Clinical manifestations

Presentation and course

	• Post-thrombolysis hemorrhagic transformation may be unnoticed until it is large enough to cause cerebral 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 often manifests as a sudden onset of focal 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 ischemic stroke with symptomatic hemorrhagic transformation include headache, a decrease in the level of consciousness, new nausea and vomiting, marked elevations in blood pressure, and worsening of focal neurologic deficits.

Prognosis and complications

Hemorrhage into an infarct is more likely to occur in a large infarction, which carries a poor prognosis independent of hemorrhagic transformation. Uncontrolled systolic blood pressure may promote post-thrombolysis hematoma expansion and worsens prognosis (67). Symptomatic hemorrhage predicts severe disability and death (89). In fact, symptomatic hemorrhage is associated with a 50% or greater 30-day mortality.

Biological basis

	• Hemorrhagic transformation is due to blood-brain barrier disruption and reperfusion that occurs after an acute ischemic stroke.
	• Post-thrombolysis hemorrhagic transformation is most often asymptomatic.
	• Symptomatic intracranial hemorrhage following thrombolysis mostly occurs after large ischemic strokes and leads to worsening of neurologic function, morbidity, and mortality.

Etiology and pathogenesis

Asymptomatic hemorrhagic transformation of an ischemic infarct (hemorrhagic infarction) is common and can occur even in the absence of thrombolytic or antithrombotic therapy. Hemorrhagic transformation has been shown to be particularly common in large-volume lesions of cardioembolic origin. However, the rate of symptomatic intracerebral hemorrhage, defined as new or worsening clinical symptoms likely due to the blood apparent on repeat imaging, is much lower. Symptomatic intracerebral hemorrhage (sICH) occurred in 0.6% of patients enrolled in the placebo arm of the NINDS rtPA trial (71). The traditional view has been that hemorrhagic infarction results from reperfusion of the vascular bed after recanalization of the blocked vessel. The more robust the reperfusion and the more severe the injury to both the vessel wall and blood-brain barrier, the more severe the hemorrhagic transformation, which may be aggravated by the presence of a thrombolytic agent.

Symptomatic intracerebral hemorrhage may be classified based on radiographic criteria alone or in combination with the presence or severity of clinical deterioration. The radiographic scheme includes the following four subgroups: (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 (40). Parenchymal hemorrhage type 2 has been correlated with poor clinical outcome (92). Parenchymal hematoma, seen in about 3% of all ischemic stroke patients, is increased in large ischemic lesions, high blood glucose, and treatment with thrombolysis (74).

The classification of symptomatic intracerebral hemorrhage has varied across studies and generally has used both radiographic and clinical criteria. In the NINDS rtPA stroke study, symptomatic intracerebral hemorrhage was defined as any clinical worsening temporally associated with radiographic evidence of hemorrhage in the opinion of the treating physician (71). The ECASS III trial incorporated more stringent criteria, defining symptomatic intracerebral hemorrhage as hemorrhage causally associated with a clinical deterioration of 4 or more points on the NIH Stroke Scale (NIHSS) within 72 hours or death at 90 days (39). Additional reviews seem to prefer a similar definition of parenchymal hemorrhage on imaging and symptomatic worsening of 4 or more points on the NIHSS within 24 to 36 hours of treatment or death within 7 to 90 days (95; 100). Not surprisingly, the choice of definition of symptomatic intracerebral hemorrhage has a considerable impact on reported hemorrhage rates.

The risk of intracerebral hemorrhage associated with thrombolysis stems from the basic physiology of thrombolytic agents and the pathophysiology of ischemia. Disruption of the blood-brain barrier that occurs with both ischemia and reperfusion contributes to hemorrhagic transformation without, and even more so, with thrombolysis therapy (50). All thrombolytic agents, whether fibrin-specific, such as rtPA, or fibrin-nonspecific, such as streptokinase, stimulate plasmin. Plasmin is a protease that cleaves fibrin as well as other proteins. If the fibrin happens to be part of a clot blocking a damaged blood vessel, lysis of the clot can lead to extravasation of blood into the tissue surrounding the blood vessel. The severity and amount of ischemic damage to blood vessels are directly related to the risk of intracerebral hemorrhage when using a thrombolytic agent (42). Thus, one would expect an increased risk of intracerebral hemorrhage in patients with severe ischemic damage to large brain regions, and a prolonged duration of ischemia, leading to disruption of the blood-brain barrier that may amplified with reperfusion following thrombolysis treatment.

Epidemiology

	• Treatment with intravenous thrombolysis increases the risk of hemorrhagic transformation compared to placebo.
	• Several factors increase the likelihood of post-thrombolysis bleeding: 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 intracerebral hemorrhage following thrombolytic therapy depends on the agent, dose, timing, route of administration, patient population, concomitant treatments, and the definition of hemorrhage used. Prior to the use of IV-tPA in stroke, intracerebral hemorrhage occurred 1% or less in patients receiving thrombolytic therapy for myocardial infarction (58; 34). A great appreciation for hemorrhagic conversion of ischemic stroke following thrombolytic therapy can be accomplished through review of selected trials (Table 1).

Intravenous thrombolytic therapy. The NINDS rtPA Stroke Study formed the basis for FDA approval of intravenous rtPA for acute ischemic stroke within 3 hours of symptom onset (71). Symptomatic intracerebral hemorrhage attributable to study drug was defined as a CT-documented hemorrhage, which was temporally related to a change in the patient's clinical condition in the judgment of the clinical investigator within 36 hours from treatment onset. Of the 312 patients treated with rtPA, 6.4% of patients had a symptomatic intracerebral hemorrhage compared to 0.6% of placebo-treated patients. An additional 4.2% of patients treated with rtPA had an asymptomatic hemorrhage on a protocol-mandatory CT scan at 24 hours as compared to 2.8% of placebo patients. A severe baseline neurologic deficit, as measured by the NIHSS, and the presence of edema or mass effect on the baseline CT scan were independently associated with an increased risk of symptomatic intracerebral hemorrhage in the NINDS trial (73). However, these patients were still likely to benefit from use of the medication.

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 prior to 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 prior to treatment • Recent stroke

Additional trials done around or shortly after the NINDS trial (ECASS, ECASS II, ATLANTIS-a, ATLANTIS-b) exploring use of similar or higher doses of IV-tPA for patients with acute stroke up to 5 or 6 hours following symptom onset often resulted in unacceptable rates of hemorrhagic conversion without clinical benefit (40; 17; 16; 55). sICH is more likely to occur with large infarction volume, severe deficits, advanced age, congestive heart failure, and the use of aspirin prior to thrombolysis. A pooled analysis including 2775 patients enrolled in randomized placebo-controlled trials of intravenous rtPA indicated that there may be a clinical benefit up to 4.5 hours from symptom onset (38). This was confirmed by the ECASS III trial (39). Treatment with rtPA significantly increased odds of a favorable outcome at 3 months, whereas sICH, defined as hemorrhage causally associated with a clinical deterioration of 4 or more points on the NIHSS or death, was 2.4% in the rtPA treatment arm and 0.2% in the placebo arm. A separate observational study of patients treated with intravenous rtPA between 3 and 4.5 hours reported a 2.2% rate of symptomatic intracerebral hemorrhage at 7 days using the ECASS III definition (96). This led to the American Heart Association/American Stroke Association (AHA/ASA) 2009 guideline update recommending intravenous rtPA for eligible patients with acute ischemic stroke up to 4.5 hours after symptom onset (23).

Intravenous rtPA in clinical practice. Initial concerns of a potentially higher risk of intracerebral hemorrhage associated with intravenous rtPA outside the clinical trial setting were refuted by several studies supporting safety of rtPA in clinical practice comparable to that of the NINDS rtPA trial (01; 91). Following FDA approval of rtPA for ischemic stroke, the Standard Treatment with Alteplase to Reverse Stroke study (STARS) and the Canadian Alteplase for Stroke Effectiveness Study (CASES), both aiming to show safety and efficacy of rtPA in clinical practice, found lower than expected symptomatic intracranial hemorrhage (sICH) rates of 3.3% and 3.8%, respectively (01; 83).

The SITS-MOST registry also reported that patients treated with intravenous rtPA 0 to 3 hours following onset of acute ischemic stroke in clinical practice were similar to those enrolled in clinical trials, with a rate of symptomatic intracerebral hemorrhage (using the NINDS rtPA trial definition) of 7.3% at 7 days (95). The safety profile demonstrated in ECASS III was also matched in a community setting when IV-tPA was provided to stroke patients within the 3- to 4.5-hour window with only a 2.4% sICH rate (68).

A meta-analysis published by the Cochrane Database of Systematic Reviews in 2009 summarized the data of 26 randomized controlled trials (majority IV-tPA in the 0- to 6-hour time window except for a few intra-arterial thrombolysis focused trials) completed by 2009 in 7152 acute stroke patients (99). Overall, the odds of symptomatic intracranial hemorrhage were increased 3-fold (odds ratio 3.49, 95% confidence interval 2.81 to 4.33) in patients who received thrombolysis. Despite this, there was a significantly reduced chance of poor outcome (combined death and dependency) during follow-up in patients who received thrombolytic therapy.

Some patients have microbleeds that are seen on imaging, raising the question of the safety of thrombolysis. A meta-analysis that included patients with prior microhemorrhages did not reveal an increased risk of thrombolysis (36).

Endovascular therapy. Early studies demonstrated higher lysis rates with endovascular delivery of thrombolytic therapy to large cerebral vessels; however, rates of endovascular-induced hemorrhage were similar to or greater than that seen in studies using IV-tPA alone, even when performed by experienced individuals (65). The PROACT II study randomized 180 patients with an acute middle cerebral artery occlusion of less than 6 hours duration to intra-arterial pro-urokinase and intravenous heparin infusion or heparin alone (32). A 15% absolute increase in favorable clinical outcome was found in the treatment group; however, an increased sICH rate was observed in 10% of the treatment group compared with 2% in the control group. Pro-urokinase never received FDA approval, nor was it made commercially available, creating a need for randomized clinical trials (in acute stroke) using obtainable aggressive treatments such as intra-arterial tPA, mechanical devices, or combination IV-tPA with endovascular therapy. 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; safety of the bridging protocol was shown, along with sICH rates of 6.6% and 9.9% respectively (44; 43). The IMS-3 trial randomized acute stroke patients within 3 hours of symptom onset to IV-tPA alone or combination IV-tPA and endovascular therapy. Surprisingly, clinical outcomes were similar in both groups, as were sICH rates of 5.9% and 6.2% in the placebo and study groups respectively (07). The Synthesis Expansion trial attempted to randomize patients within 4.5 hours of stroke onset into either an endovascular group where any type of accepted intervention was allowed or a control group where IV-tPA alone was provided. Results of this trial also showed no difference in outcome nor in sICH rates (6% in both groups); however, onset of treatment in endovascular patients was approximately 1 hour later than the IV-tPA-treated patients (15).

As early trials with emphasis on intra-arterial tPA were nearing completion, increased attention was placed on mechanical thrombectomy to promote arterial recanalization. Initially available were two catheter systems, the Merci Retriever® (Concentric Medical, Inc., Mountain View, CA) and the Penumbra System® (Penumbra, Inc., Alameda, CA). Later, two retrievable stents, Solitaire™ FR Revascularization Device and Trevo Device, were also used for revascularization of patients with acute ischemic stroke secondary to large vessel occlusive disease. The MERCI and the Multi MERCI trials evaluated the safety and efficacy of the Merci clot retriever system in the treatment of ischemic stroke patients with a large vessel occlusion within 8 hours of symptom onset. Multi MERCI showed both a higher recanalization rate (69.5% vs 46%) and higher sICH rate (9.8% vs 7.8%) than that seen in MERCI, but both compared well to the placebo arm of PROACT II recanalization rate of 18% (86; 85). The Penumbra catheter was evaluated in a single-arm study of patients with acute ischemic stroke within 8 hours of symptom onset with a treatable intracranial large vessel occlusion (76). Patients who were refractory to intravenous rtPA were included. Successful recanalization was reported in 81.6% of treated vessels, whereas sICH was reported in 11.2% of patients. MR Rescue was then designed with a goal to compare patients receiving Merci clot retriever or Penumbra system to standard treatment, with each group further divided into those with good MRI penumbral patterns (small infarct core and substantial salvageable brain tissue) and those without (large infarct core with little to no salvageable tissue). Despite an advanced imaging protocol with potential to improve selection of thrombolytic candidates, outcomes and sICH rates were similar in all groups (51). Although not heavily studied in these early randomized trials, the “stentriever” (Solitaire™ FR Revascularization Device and Trevo Device retrievable stents) did make their way onto the scene in the later years of the IMS-3 investigation (14). Stent retrievers were considered underrepresented in IMS-3 by most experts, deserving of further investigation in acute stroke. Following completion of the 2013 published studies, (IMS-3, Synthesis expansion, MR RESCUE) it was still widely accepted that treatment of acute stroke with combination IV-tPA and endovascular therapy or endovascular treatment alone independently predicted a high risk of symptomatic intracerebral hemorrhage (84).

The early endovascular stroke trials mentioned so far were flawed with one or more of the following: use of commercially unavailable agents, under-dosed IV-tPA groups, nonspecific patient selection, delayed treatment times, rare use of new thrombectomy devices, and prolonged trial completion times. New trials were needed to assess efficacy of endovascular therapy in acute ischemic stroke through expedited treatment protocols using newer devices with timely completion of trials. Pragmatic style, preference for stent retrievers (stentrievers), imaging proof of cerebral large vessel occlusion, and consistent use of similar outcome measures, were indeed recurrent themes amongst all new generation endovascular stroke trials. Additional consistencies in all new trials included prospective 1:1 randomization of patients treated with IV-tPA alone (control group) compared to combination IV-tPA and endovascular treatment (treatment group), open label with blinded endpoints, carefully monitored treatment times, and several outcome measures. Outcomes always included were rates of sICH and the modified Rankin scale (mRS), where mRS score of 0 to 2 was considered good outcome consistent with a patient’s ability to live independently.

The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) was the first new generation endovascular stroke trial published (and only one to complete its planned enrollment) that enrolled and randomized 500 stroke patients within 6 hours of symptom onset to control and treatment groups (06). Results favored intervention with mRS score of 0 to 2 found more frequently in the endovascular treatment group, whereas sICH rates were 6% and 8% in the control and treatment groups respectively (06). Following publication of MR CLEAN, several ongoing endovascular stroke trials were terminated early due to futility, 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 and allowed treatment with endovascular therapy up to 12 hours but otherwise was similar to the other trials (35). Outcomes included significant clinical improvement in the treatment group of 53% compared to 29% in the control group, no significant difference with regards to sICH at near 3% in both groups, whereas mortality was lower in the treatment group. 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 were all similar in that they allowed use of only stentriever devices in the treatment group. Differences occurred within the imaging inclusion criteria where EXTEND-IA and SWIFT PRIME required perfusion imaging demonstrating good penumbra-core ratios, and REVASCAT required only large vessel occlusion and ASPECTS scores. The three trials all demonstrated significant improvement in the treatment group, although better recanalization rates were seen in EXTEND-IA and SWIFT PRIME, and similar rates of sICH were seen in both control and treatment groups (12; 47; 82).

Meta-analysis of all five published 2015 trials and THERAPY, another endovascular in acute stroke trial presented at an International Stroke Conference in Glascow, echoed improved outcome with combination IV-tPA and endovascular acute stroke therapy. Additionally, combination therapy demonstrated lower sICH rates, especially in those with the fastest treatment times (77). Following publication of the above summarized endovascular stroke trials in 2015, expedient recanalization with IV-tPA and endovascular treatment has become the standard of care for acute ischemic stroke caused by large vessel occlusion (77). Symptomatic intracerebral hemorrhage rates are now known to be similar or potentially lower in patients receiving expedited endovascular therapy while delivering improved outcomes, commanding endovascular treatment into mainstream comprehensive stroke care.

Potential risk factors for post-thrombolysis symptomatic intracerebral hemorrhage. A systematic review of 12 studies identified a few risk factors that are associated with hemorrhagic transformation: CT characteristics, elevated serum glucose or a history of diabetes, and elevated NIHSS (53). Lansberg and colleagues identified 12 studies that met their inclusion criteria, of which CT characteristics, elevated serum glucose or history of diabetes, and elevated NIHSS repeatedly were found to be independently associated with post-thrombolysis symptomatic intracerebral hemorrhage (53). 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 sICH in various publications (59; 94; 97; 66; 67; 104). However, not all risks were consistently replicated in follow-up studies. The following are potential post-thrombolysis sICH risks selected for further review.

Hyperglycemia and a history of diabetes mellitus independently predict hemorrhage in stroke patients treated with thrombolytic therapy (73; 09; 04), as well as lead to worse outcomes 3 months post-stroke (78). Both acute and chronic hyperglycemia as well as continuous and episodic post-thrombolysis hyperglycemia have all been implicated in contributing to tPA-induced sICH (107; 60). The exact pathophysiologic connection between glucose and post-thrombolysis hemorrhage is unclear. Current American Stroke Association guidelines recommend maintaining blood glucose within the 140 to 180 mg/dL range during hospitalization for acute stroke (46) and allow consideration of treatment with tPA in patients presenting with acute stroke where focal symptoms persist after attempts are made to treat hyper- or hypoglycemia (24). No guidelines are available regarding glucose management during tPA administration (41).

Severe stroke, indicated by high NIHSS scores, is associated with an increased risk of post-thrombolysis hemorrhage (73; 28; 18; 19). Despite a higher risk of hemorrhage, patients with severe strokes are still more likely than not to benefit from thrombolytic therapies (73). Ischemic stroke patients 80 years of age and older treated with thrombolysis had almost 3 times the likelihood of sICH development in the NINDS trial (56). Despite being chosen as 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 thrombolysis in stroke patients within 3 hours of onset.

Prior antiplatelet use is thought to increase the rate of thrombolytic-associated intracerebral hemorrhage; however, reports of acetylsalicylic acid (ASA) use preceding IV-tPA -treated strokes have provided conflicting results (55; 91; 94). Patients receiving dual antiplatelet therapy with acetylsalicylic acid and clopidogrel may have particularly greater risk of thrombolysis-related sICH (19). In the SITS-MOST database, the rates of sICH were reported to be: 1.1% for antiplatelet naïve patients, 2.5% for any antiplatelet use, 2.5% for acetylsalicylic acid monotherapy, 1.7% for clopidogrel monotherapy, 2.3% for acetylsalicylic acid plus dipyridamole, and 4.1% for acetylsalicylic acid and clopidogrel (27). Although the rate of sICH is higher in those receiving antiplatelet therapy before stroke, improved functional outcomes have been reported in tPA-treated patients when compared to those not receiving antiplatelet therapy (103). Antiplatelet use should not exclude otherwise appropriate patients from acute therapy. In fact, newer publications are now reporting no increased risk of sICH in acute stroke patients with prior antiplatelet use treated with IV-tPA (93) or endovascular stroke therapy (64).

Most stroke patients who are tPA candidates present with elevated blood pressure; however, high rates of sICH have been shown in those patients with high pre- and post-tPA treatment blood pressure recordings (53; 96). High risk of sICH has occurred in studies where elevated blood pressure was found during the initial 24 hours following thrombolysis (26). Aggressive blood pressure control prior to thrombolysis did not correlate with adverse outcomes in one study (21), whereas another publication demonstrated greater early neurologic improvement when systolic blood pressure was restored toward normal limits (33). Guidelines have, thus, evolved over the years to allow aggressive therapies in order to obtain blood pressure readings lower than 185/110 prior to treatment with tPA (46).

A recent stroke within 3 months of an acute infarction is frequently listed as a contraindication to treatment with intravenous thrombolysis because of a perceived risk of increased hemorrhage risk into necrotic tissue (46). Up to 50% of patients who have experienced a transient ischemic attack actually experienced subclinical acute strokes, demonstrated by diffusion-weighted positive areas on MRI (80). There may be an increased risk of hemorrhagic transformation with thrombolysis in stroke patients who report a recent transient ischemic attack; however, data are conflicting. One study reported the rate of sICH in this group to be 8.3% (61), and another reported no influence of recent transient ischemic attack on post-thrombolysis outcomes (22). The most updated literature suggests that recent stroke is not associated with increased tPA-induced sICH but is associated with increased death rates (63).

Imaging characteristics. Several studies have demonstrated an increased risk of intracerebral hemorrhage following intravenous rtPA treatment in patients with evidence of early infarct signs on CT (73; 25; 45; 05; 28; 55; 91; 19). These early ischemic changes include hypoattenuation of the brain parenchyma, loss of cortical grey-white junction differentiation, and swelling with sulcal effacement. 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 (75).

The Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitated CT score that helps predict functional outcome and intracerebral hemorrhage risk following thrombolytic therapy for acute ischemic stroke (05). This score quantifies early ischemic CT changes in patients with anterior circulation strokes by subtracting points for each area of hypodensity. Several studies have correlated lower ASPECTS with higher rates of post-thrombolysis hemorrhage (91; 29).

Leukoaraiosis on CT of the brain is associated with an increased risk of symptomatic hemorrhagic transformation and worse clinical outcomes in tPA-treated stroke patients when compared to patients without leukoaraiosis (03; 102); however, rtPA should not be withheld in such cases. Despite increased risk of sICH in patients with subtle but common early infarct signs on CT, such imaging findings should not prevent an otherwise eligible patient from being treated with thrombolytic therapy where favorable outcome usually outweighs risk. Future investigation will search for imaging predictors in endovascular treatment of acute stroke, such as showing that CTA with APECTS may allow prediction of poor outcome despite successful recanalization of a large vessel occlusion (49).

On brain MRI, DWI lesion volume predicted sICH in a retrospective analysis of patients treated with both intravenous and intra-arterial thrombolytics (53b; 84). Restoration of blood flow to ischemic brain with pretreatment regions of very low cerebral blood flow on perfusion-weighted imaging was a strong predictor of parenchymal hemorrhage (10). When ASPECTS is applied to DWI (DWI-ASPECTS), lower scores are associated with post tPA sICH as would be expected, whereas higher DWI-ASPECTS is not without risk (72). ASPECTS + W (DWI-ASPETS with DWI white matter scoring system) may be a better predictor of sICH risk following tPA (48).

Other potential MRI post-thrombolysis sICH predictors include use of T2* weighted MRI imaging and fluid-attenuated inversion recovery (FLAIR) sequences. Microbleeds on pretreatment T2* MRI sequence are associated with new post-treatment microbleeds and subsequent increased sICH (52). FLAIR hyperintensity on MRI seen within hours of stroke onset is thought to be associated with infarction that has evolved beyond the opportunity for thrombolysis; however, other studies have not validated sICH risk when FLAIR hyperintensities are seen in thrombosed patients 3 to 6 hours after stroke onset (11).

Risk scores for predicting post-thrombolysis intracerebral hemorrhage. Several groups have proposed risk-scoring systems to better quantify the hemorrhagic risk associated with thrombolytic treatment of acute ischemic stroke. The Multicenter Stroke Survey Scale was developed using markers identified in the Multicenter rtPA Stroke Survey of post-thrombolysis risk factors (91; 20).

The risk factors used in this scale are age greater than 60 years, NIHSS greater than 10, admission serum glucose greater than 150 mg/dL, and platelet count less than 150,000. This scoring system was both developed and tested using the Multicenter rtPA Stroke Survey data set and has not been validated in an independent prospective cohort. 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 (20). The Hemorrhage After Thrombolysis (HAT) Score was developed using a combination of previously published markers of increased post-thrombolysis hemorrhage risk that provided the highest predictive ability in their cohorts (57). Using this method, the authors identified a history of diabetes or admission glucose above 200 mg/dL, pretreatment NIHSS, and early CT hypodensity as 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. This scale was largely derived and refined from the NINDS trial data set and has only independently been validated in a single small cohort of patients at the authors’ institution. 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 determination of symptomatic intracerebral hemorrhage risk following treatment with IV-tPA (62). Additional scores include SEDAN (sugar, early infarct signs, dense artery, age, NIHSS) (87), THRIVE (with high scores correlating with older age, higher NISS, and whether or not patients have hypertension, diabetes, and/or atrial fibrillation) (30), and DRAGON (dense artery, Rankin score, age, glucose, onset to treatment time, and NIHSS) (88).

Initially, it was thought that clinical risk-scoring schemes could provide clinicians with an additional tool to better estimate the risks associated with thrombolytic treatment in an individual patient. A published analysis of the Third International Stroke Trial looked at scoring potential of the above-mentioned scores as well as several others, as they pertain to prediction of sICH and overall outcome. Patients were found to have more benefit than risk when treated with tPA regardless of concerning sICH prediction scores, and clinical prediction scores may not play nearly as much of a role in patient selection for tPA treatment as initially thought (101).

Prevention

	• Prevention starts with proper patient selection for thrombolysis.
	• Adherence to thrombolysis administration protocol is key.
	• Risk factors, such as uncontrolled hypertension and hyperglycemia, should be treated.
	• Avoid delays in treatment.
	• Patients should be closely monitored after thrombolysis.

Prevention of intracerebral hemorrhage due to thrombolytic therapy treatment in acute ischemic stroke starts with proper patient selection and adherence to established treatment protocols. Patients should be treated in accordance with the guidelines for thrombolytic therapy published by the American Heart Association (46; 77). The admission CT scan must be evaluated to rule out bleeding and early signs of a large infarction before using rtPA. Furthermore, blood pressure must be managed carefully and sometimes aggressively, and patients should be monitored in the stroke unit or intensive care unit. Study of improved selection of tPA candidates through use of CT or MRI perfusion is underway to look for possible reduction of hemorrhagic complications.

Current strategies to improve clinical outcomes in tPA-treated patients focuses on reduction of time from hospital arrival to initiation of thrombolysis. Analysis of the National Get With the Guidelines-Stroke Registry (GWTG-Stroke), representing clinical practice in the United States, demonstrates reduced mortality and sICH with earlier thrombolytic treatment, supporting improved and rapid treatment of patients with acute stroke (81). Guidelines regarding stroke systems of care are now moving toward timely administration of endovascular acute stroke therapy in those patients with stroke caused by large vessel occlusions (77). Successful endovascular-induced recanalization in large vessel occlusion strokes is now trending toward reduction of post-treatment sICH; however, publications are pending regarding the timeliness of reperfusion being associated with reduced post-thrombolysis sICH (98).

Differential diagnosis

The differential diagnosis of post-thrombolysis hemorrhage consists of conditions that may cause additional neurologic deterioration in a patient with an ischemic stroke:

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

Diagnostic workup

	• 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.

Symptomatic intracerebral hemorrhage following thrombolysis is associated with early neurologic deterioration, more so than any other clinical presentation (69). If brain hemorrhage is suspected, rtPA infusion should be stopped if it has not already been completed, and a CT scan of the head should be obtained immediately. Blood should be drawn to measure prothrombin time, activated partial thromboplastin time, platelet count, hemoglobin, and fibrinogen levels. Blood should be typed and cross-matched.

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

If brain hemorrhage is suspected, the American Heart Association recommends the maintenance of vital functions like breathing and circulation, including blood pressure control, discontinuing the thrombolytic drug, performing rapid brain imaging, performing coagulation tests, obtaining an emergent neurosurgery consult, and considering coagulopathy reversal (46). 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.

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.

Any symptomatic hemorrhage may be initially asymptomatic. The risk of hematoma expansion may be inferred from the presence of risk factors. More research is needed to determine to what degree controlling the risk factors reduces hematoma expansion. If there is a window of opportunity to intervene, it is limited by the insidious nature of expansion and the rapid deterioration once detected clinically. Therefore, it is unclear if only PH2 is associated with poor prognosis and, therefore, whether other less severe forms of hemorrhage warrant treatment.

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

Cryoprecipitate has the potential to benefit most patients after thrombolysis. Because of the delay caused by thawing of the cryoprecipitate, 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 (106). One retrospective study found no difference in conservative management when compared to treatment with clotting factors (fresh frozen plasma or cryoprecipitate) in post-tPA sICH patients, suggesting that more research is needed (02). In another multicenter retrospective review, cryoprecipitate was the most used agent (105). Hypofibrinogenemia was associated with hematoma expansion, but the in-hospital mortality rate of 52% did not significantly diminish with treatment. Subsequent guidelines now recommend cryoprecipitate as a first-line treatment consideration, followed by platelets in those with contraindications to cryoprecipitate (31).

If cryoprecipitate is not available or blood products are either contraindicated or refused by the patient or family, antifibrinolytics may be used. Aminocaproic acid is usually administered, 4 g intravenously, during the first hour followed by 1 g/h for 8 hours. Alternatively, tranexamic acid is given 10 mg/kg 3 to 4 times per day.

Other blood products may be considered depending on the clinical situation. For example, platelet transfusion 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 they received thrombolysis. All of these procoagulant factors should be used cautiously, bearing in mind the risk of thromboembolism (106).

Prevention of hematoma expansion. Uncontrolled high blood pressure is one of the risk factors for hematoma expansion in patients with spontaneous intracerebral hemorrhage. There is insufficient information regarding thrombolysis-related hemorrhage; however, the principles of treatment are derived from the guidelines for the treatment of spontaneous hemorrhage. Although uncontrolled blood pressure is associated with hematoma expansion, clinical trials of aggressive control of systolic blood pressure to less than 140 mmHg failed to improve outcome (79). It is unclear what the blood pressure target is for sICH after thrombolysis. A balance must be struck between the risk of hematoma expansion and hypoperfusion of ischemic brain tissue. Blood pressure should be reduced in a smooth, continuous, and sustained fashion to avoid peaks and high variability (70). 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 (37). Whether this approach is effective in cases of thrombolysis-related hemorrhage is unclear.

Neurosurgical evacuation of hematoma presents several challenges, such as the presence of coagulopathy, patient selection, timing, and optimal technique. Hematoma evacuation has a limited role in patients with spontaneous intracerebral hemorrhage. Cerebellar lesions causing tissue herniation and brainstem dysfunction as well as large supratentorial hematomas causing herniation and coma, which are refractory to medical treatment, can be attributed to hematoma (106).

Special considerations

Pregnancy

Pregnancy is not an absolute contraindication for the use of rtPA. rtPA is currently listed as a “category C” medication. There are a few anecdotal reports on the use of both intravenous rtPA and intra-arterial tPA in pregnant women with acute stroke with positive outcomes of mother and fetus being reported more often than complications. Current guidelines state that IV-tPA may be considered in pregnant women if anticipated benefits of treating moderate stroke outweighs risk of bleeding (24).

Anesthesia

No data are available concerning the relationship of general anesthesia and intracerebral hemorrhage as a complication of thrombolytic therapy.