use of tissue rather than a time window. A study that was stopped prematurely used MRI to determine eligibility for rtPA. The favorable outcome (mRS 0-1) was more frequent in the rtPA than in the placebo arm but without an increased risk of symptomatic intracerebral hemorrhage (125).

The tissue window facilitated by perfusion studies has been used to expand the therapeutic window. The patients likely to benefit have a relatively large ischemic penumbra compared to the core. A phase 3 multicenter, randomized, placebo-controlled trial that enrolled 225 patients within 4.5 to 9 hours from stroke onset found that rtPA increased the chance of excellent outcome, defined as a modified Rankin scale score of 0 to 1 at 90 days. There was no difference in mortality between the two arms. The rates of symptomatic intracerebral hemorrhage were 6.2% and 0.6% in the rtPA and placebo arms, respectively (66).

Intravenous rtPA in clinical practice. Following FDA approval of rtPA, symptomatic intracerebral hemorrhage rates of 3.3% to 3.8% were recorded in the clinical practice (03; 112; 101). The symptomatic intracerebral hemorrhage rate following rtPA administration within the 3-hour window reported by the SITS-MOST registry was 7.3% at 7 days, similar to that of clinical trials (122). In the community setting, the safety profile of rtPA within the 3- to 4.5-hour window was not different from that of ECASS III, with only a 2.4% symptomatic intracerebral hemorrhage rate (80).

Tenecteplase. Tenecteplase is a thrombolytic agent similar to rtPA but with fibrin specificity and longer activity than rtPA; it can be given as an intravenous bolus. Tenecteplase has become more popular than rtPA because of its ease of use and lower cost. Administered before endovascular thrombectomy for large vessel occlusion, tenecteplase resulted in a better 90-day functional outcome comparable to rtPA. The symptomatic intracerebral hemorrhage rate was 1% in both arms (EXTEND-IA TNK Investigators). Implemented on a larger scale, tenecteplase administered before mechanical thrombectomy is equally effective and safe as rtPA (50).

A meta-analysis of five randomized trials enrolling 1585 patients demonstrated that tenecteplase is noninferior to rtPA (11). An updated systematic review and meta-analysis of nine randomized trials searching for the optimal dose found that tenecteplase in a dose of 0.25 mg is the most viable candidate to displace rtPA as the standard of care of ischemic stroke within the 4.5-hour window. Although the recanalization rate of tenecteplase was superior to rtPA, the excellent neurologic outcome and hemorrhagic complications were not significantly different (01).

Endovascular therapy. Early studies demonstrated a higher recanalization rate of large arterial occlusion with intra-arterial thrombolysis than intravenous rtPA alone; however, the hemorrhagic complications were similar or greater (77).

The PROACT II study randomized 180 patients with acute middle cerebral artery occlusion earlier than 6 hours to intra-arterial pro-urokinase and heparin versus heparin alone. The 15% increase in favorable clinical outcomes was counterbalanced by a 10% symptomatic intracerebral hemorrhage rate, compared with 2% in the control group (40).

As pro-urokinase is no longer available, intra-arterial rtPA, endovascular thrombectomy, or a combination were used for large artery occlusion. The Interventional Management of Stroke (IMS) and the IMS-II studies evaluated intra-arterial rtPA administered following a reduced “bridging” dose (0.6 mg/kg) of intravenous rtPA. The symptomatic intracerebral hemorrhage rates were 6.6% and 9.9%, respectively (52; 51). The IMS-3 trial randomized acute stroke patients within 3 hours of onset to intravenous rtPA versus rtPA and endovascular therapy. The clinical outcomes were similar in both groups. The symptomatic intracerebral hemorrhage rates were 5.9% and 6.2% in the placebo and study group, respectively (08). Similar results were observed in the SYNTHESIS Expansion trial, which randomized patients within 4.5 hours of stroke onset. The symptomatic intracerebral hemorrhage rate was 6% in both groups (21).

The MERCI and the Multi MERCI trials evaluated the safety and efficacy of the endovascular clot retriever within 8 hours of symptom onset. The Multi MERCI trial demonstrated a higher recanalization rate (69.5% vs. 46%) and a higher symptomatic intracerebral hemorrhage rate (9.8% vs. 7.8%) when compared to the MERCI trial (104; 103).

The Penumbra catheter was evaluated in a single-arm study of patients with acute ischemic stroke within 8 hours of symptom onset due to intracranial large vessel occlusion. Successful recanalization was reported in 81.6% of treated vessels, and symptomatic intracerebral hemorrhage was reported in 11.2% of patients (92). The MR RESCUE trial compared endovascular thrombectomy to standard treatment. Each group was divided based on the core-penumbra mismatch. However, the clinical outcomes and symptomatic intracerebral hemorrhage rates were similar (58).

Following the completion of the IMS-3, SYNTHESIS Expansion, and MR RESCUE trials, it was still accepted that the combination of intra-arterial rtPA and intravenous plus intra-arterial rtPA resulted in a higher risk of symptomatic intracerebral hemorrhage than intravenous rtPA alone (102).

The introduction of the stent retriever has marked an important phase in endovascular thrombectomy. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN) that enrolled patients within 6 hours of onset demonstrated the superiority of the endovascular stentriever compared to the standard treatment. The symptomatic intracerebral hemorrhage rates were 6% and 8% in the control and treatment groups, respectively (83). Following the publication of MR CLEAN, several ongoing endovascular thrombectomy trials were discontinued early yet still produced positive results.

The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial had the most practical imaging selection protocol of CT head and multiphase CTA within 12 hours but was similar to the other trials. Outcomes included significant clinical improvement in the treatment group of 53% compared to 29% in the control group, no significant difference in symptomatic intracerebral hemorrhage at nearly 3% between the groups, and lower mortality in the treatment group (44).

SWIFT PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment of Acute Ischemic Stroke), EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial), and REVASCAT used only stentriever in the treatment group but differed in the imaging-based inclusion criteria. Although EXTEND-IA and SWIFT PRIME assessed penumbra-core ratios based on perfusion imaging, REVASCAT required only large vessel occlusion and ASPECTS scores. All these trials demonstrated significant improvement in the treatment group, but better recanalization rates were seen in EXTEND-IA and SWIFT PRIME, and similar rates of symptomatic intracerebral hemorrhage were seen in both control and treatment groups (14; 54; 99).

Meta-analysis of all five published 2015 trials and THERAPY, another endovascular in acute stroke trial presented at an International Stroke Conference in Glasgow, echoed improved outcomes with combination IV-tPA and endovascular acute stroke therapy. Additionally, combination therapy demonstrated lower symptomatic intracerebral hemorrhage rates, especially in those with the fastest treatment times. Following the publication of the above summarized endovascular stroke trials in 2015, urgent recanalization with IV-tPA followed by endovascular treatment has become the standard of care for acute ischemic stroke caused by large vessel occlusion (93).

Because of the concern for increased risk of symptomatic intracerebral hemorrhage caused by intravenous rtPA, the MR CLEAN-NO IV trial compared rtPA followed by endovascular thrombectomy with thrombectomy alone. Of 539 patients, 6% developed symptomatic intracerebral hemorrhage. rtPA administered before thrombectomy was not associated with an increased risk of symptomatic intracerebral hemorrhage (84). Data from The Endovascular Treatment in Ischemic Stroke (ETIS) registry suggest that the patients treated with rtPA before endovascular thrombectomy had a similar rate of symptomatic intracerebral hemorrhage as those treated with endovascular thrombectomy alone (6.0% vs 4.3%; p = 0.70) but had improved clinical outcome at 90 days (43). However, in mild strokes with NIHSS less than 5 due to large vessel occlusion, the addition of endovascular thrombectomy to intravenous rtPA was associated with a similar rate of symptomatic intracerebral hemorrhage (3.3% vs. 1.1%; p = 0.08) but worse clinical outcomes compared to rtPA alone (100).

Potential risk factors for post-thrombolysis symptomatic intracerebral hemorrhage

Advanced age, increased time to treatment, high systolic blood pressure, low platelet count, low plasminogen activator inhibitor levels, fibrinogen concentration, and prior antiplatelet use have also been associated with post-thrombolysis symptomatic intracerebral hemorrhage (68; 121; 124; 78; 79; 132). A systematic review of 12 studies identified several risk factors that are associated with hemorrhage after thrombolysis: elevated NIHSS, hyperglycemia or a history of diabetes, and CT characteristics (61). A more recent meta-analysis and systematic review of 120 studies that analyzed 100 risk factors, most reported in single studies only, found that the common predictors for symptomatic intracerebral hemorrhage after intravenous and endovascular thrombolysis were advanced age and hyperglycemia. Atrial fibrillation, high NIHSS, and onset-to-treatment time predicted symptomatic intracerebral hemorrhage after intravenous thrombectomy. A low ASPECTS score and a higher number of thrombectomy passes predicted symptomatic intracerebral hemorrhage after endovascular thrombectomy (110). The following are potential post-thrombolysis symptomatic intracerebral hemorrhage risks selected for further review.

Advanced age. In the NINDS trial, patients 80 years or older treated with rtPA had almost three times the likelihood of symptomatic intracerebral hemorrhage (63). Despite being an exclusion criterion in treatment within the 3- to 4.5-hour poststroke window in ECASS III, age alone has not been shown to offset the benefits of rtPA in stroke patients within 3 hours of onset.

Severe stroke. A high NIHSS score is associated with an increased risk of post-thrombolysis hemorrhage (87; 35; 24; 25). However, patients with severe strokes may still benefit from rtPA (87).

Recent stroke. A recent stroke, within 3 months, is a contraindication to rtPA because of the increased risk of hemorrhage into the necrotic tissue (94). In 50% of patients who experience a transient neurologic deficit, brain MRI demonstrates areas of diffusion restriction suggestive of acute infarction (96). The concern about an increased risk of bleeding after rtPA in patients with a recent transient ischemic attack was not confirmed (28; 72; 120). More recently, a recent stroke was not found to be associated with increased rtPA-induced symptomatic intracerebral hemorrhage but with an increased death rate (75).

Glycemic control. Hyperglycemia and a history of diabetes mellitus independently predict hemorrhage after rtPA (87; 10; 06; 134; 69). The mechanism is unknown. Nevertheless, rtPA may still be indicated if the focal symptoms persist after achieving glycemic control (31). The American Stroke Association recommends maintaining the glycemic level between 140 to 180 mg/dL during acute stroke (94).

Direct oral anticoagulant use. Stroke management guidelines recommend avoidance of intravenous rtPA in patients who received direct oral anticoagulants within 48 hours. However, an international multicenter retrospective cohort that included 33,207 patients did not find an increased risk of hemorrhage or worse outcomes (73).

Antiplatelet use. Several studies raised the concern of increased risk of symptomatic intracerebral hemorrhage after rtPA in patients who used antiplatelet medication (62; 112; 34). However, the functional outcomes in these patients were not worse than those not receiving antiplatelet therapy (121; 25; 131). Several systematic reviews and meta-analyses found no association between antiplatelet use or worse outcomes (76; 65; 117). A cohort study using the data from the Get With the Guidelines stroke registry of 320,493 patients found a small increase in the rate of symptomatic intracerebral hemorrhage and lower odds of discharge with mRS of 0 to 2 with dual antiplatelet use before rtPA, but comparable to the major clinical trials that demonstrated the benefit of rtPA (91).

Fibrinogen depletion. Consumption of fibrinogen during rtPA was associated with a higher risk of intracerebral hemorrhage (71; 97). However, it is unclear if fibrinogen repletion is likely to mitigate the bleeding risk.

Hypertension. Most stroke patients present with elevated blood pressure. Symptomatic intracerebral hemorrhage has been associated with high blood pressure before and after rtPA administration (32; 61; 123).

Imaging characteristics

Early signs of infarct. Early signs of ischemia on CT were found to predict an increased risk of symptomatic intracerebral hemorrhage following rtPA. These signs include hypoattenuation of the brain parenchyma, loss of cortical grey-white junction differentiation, and swelling with sulcal effacement (70; 07; 35; 62; 112; 25). Another study did not find such an association (90). The risk of symptomatic intracerebral hemorrhage was increased in rtPA-treated patients with prominent signs of edema or mass effect on the baseline CT in the NINDS rtPA Stroke Trial. Despite an increased risk of symptomatic intracerebral hemorrhage, these patients may still benefit from thrombolysis (87).

Large stroke. On brain MRI, DWI lesion volume predicted symptomatic intracerebral hemorrhage in a retrospective analysis of patients treated with intravenous and intra-arterial thrombolytics (29; 102). Restoration of blood flow in severely hypoperfused areas predicts parenchymal hemorrhage (12).

The Alberta Stroke Programme Early CT Score (ASPECTS) helps predict the functional outcomes and intracerebral hemorrhage risk following thrombolysis. ASPECTS quantifies the early ischemic changes on head CT visible in patients with anterior circulation stroke by subtracting 1 point for each area of hypodensity. A lower ASPECTS correlates with higher rates of post-thrombolysis symptomatic intracerebral hemorrhage (07; 112; 36).

When ASPECTS is applied to DWI (DWI-ASPECTS), lower scores correlate with symptomatic intracerebral hemorrhage after rtPA, whereas higher scores do not (86). ASPECTS + W (DWI-ASPECTS with DWI white matter scoring system) may be an even better predictor of symptomatic intracerebral hemorrhage risk following rtPA (56).

Leukoaraiosis. Leukoaraiosis or white matter disease was found to be associated with symptomatic intracerebral hemorrhage and worse clinical outcomes after intravenous thrombolysis in some but not all studies (05; 130; 18).

Fluid-attenuated inversion recovery hyperintensity on brain MRI. FLAIR hyperintensity on MRI occurs within 3 to 6 hours of stroke onset when intravenous thrombolysis is no longer thought to be beneficial. Moreover, white matter hyperintensities detected by FLAIR may indicate an increased risk of intracerebral hemorrhage and symptomatic intracerebral hemorrhage (20). Some patients develop hyperintensity on FLAIR before 4.5 hours from stroke onset. These patients are also at risk of developing symptomatic intracerebral hemorrhage (60). However, another study found no predictive value of FLAIR hyperintensity as it may not be visible, depending on image windowing (13).

Cerebral microbleeds. Another predictor of symptomatic intracerebral hemorrhage is the presence of cerebral microbleeds visible on T2-weighted imaging, susceptibility-weighted imaging, and fluid-attenuated inversion recovery sequences. Microbleeds detected on pre-treatment MRI are associated with symptomatic intracerebral hemorrhage (59). In a meta-analysis of nine studies of acute strokes treated with rtPA, the risk of symptomatic intracerebral hemorrhage in patients with more than 10 cerebral microbleeds was 12.1%; in those with 0 to 9 microbleeds, the risk was 7.01% (118). Another meta-analysis confirms that rtPA is associated with the risk of symptomatic intracerebral hemorrhage and poor outcomes in patients with cerebral microbleeds but did not determine its impact on the clinical outcome (19).

A retrospective study of 445 patients, of whom 15.7% had cerebral microbleeds on baseline MRI, did not show an increased risk of symptomatic intracerebral hemorrhage after endovascular thrombectomy (02). However, a systematic review and meta-analysis that included 1709 patients with cerebral microbleeds on baseline brain MRI found an increased risk of symptomatic intracerebral hemorrhage and worse outcomes than those without cerebral microbleeds after intravenous thrombolysis, endovascular thrombectomy, or a combination of these (115).

Risk scores for predicting post-thrombolysis intracerebral hemorrhage. The Multicenter Stroke Survey Scale was developed using markers identified in the Multicenter rtPA Stroke Survey of post-thrombolysis risk factors (112; 26). The risk factors used in this scale are age older than 60 years, NIHSS greater than 10, admission serum glucose greater than 150 mg/dL, and platelet count less than 150,000. The rate of symptomatic intracerebral hemorrhage using this tool was 0%, 5%, 4%, and 18% for 0, 1, 2, and 3 or more risk factors present, respectively (26).

The Hemorrhage After Thrombolysis (HAT) Score was developed by using a combination of previously published markers of increased post-thrombolysis hemorrhage risk that provided the highest predictive ability in their cohorts. A history of diabetes or admission glucose above 200 mg/dL, pretreatment NIHSS, and early CT hypodensity are the most important risk factors. The rate of symptomatic intracerebral hemorrhage using this scale was 2%, 5%, 10%, 15%, and 44% for HAT Scores of 0, 1, 2, 3, and more than 3, respectively (64).

The GRASPS score assigns points for hemorrhagic risks, including glucose at presentation (G), race (Asian) (R), age (A), sex (male) (S), systolic blood pressure (P), and stroke severity (S) based on the NIHSS score. GRASPS is the first prediction tool validated in a large national data set that is available to assist clinicians in calculating the symptomatic intracerebral hemorrhage risk after treatment with IV-tPA (74).

Additional scores include SEDAN (sugar, early infarct signs, dense artery, age, NIHSS) (107), THRIVE (with high scores correlating with older age, higher NISS, hypertension, diabetes, and atrial fibrillation) (38), and DRAGON (dense artery, Rankin score, age, glucose, onset to treatment time, and NIHSS) (108). In a small cohort of 89 patients, of whom 5.7% had symptomatic intracerebral hemorrhage, the HAT and DRAGON scores were the best predictors of the development of symptomatic intracerebral hemorrhage (88). A published analysis of the Third International Stroke Trial found a benefit from tPA regardless of the prediction scores (129).

Prevention

	• Prevention starts with proper patient selection for thrombolysis.
	• Adherence to the thrombolysis administration protocol is key.
	• Uncontrolled hypertension and hyperglycemia should be treated.
	• Minimize the delays in treatment.
	• Patients should be closely monitored after thrombolysis.

Patient selection. Prevention of intracerebral hemorrhage after thrombolysis starts with proper patient selection and adherence to the guidelines for thrombolytic therapy (93; 94). An urgently performed head CT scan helps exclude the patients with bleeding. Blood pressure should be managed promptly, and the patients should be monitored closely for neurologic deterioration in a stroke or intensive care unit.

Early treatment. Improving the clinical outcome relies on minimizing the interval from onset to thrombolysis. Analysis of the National Get with the Guidelines-Stroke Registry (GWTG-Stroke), reflecting clinical practice in the United States, demonstrates reduced mortality and symptomatic intracerebral hemorrhage with earlier thrombolytic treatment (98). Simultaneously, an immediate evaluation of the eligibility for endovascular thrombectomy is undertaken (93).

Large stroke. Successful endovascular recanalization in large vessel occlusion is associated with a reduction of post-treatment symptomatic intracerebral hemorrhage (126). Although large stroke was associated with an increased risk of symptomatic intracerebral hemorrhage, intravenous thrombolysis added to endovascular thrombectomy improved the outcome compared to endovascular intervention alone (33).

Blood pressure control. Rapid blood pressure control before thrombolysis was associated with greater early neurologic improvement but not adverse outcomes (27; 41). The target blood pressure before rtPA administration is below 185/110 mmHg (94).

MRI-guided thrombolysis. MRI may be used to select patients with unknown time of onset who might still benefit from thrombolysis. A multicenter trial that enrolled 503 patients out of 800 planned, prematurely discontinued because of insufficient funding, compared the MRI-guided thrombolysis with placebo. The patients in the rtPA arm had a better outcome than those who received placebo but without a significant difference in symptomatic intracerebral hemorrhage (2% vs. 0.4%) and death (114). However, in a meta-analysis of four clinical trials that included 843 patients, rtPA was associated with an increased shift towards good outcomes but with a significantly higher risk of symptomatic intracerebral hemorrhage, 3% versus less than 1% in the placebo arm, and death 6% versus 3% at 90 days, respectively (113). Analysis of data from 730 patients enrolled in a Norwegian stroke registry found that MRI-guided thrombolysis increased the odds of favorable outcomes compared to placebo in patients with wake-up stroke but not the risk of symptomatic intracerebral hemorrhage (4.4% vs. 3.9%) (106). Although there may be pathophysiologic and severity differences between the wake-up stroke and unwitnessed onset stroke, the patients treated with MRI-guided thrombolysis from these two groups had similar outcomes. In the wake-up stroke, the favorable outcome in the rtPA and placebo arms was 54.8% and 45.5%, respectively. The symptomatic intracerebral hemorrhage rate was 1.8% compared to 0.3% in the placebo arm (P=0.194), and the death rate was similar (55).

Glycemic control. Although hyperglycemia is associated with an increased risk of symptomatic intracerebral hemorrhage, intensive insulin infusion was not more effective than standard sliding scale regimens in preventing symptomatic intracerebral hemorrhage after rtPA (105).

White matter disease. The clinical studies demonstrating the benefit of rtPA did not exclude patients with white matter disease. Even though white matter disease was not a contraindication for rtPA, there is a concern that it may increase the risk of symptomatic intracerebral hemorrhage. In a study of 434 patients, the presence of white matter disease was not associated with worse outcomes after thrombolysis (15).

Cerebral microbleeds. Most patients receive thrombolysis based on the admission CT, which cannot exclude cerebral microbleeds. Although cerebral microbleeds indicate an increased risk of symptomatic intracerebral hemorrhage, thrombolysis should still be considered (16). In another study, cerebral microbleeds were not associated with worse outcomes after thrombolysis (15).

Management

	• Thrombolysis should be followed by close monitoring in a specialized unit. • The following measures are important in treating post-thrombolysis hemorrhage:
		- Maintenance of vital functions - Stop administration of thrombolysis - Check coagulation parameters - Reverse coagulopathy - Prevention of hematoma expansion.

General measures

If intracerebral hemorrhage is suspected, the thrombolytic drug should be discontinued, and the vital functions monitored and maintained. Urgent brain CT, coagulation testing, and neurosurgery consult should be obtained. Coagulopathy reversal should be considered (94). Other measures include monitoring for neurologic deterioration, prevention of hematoma expansion, maintenance of normal intracranial pressure, and prevention of complications like aspiration, sepsis, and seizures.

Prevention of hematoma expansion. Any intracerebral hemorrhage may be asymptomatic initially. More research is needed to determine to what degree controlling the risk factors reduces hematoma expansion. Hematoma expansion may be insidious initially, followed by rapid deterioration once detected clinically.

Reversal of coagulopathy. Indications for the reversal of thrombolysis-induced coagulopathy include (1) the risk of hematoma expansion, (2) symptomatic hemorrhage, and (3) the radiographic appearance of hematoma, suggesting parenchymal hematoma type 2.

Several blood products may be considered for correction of coagulopathy following thrombolysis: cryoprecipitate, fresh frozen plasma, prothrombin complex concentrate, vitamin K, and recombinant factor VIIa. There is little information about the optimal medication and approach for patients with thrombolytic-related hemorrhage.

Cryoprecipitate. Cryoprecipitate is recommended for most symptomatic intracerebral hemorrhage after thrombolysis (39). Because of the delay caused by the thawing of the cryoprecipitate, the fibrinogen level should be measured immediately, and 10 U of cryoprecipitate should be administered empirically. A repeat dose may be needed to elevate the fibrinogen level above 150 mg/dL (133). One retrospective study found no difference between conservative management and administration of clotting factors (fresh frozen plasma or cryoprecipitate) in patients with post-rtPA symptomatic intracerebral hemorrhage, suggesting that more research is needed (04).

Antifibrinolytics. Antifibrinolytics may be used if the cryoprecipitate is unavailable, contraindicated, or refused. Aminocaproic acid is usually administered, 4 to 5 g intravenously. Alternatively, 10 to 15 mg/kg intravenous tranexamic acid is given over 20 minutes (39).

Other blood products. Other blood products may be considered depending on the clinical situation. For example, platelet transfusions of 8 to 10 U should be reserved for patients with thrombocytopenia. Vitamin K, 10 mg intravenously, and fresh frozen plasma (12 mL/kg) or prothrombin complex concentrate (25 to 50 U/kg) may be useful in patients who received warfarin before thrombolysis. These procoagulant factors should be used cautiously, bearing in mind the risk of thromboembolism (133).

Blood pressure control. Uncontrolled hypertension is a risk factor for hematoma expansion in patients with spontaneous intracerebral hemorrhage. There is insufficient information regarding thrombolysis-related hemorrhage. The principles of treatment are derived from the guidelines for spontaneous intracerebral hemorrhage.

Although uncontrolled hypertension is associated with hematoma expansion, the clinical trials of aggressive control of systolic blood pressure to less than 140 mmHg failed to improve the outcomes (95). It is unclear what the blood pressure target is for symptomatic intracerebral hemorrhage after thrombolysis.

A balance must be struck between the risk of hematoma expansion and hypoperfusion of ischemic brain tissue. To avoid peaks and high variability, the blood pressure reduction should be smooth, continuous, and sustained (82). If blood pressure lowering is considered, initiation within 2 hours and reaching the target within 1 hour may prevent hematoma expansion in patients with spontaneous intracerebral hemorrhage. However, lowering systolic blood pressure below 130 mmHg is potentially harmful (45).

Hematoma evacuation. Hematoma evacuation plays a limited role in patients with spontaneous intracerebral hemorrhage. After thrombolysis, the neurosurgical evacuation of hematoma presents several challenges: coagulopathy, patient selection, timing, and the optimal technique. Cerebellar lesions causing tissue herniation and brainstem dysfunction, as well as large supratentorial hematomas causing herniation and coma, which are refractory to medical treatment, may be considered for neurosurgical evacuation (133). Patients with hypertensive intracerebral hemorrhage may benefit from minimally invasive surgery that avoids the complications related to craniotomy.

Outcomes

Data from Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) reveal that only 2.8% achieved good clinical outcomes (mRS 0-2) and 80.9% died within 3 months. Baseline NIHSS and simultaneous local and remote hematoma predicted mortality within 24 hours. At 3 months, mortality was predicted by advanced age, high baseline NIHSS, degree of change in NIHSS, hyperglycemia, and simultaneous local and remote hematoma location (119).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Adrian Marchidann MD

Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.
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Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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Former Authors

Joseph P Broderick MD
Christine AC Wijman MD
Shylaja Rachabattula MD
James S McKinney MD
Steven R Messe MD
Kathleen Burger DO

Patient Profile

Age range of presentation: 45 to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Intracerebral hemorrhage, unspecified: I61.9

Nontraumatic epidural haemorrhage: I62.1

Occlusion and stenosis of other cerebral artery: I66.8

Acute cerebrovascular insufficiency NOS: 167.8

Cerebrovascular accident NOS: I64
ICD-11: Intracerebral haemorrhage, site unspecified: 8B00.Z

Nontraumatic epidural haemorrhage: 8B03

Cerebral ischaemic stroke of unknown cause: 8B11.5

Stroke not known if ischaemic or haemorrhagic: 8B20

Other specified cerebrovascular disease: 8B22.Y

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Intracerebral hemorrhage due to thrombolytic therapy

Associated Disorders

Ischemic stroke
Hemorrhagic stroke
Cerebral arterial occlusion

Differential Diagnosis

worsening brain ischemia
progressive brain edema and mass effect
nonconvulsive seizures due to ischemic stroke
sepsis
pneumonia
- myocardial infarction
- acute heart failure
- severe hyperglycemia

Also Relevant

Alteplase (tissue plasminogen activator)
Cerebral venous thrombosis
Cerebral venous thrombosis in infants and children
Hypertensive intracerebral hemorrhage
Nontraumatic intracerebral hemorrhage
- Stroke associated with myocardial infarction
- Stroke: supportive care
- Stroke therapy

Clinical Categories

Stroke & Vascular Disorders

Web References

Clinical Trials

NIH: Intracerebral Hemorrhage

	• Worsening brain ischemia
	• Progressive brain edema and mass effect
	• Convulsive or nonconvulsive seizures due to ischemic stroke
	• Concomitant serious medical conditions such as sepsis, pneumonia, myocardial infarction, acute heart failure, or severe hyperglycemia.

	• If hemorrhagic transformation is suspected (headache, nausea, vomiting, or neurologic worsening), a CT of the head should be obtained immediately.
	• Check coagulation parameters, including fibrinogen level.

Intracerebral hemorrhage due to thrombolytic therapy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Introduction

Intravenous thrombolytic therapy

Table 1. Incidence of Symptomatic Intracerebral Hemorrhage in Selected Randomized Clinical Trials Using Intravenous Thrombolytic Therapy +/- Endovascular Treatment in Acute Ischemic Stroke

Table 2. Risk Factors for Intracerebral Hemorrhage in Patients with Acute Ischemic Stroke

Potential risk factors for post-thrombolysis symptomatic intracerebral hemorrhage

Imaging characteristics

Prevention

Differential diagnosis

Diagnostic workup

Management

General measures

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

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Neuroimaging in acute stroke

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