Clinical manifestations

Presentation and course

Acute ischemic stroke manifests as the 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

Hemorrhage into an ischemic stroke is more likely to occur in a large infarction, which carries a poor prognosis independent of hemorrhagic transformation. Uncontrolled systolic blood pressure may promote hematoma expansion and worsen prognosis (70). Symptomatic hemorrhage predicts severe disability and death (95). In fact, symptomatic hemorrhage is associated with a 50% or greater 30-day mortality.

Biological basis

Etiology and pathogenesis

Hemorrhagic transformation of an ischemic infarct often occurs in absence of thrombolytic or antithrombotic therapy. This has been observed in large cardioembolic lesions, especially. In the NINDS trial, the rate of sICH, defined as new or worsening clinical symptoms presumably caused by bleeding within the infarct, was 0.6% in the placebo arm (76). The mechanism is thought to be reperfusion injury of the occluded 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 thrombolytic agent.

Intracerebral hemorrhage may be classified into four subgroups 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 (43). Parenchymal hemorrhage type 2 has been correlated with poor clinical outcome (98). Parenchymal hematoma, seen in about 3% of all ischemic stroke patients, occurs with large ischemic lesions, high blood glucose, and thrombolysis (79).

The classification of sICH varies across studies. In the NINDS rtPA stroke study, sICH was defined as any clinical worsening thought to be caused by a simultaneously diagnosed hemorrhage by neuroimaging (76). However, the ECASS III trial defined sICH as intracerebral hemorrhage responsible for clinical deterioration of four or more points of the NIH Stroke Scale (NIHSS) within 72 hours or death at 90 days of IV-rtAPA (42). Additional reviews favor a similar definition of parenchymal hemorrhage within 24 to 36 hours of treatment or death within 7 to 90 days (101; 107). The choice of definition of sICH has a considerable impact on reported hemorrhage rates.

Thrombolysis aggravates the disruption of the blood-brain barrier caused by ischemia. The resultant reperfusion renders the artery friable and causes intracerebral hemorrhage (51). All thrombolytic agents, whether fibrin-specific, such as rtPA, or fibrin-nonspecific, such as streptokinase, stimulate plasmin. Plasmin cleaves fibrin within the clot and leads to bleeding. The severity and amount of ischemic damage to the blood vessels determines the risk of intracerebral hemorrhage during thrombolysis (45).

Epidemiology

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 its use in stroke, IV-rtPA was responsible for intracerebral hemorrhage in 1% or less of patients with myocardial infarction (59; 37). 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 rtPA Stroke Study led to FDA approval of IV-rtPA for ischemic stroke within 3 hours of symptom onset (76). sICH was defined as intracerebral hemorrhage diagnosed by CT that contributed to the patient's clinical worsening within 36 hours from treatment onset. Of the 312 patients treated with rtPA, 6.4% of patients had a sICH 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. 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 sICH in the NINDS trial (78). However, these patients were still likely to benefit from thrombolysis.

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

Additional trials (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 to 6 hours from onset often resulted in unacceptable rates of hemorrhagic conversion without clinical benefit (43; 18; 17; 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 of 2775 patients enrolled in randomized placebo-controlled trials of rtPA suggested a clinical benefit up to 4.5 hours from onset (41). This was confirmed by the ECASS III trial (42). rtPA significantly increased odds of a favorable outcome at 3 months, whereas sICH, defined as hemorrhage resulting in clinical deterioration of four or more points on the NIHSS or death, was 2.4% in the rtPA arm and 0.2% in the placebo arm.

A separate observational study of treatment within the 3- to 4.5-hour window reported a 2.2% rate of sICH at 7 days using the ECASS III definition (102). This led the American Heart Association/American Stroke Association (AHA/ASA) to recommend, in eligible patients, extension of the therapeutic window of IV-rtPA to 4.5 hours after symptom onset (25).

As approximately one in six patients have an unclear time of stroke onset, MRI has been used to determine if the patient is still eligible for IV-rtPA (104). This occurs mostly when the patient wakes up from sleep. An ischemic lesion present on diffusion-weighted imaging (DWI) but absent on fluid-attenuated inversion recovery (FLAIR) sequence suggests that the onset of stroke is less than 4.5 hours. Although the study was stopped prematurely due to lack of funding, data analysis from the 503 patients enrolled demonstrated that the favorable outcome (mRS 0-1) was more frequent in the IV-rtPA arm than in the placebo arm (adjusted common odds ratio: 1.62; 95% CI: 1.17 to 2.23; P=0.003). The risk of sICH was 2% and 0.4% in the alteplase and placebo arm, respectively (odds ratio: 4.95; 95% CI: 0.57 to 42.87; P=0.15).

A similar approach of using the tissue therapeutic window rather than the time window was spurred by the knowledge that some patients had a good outcome even if treated later than 4.5 hours from stroke onset. Careful patient selection may increase the number of cases successfully treated. Selection for the increased therapeutic window of rtPA was facilitated by processing of the perfusion scanning and determining the extent of hypoperfused but salvageable brain tissue relative to the ischemic core. A phase 3 multicenter, randomized, placebo-controlled trial that enrolled 225 patients within 4.5 to 9 hours from stroke onset found that rt-PA increased the chance of excellent outcome, defined as a modified Rankin scale score of 0 to 1 at 90 days (58). There was no difference in mortality between the two arms. The rate of sICH was 6.2% and 0.6% in the alteplase and placebo arms, respectively.

Intravenous rtPA in clinical practice. Following FDA approval, the sICH rates of 3.3% to 3.8% recorded in clinical practice were lower than expected (02; 97; 89).

The SITS-MOST registry also reported that in clinical practice, the sICH rate following IV-rtPA administered within the 3-hour window was 7.3% at 7 days, similar to that of clinical trials (101). The safety profile of IV-rtPA within the 3- to 4.5-hour window in the community setting was similar to that of ECASS III, with only a 2.4% sICH rate (71).

A meta-analysis summarized the data of 26 randomized controlled trials (majority IV-tPA was given in the 0- to 6-hour time window except for a few intra-arterial thrombolysis focused trials) in 7152 acute stroke patients (106). 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.

The presence of microbleeds on MRI raises the question of the safety of thrombolysis. A meta-analysis that included patients with prior microhemorrhages did not reveal an increased risk of thrombolysis (39).

Tenecteplase. Tenecteplase is a new thrombolytic agent that is more fibrin-specific and has longer activity than rtPA; it may be given as intravenous bolus (EXTEND-IA TNK Investigators). Given before endovascular intervention for large vessel occlusion, tenecteplase resulted in a better 90-day functional outcome compared to rtPA given in similar conditions. The risk of sICH was 1% in both arms.

A meta-analysis of five randomized trials enrolling 1585 patients demonstrated that tenecteplase is non-inferior to rtPA (10). 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 alteplase 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 as well as hemorrhagic complications were not significantly different (01).

Endovascular therapy. Early studies demonstrated a higher recanalization rate of large arterial occlusion with intraarterial thrombolysis than with intravenous rtPA alone; however, the hemorrhagic complications were similar or greater (68).

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 versus heparin alone (35). The 15% increase in favorable clinical outcome was counterbalanced by a 10% sICH rate, compared with 2% in the control group. Pro-urokinase was not approved by the FDA and was not commercially available. Instead, intra-arterial tPA, mechanical devices, or combination IV-tPA with endovascular therapy 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; safety of the bridging protocol was shown, along with sICH rates of 6.6% and 9.9% respectively (47; 46). 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 randomized patients within 4.5 hours of stroke onset into either an endovascular intervention group 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 (16).

As early trials with an emphasis on intra-arterial tPA were nearing completion, recanalization by mechanical thrombectomy became available.

The MERCI and the Multi MERCI trials evaluated the safety and efficacy of the endovascular clot retriever within 8 hours of symptom onset (92; 91). 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. Both compared well to the heparin alone arm of PROACT II recanalization rate of 18%.

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 (81). 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. The MR Rescue trial compared endovascular thrombectomy to standard treatment (52). To improve selection, each group was divided based on core/penumbra mismatch. Despite this, outcomes and sICH rates were similar in all groups.

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 (90).

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. Results favored endovascular intervention, and an mRS score of 0 to 2 was found more frequently; sICH rates were 6% and 8% in the control and treatment groups, respectively (74). Following the 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 (38). 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 (13; 48; 88).

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 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. 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 (82).

Due to concern for increased risk of sICH due to rtPA, the MR CLEAN-NO IV trial compared IV-rtPA followed by endovascular thrombectomy with endovascular treatment alone (75). Of 539 patients, 6% developed sICH. Use of IV-rtPA before thrombectomy was not associated with increased overall intracerebral hemorrhage, hemorrhage volume, or sICH.

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 (54). 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 (60; 100; 103; 69; 70; 111). However, not all risks were consistently replicated in follow-up studies. The following are potential post-thrombolysis sICH risks selected for further review.

Glycemic control. Hyperglycemia and a history of diabetes mellitus independently predict hemorrhage after thrombolysis (78; 09; 05). Both acute and chronic hyperglycemia have been implicated in sICH (114; 61). 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 (83) 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 (26). No guidelines are available regarding glucose management during tPA administration (44).

Fibrinogen depletion. In a multicenter cohort study that enrolled 1678 consecutive patients who received intravenous rtPA, consumption of fibrinogen was associated with increased risk of ischemic stroke (86). It is unclear if fibrinogen repletion is likely to mitigate the bleeding risk.

Severe stroke. Severe stroke, indicated by high NIHSS scores, is associated with an increased risk of post-thrombolysis hemorrhage (78; 30; 19; 20). Despite a higher risk of hemorrhage, patients with severe strokes may still benefit from thrombolysis (78).

Advanced age. Ischemic stroke patients 80 years of age and older treated with thrombolysis had almost three times the likelihood of sICH development in the NINDS trial (56). 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 thrombolysis in stroke patients within 3 hours of onset.

Antiplatelet use. 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; 97; 100). Patients receiving dual antiplatelet therapy with acetylsalicylic acid and clopidogrel may have a greater risk of thrombolysis-related sICH (20).

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 (29).

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 (110). 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 (99) or endovascular stroke therapy (67).

Prior direct oral anticoagulant use. Stroke management guidelines recommend avoidance of intravenous rtPA in patients who received direct oral anticoagulants within 48 hours. An international multicenter retrospective cohort that included 33,207 patients did not confirm the concern regarding significantly increased risk of hemorrhage and worse outcome (64).

Hypertension. 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 (54; 102). High risk of sICH has occurred in studies where elevated blood pressure was found during the initial 24 hours following thrombolysis (28). Aggressive blood pressure control prior to thrombolysis did not correlate with adverse outcomes in one study (22), whereas another publication demonstrated greater early neurologic improvement when systolic blood pressure was restored toward normal limits (36). 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 (83).

Recent stroke. 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 (83). 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 (85). 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% (63), and another reported no influence of recent transient ischemic attack on post-thrombolysis outcomes (23). The most updated literature suggests that recent stroke is not associated with increased tPA-induced sICH but is associated with increased death rates (66).

Imaging characteristics

Leukoaraiosis. Although rtPA administered to patients with leukoaraiosis on CT of the brain is associated with an increased risk of sICH and worse clinical outcome, it should not be withheld (04; 109).

Early signs of infarct. Several studies have demonstrated an increased risk of intracerebral hemorrhage following intravenous rtPA treatment in patients with evidence of early infarct signs on CT (78; 27; 62; 06; 30; 55; 97; 20). 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 sICH was increased in rtPA-treated patients with prominent signs of edema or mass effect on the baseline CT in the NINDS rtPA Stroke Trial (80). Despite increased risk of sICH in patients with subtle but common early infarct signs on CT, the patients may still benefit from thrombolysis.

ASPECT score. 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 (06). 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 (97; 31).

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 (50).

Large stroke. On brain MRI, DWI lesion volume predicted sICH in a retrospective analysis of patients treated with both intravenous and intra-arterial thrombolytics (24; 90). 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 (11). 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 (77). ASPECTS + W (DWI-ASPECTS with DWI white matter scoring system) may be a better predictor of sICH risk following tPA (49).

Microhemorrhages on brain MRI. 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 (53).

Fluid-attenuated inversion recovery (FLAIR) hyperintensity on brain MRI. FLAIR hyperintensity on MRI occurs within 3 to 6 hours of stroke onset. Thrombolysis is not thought to be beneficial. Moreover, the presence of hyperintensity in FLAIR may indicate an increased risk of ICH and sICH (15). Other studies have not validated the sICH risk prediction of FLAIR hyperintensity (12).

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 (97; 21). 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 (21).

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 (57). 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 sICH 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 sICH risk following treatment with IV-tPA (65).

Additional scores include SEDAN (sugar, early infarct signs, dense artery, age, NIHSS) (93), THRIVE (with high scores correlating with older age, higher NISS, and whether or not patients have hypertension, diabetes, or atrial fibrillation) (33), and DRAGON (dense artery, Rankin score, age, glucose, onset to treatment time, and NIHSS) (94).

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 (108).

Prevention

Patient selection. Prevention of intracerebral hemorrhage due to thrombolysis starts with proper patient selection and adherence to established guidelines for thrombolytic therapy as published by the American Heart Association (82; 83). The admission CT scan must be evaluated to rule out bleeding and early signs of a large infarction before using rtPA. Blood pressure must be managed carefully and promptly, and patients must be closely monitored in a stroke or intensive care unit. Studies of improved selection of tPA candidates through the use of CT or MRI perfusion are underway.

Early treatment. The current strategy to improve the clinical outcome relies on minimizing the interval from hospital arrival 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 sICH with earlier thrombolytic treatment and supports urgent treatment (87). Simultaneously, immediate evaluation for the need of endovascular recanalization of large vessel occlusions is undertaken (82). Successful endovascular recanalization in large vessel occlusion is now trending toward reduction of post-treatment sICH; however, publications are pending regarding the association between timeliness of reperfusion and reduced post-thrombolysis sICH (105).

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:

Diagnostic workup

Symptomatic intracerebral hemorrhage following thrombolysis is associated with early neurologic deterioration, more so than any other clinical presentation (72). 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. Urgent laboratory testing includes prothrombin time, activated partial thromboplastin time, platelet count, hemoglobin, and fibrinogen levels. Blood should be typed and cross-matched.

Management

General measures

If brain 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 (83). 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.

Prevent the hematoma expansion. 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.

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, 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. 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 (113).

One retrospective study found no difference between conservative management and administration of clotting factors (fresh frozen plasma or cryoprecipitate) in post-tPA sICH patients, suggesting that more research is needed (03). In another multicenter retrospective review, cryoprecipitate was the most used agent (112).

Hypofibrinogenemia was associated with hematoma expansion; however, 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 (34).

Antifibrinolytics. 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 three to four times per day.

Other blood products. 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 (113).

Prevention of hematoma expansion

Blood pressure control. Uncontrolled hypertension 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 (84). 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 (73).

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 (40). Whether this approach is effective in cases of thrombolysis-related hemorrhage is unclear.

Hematoma evacuation. Neurosurgical evacuation of hematoma presents several challenges: 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 (113).

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 (26).

Anesthesia

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