Intracerebral Hemorrhage Complicating Intravenous Tissue Plasminogen Activator Treatment Scott E. Carlson, MD; Michael S. Aldrich, MD; Harry S. Greenberg, MD; Eric J. Topol, MD \s=b\ Tissue plasminogen activator's thrombolytic action is relatively specific for fibrin; however, systemic bleeding can occur in patients, especially when heparin is simultaneously administered. We de- The major limitation of streptokinase and urokinase is that they activate both fibrin-bound plasminogen and circulating plasminogen and thereby scribe two cases of intracerebral hemorrhage from a cohort of 450 patients (0.44%) treated at one institution with tissue plasminogen activator and heparin for acute myocardial infarction. A pooled worldwide review of 5258 cases from several clinical protocols for treatment of acute myocardial infarction, using tissue plasminogen activator from one source, revealed a similar overall incidence of 0.68%. The incidence of intracerebral hemorrhage may be reduced by lowering the total dose of tissue plasminogen activator or by reducing the infusion rate and duration. The incidence of central nervous system hemorrhage with tissue plasminogen activator is within the range reported with streptokinase, but because equal coronary artery thrombolytic doses are not known, no definitive comparison is possible. {Arch Neurol 1988;45:1070-1073) state.1·2 While thrombolysis of coro¬ nary artery clots is often successful, rPhrombolytic treatment within the first few hours of acute myocardial infarction has been used with in¬ creased frequency since initial studies with streptokinase and urokinase.1 Accepted for publication April 17, 1988. From the Department of Neurology (Drs Carl- Aldrich, and Greenberg), and Division of Cardiology, Department of Internal Medicine (Dr Topol), University of Michigan Medical Censon, ter, Ann Arbor. Presented in part at the 40th annual meeting of the American Academy of Neurology, Cerebrovascular Disease Scientific Section, Cincinnati, April 19, 1988. Reprint requests to Department of Neurology, 1920/0316 Taubman Center, 1500 E Medical Dr, Ann Arbor, MI 48109-0316 (Dr Aldrich). produce a systemic fibrinolytic bleeding complications severe enough to require transfusion have occurred in up to 9% of patients treated with streptokinase or urokinase, and cen¬ tral nervous system hemorrhage in up to 1.6% of patients.3·4 Tissue plasminogen activator is a clot-selective activator which should, in theory, have fewer bleeding compli¬ cations than nonspecific thrombolytic agents. Several randomized trials comparing intravenous tissue plas¬ minogen activator and intravenous streptokinase have shown a higher frequency of coronary artery patency with tissue plasminogen activator than with streptokinase,2·3·57 and although hemorrhagic events appear to be less frequent with tissue plas¬ minogen activator than streptoki¬ nase,2 the difference in the incidence of bleeding may be due, at least in part, to differing degrees of fibrinoly- sis at the doses used. In patients receiving tissue plasminogen activa¬ tor alone, oozing around the catheter site has been the most common bleed¬ ing complication, occurring in 26% to 45% of patients treated.3·8·9 Neurologic complications during catheterization in patients treated with tissue plasminogen activator include transient ischemie attack and ischemie stroke.2·3 In one study,8 brief mention was made of intracranial hemorrhage but to date there are no detailed reports of intracranial hem¬ orrhages complicating tissue plasmin¬ ogen activator use. In this article, we Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/20/2015 describe two cases of intracerebral hemorrhage occurring during tissue plasminogen activator use for acute myocardial infarction. PATIENTS AND METHODS The two patients we describe are part of a cohort of 450 patients entered thus far at the University of Michigan (Ann Arbor) as part of the multicenter Thrombolysis in Acute Myocardial Infarction (TAMI) Study. Criteria for inclusion in this study have been published elsewhere.9·10 Patients were excluded from the cohort if they had any of the following: cardiogenic shock, previous coronary artery bypass surgery, prior transmurai infarcì in the same myo¬ cardial territory, bleeding diathesis, head trauma or stroke in the previous three months, or major surgery in the past two weeks. Exclusion criteria also included the use of warfarin sodium (coumadin), but did not include use of antiplatelet agents or other medications. The tissue plasminogen activator used was a single-chain preparation (G11035, Gen¬ entech, South San Francisco)."12 The ini¬ tial intravenous dose of tissue plasminogen activator was 1.0 mg/kg over the first hour with 10% given as a bolus. An additional 0.5 mg/kg infusion was administered over the next four hours to a total maximum dose of 135 to 150 mg, depending on the specific protocol. Case 1 was part of the TAMI I Study, a randomized protocol com¬ paring patients treated with tissue plas¬ minogen activator followed by angioplasty and those receiving only tissue plasmino¬ gen activator and cardiac catheterization.9 Case 2 was part of the TAMI III protocol comparing patients receiving tissue plas¬ minogen activator and early heparinization, and those receiving tissue plasmino¬ gen activator alone for 90 minutes, fol¬ lowed by later postcatheterization heparinization.13 A 5000-U heparin bolus was given to all patients immediately following cardiac catheterization, followed by a 500U/h infusion. These two patients were selected for evaluation because of the development of a Fig 1.—Left, Noncontrasted computed tomographic scan of brain done after neurologic presentation following intravenous tissue plasminogen activator treatment showing an acute lobar intracerebral hemorrhage in right subcortical frontoparietal region. Right, Noncontrasted follow-up computed tomographic scan of brain showing resolution of hemorrhage 2V2 weeks later. Fig 2.—Left, Noncontrasted computed tomographic scan of brain done after neurologic presentation following intravenous tissue plasminogen activator treatment showing an acute intracerebral hemorrhage in left frontal region. Right, Noncontrasted follow-up computed tomographic scan of brain showing resolution of hemorrhage ten days later. neurologie deficit within hours of receiving intravenous tissue plasminogen activator therapy. Pretreatment computed tomo¬ graphic (CT) scans of the head and random posttreatment scans were not performed as part of the TAMI protocols. Computed tomographic scans of the head in the two patients described were performed on a scanner (GE9800) without intravenous contrast. Fibrinogen and fibrinogen degra¬ dation product measurements were per¬ formed using the methods of Gauss14 and Mersky et al,15 respectively. Blood used for analysis was collected into tubes contain¬ ing protease inhibitor (Trasylol) to prevent in vitro activation of tissue plasminogen activator. REPORT OF CASES Case 1.—A 63-year-old woman with a 20-year history of intermittent angina, controlled hypertension, and smoking was admitted with substernal chest pain and electrocardiographic changes consistent with an acute posterior wall myocardial infarction. Initial blood pressure was 188/ 108 mm Hg. Physical examination was otherwise unremarkable. Lidocaine and morphine sulfate were administered intra¬ venously without relief. After consenting to enter the TAMI I protocol, she was randomized to receive tissue plasminogen activator without angioplasty. She re¬ ceived an 8-mg bolus of tissue plasminogen Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/20/2015 activator followed by an infusion of 68 mg/h for one hour and by a 15-mg/h infusion thereafter to a total dose of 150 mg. Cardiac catheterization revealed abnormalities of all three major vessels and occlusion of the distal circumflex artery. Blood pressure immediately after the procedure was 150/78 mm Hg. A hepa¬ rin bolus of 5000 U was given immediately after cardiac catheterization followed by infusion of 500 U/h. Two hours after cath¬ eterization she developed sudden left face and arm weakness with minimal associat¬ ed sensory changes. Laboratory analysis at the time of clinical deterioration revealed a partial thromboplastin time of 100 s; prothrombin time, 15.7 s; fibrin split products, 256 µg/mL (normal, 0 to 7 Mg/mL); fibrino¬ gen, 0.77 g/L (normal, 2.0 to 3.5 g/L); and platelet count, 264 X lO'/L. Computed tomographic brain scan showed a right hemisphere lobar hemorrhage (Fig 1, left). Protamine, fresh frozen plasma, cryoprecipitate, and aminocaproic acid were admin¬ istered. Twelve hours later, fibrinogen, prothrombin time, and partial prothrombin time were normal. A follow-up CT scan of the head 2% weeks later showed resolu¬ tion of the intracerebral hemorrhage (Fig 1, right). She was discharged to a rehabili¬ tation unit with moderate left hemiparesis and hemineglect. Case 2.—A 59-year-old man without prior cardiac, hypertensive, or cerebrovas¬ cular disease was admitted with subster¬ nal chest pain and electrocardiographic changes consistent with inferior wall myo¬ cardial infarction. Initial blood pressure was 180/112 mm Hg. Results of physical examination were otherwise normal. He was treated with nitroglycerin, lidocaine, and morphine sulfate. After informed con¬ sent he entered the TAMI III protocol and was randomized to receive tissue plasmin¬ ogen activator and postcatheterization heparin. He received a 9-mg bolus of tissue plasminogen activator over five minutes followed by infusion of 81 mg over the next hour. Cardiac catheterization revealed 80% to 90% stenosis of the right coronary artery. A 5000-U bolus of heparin was administered intravenously after catheter¬ ization followed by a 500-U/h infusion. Forty-five minutes after catheterization, he developed sudden severe expressive aphasia with mild right facial and hand weakness. Blood pressure was 138/94 mm Hg. Laboratory analysis revealed a partial thromboplastin time of 65 s; prothrombin time, 16.7 s; fibrin split products, 512 ßg/ mL; fibrinogen, 0.77 g/L; and platelet count, 145 X lO'/L. Heparin was discontin¬ ued, and 3 U of fresh frozen plasma were given. A CT scan of the brain revealed a subcortical hemorrhage in the left frontal hemisphere (Fig 2, left). Over the next two weeks his weakness resolved and his abili¬ ty to speak simple words and syllables returned. A second CT scan ten days later showed resolution of the clot (Fig 2, right). COMMENT Two patients suffered acute lobar hemorrhages within four hours of Incidence of Intracranial Hemorrhage in Over 5000 Patients Receiving Intravenous Tissue Plasminogen Activator (Activase) No. of Intracranial Patients_Dose, mg_Hemorrhages_Incidence, % _175_Up to 80_1_06_ _3361_80-120_14_04_ No. of _1722_120-180_2 _U2_ Total 36" 5258 0.68t ... Three events occurred more than 48 hours after intravenous tissue plasminogen activator treatment, tlncidence of hemorrhage occurring less than 48 hours after intravenous tissue plasminogen activator treatment was .63% beginning tissue plasminogen activa¬ tor therapy and within two hours of completing cardiac catheterization and beginning heparin therapy. To our knowledge these are the first two reports of central nervous system hemorrhages occurring within four hours of intravenous tissue plasmino¬ gen activator treatment. A posterior fossa hemorrhage occurring 48 hours after tissue plasminogen activator infusion and emergency coronary artery bypass graft has been reported, but the 48-hour interval between tis¬ sue plasminogen activator therapy and the interposition of open heart surgery make it uncertain whether the hemorrhage was secondary to fibrinolytic therapy.10 Five cases of intracerebral hemorrhage that oc¬ curred from five to 72 hours after initiation of tissue plasminogen acti¬ vator treatment have been reported as part of the TAMI II Pilot Study.16 These two cases represent a 0.44% incidence of intracerebral hemor¬ rhage in the 450 patients who have received intravenous tissue plasmino¬ gen activator therapy at the Universi¬ ty of Michigan. An incidence of hem¬ orrhage of 0.44% in patients treated with tissue plasminogen activator and heparin is similar to the reported incidence of intracerebral hemor¬ rhage of 0.0% to 1.6% in patients with acute myocardial infarction treated with streptokinase intravenously and heparin or antiplatelet agents.417 Our data represent the experience of one institution and may not repre¬ sent the true, overall incidence of intracerebral hemorrhage. Other re¬ ports describe an incidence of intra¬ cerebral hemorrhage in the 48 hours after infusion of tissue plasminogen activator of 0.3% (three of 998 patients).18 Pooled data from over 5000 patients treated with tissue plasmino¬ gen activator, including all United States trials through May 31, 1987 (TAMI, 2000 patients through April 29, 1987) and five large European tri¬ als (over 1500 patients) show a com¬ bined incidence of intracerebral hem- orrhage of 0.68% (Table).19 Although these trials used varying study de¬ signs, dose regimens, and selection criteria, the data from these studies suggest an increased incidence of hemorrhage with higher doses of tis¬ sue plasminogen activator. Recent TAMI protocols have lowered the rec¬ ommended maximum dose of tissue plasminogen activator.20 At these low¬ er doses, the overall incidence of hem¬ orrhage may be reduced. Although the cause of the intracere¬ bral hemorrhage in our patients is unknown, in both cases a systemic fibrinolytic state existed (abnormally low fibrinogen levels and elevated fibrin split products), and this state probably contributed to the lobar hemorrhages. Clinical experience and in vivo studies21 have shown that the likelihood of producing a systemic fibrinolytic state increases with high¬ er doses (Table), long infusion times, and higher infusion rates. Pooled data from three studies of the European Cooperative Study Group indicated that bleeding complications were 2.4 times more frequent if fibrin split product levels exceeded 85 mg/L at the end of tissue plasminogen activa¬ tor infusion than if the levels stayed below 22 mg/L.22 Multicenter United States data of patients receiving 150 mg of tissue plasminogen activator over 6 to 8 hours have shown that nadir fibrinogen levels are inversely proportional to bleeding incidence.23 These data suggest an association between systemic fibrinolysis and bleeding complications. Spontaneous intracerebral hemor¬ rhages are also described in hypofibrinogenic or dysfibrinogenic states,24 including disseminated intravascular coagulopathy.25 Whether a predispos¬ ing vascular abnormality is required for hemorrhage to occur during sys¬ temic fibrinolysis, or whether fibrino¬ lysis disrupts normally occurring microhemostasis within the cerebral vasculature is not known. The value of tissue plasminogen activator is based on the enzyme's high affinity for the Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/20/2015 fibrin-plasminogen complex which should make the enzyme's action clot selective and prevent a systemic fibri¬ nolytic state.18·21·26 However, the clot selectivity is incomplete and systemic activation of plasminogen can oc¬ cur.21·27 If a fibrinolytic state occurs, the potential advantage of this drug over other thrombolytic agents may be eliminated. We cannot exclude heparin as a contributing factor in our patients since the hemorrhages occurred 45 minutes and two hours, respectively, following the initiation of heparin infusion. At the time of hemorrhage, the partial prothrombin time was ele¬ vated in case 1, and therapeutic, 2.0 to 2.5 times control, in case 2. Although both cases had elevated blood pres¬ sure on presentation, lobar cerebral hemorrhages are not typical of hyper¬ tensive hemorrhages.28·29 There was no evidence of other possible causes of lobar hemorrhages such as amyloid, arteriovenous malformation, and metastatic tumor.30 Cerebrovascular complications following acute myo¬ cardial infarction are usually embolie infarctions and not lobar hemor¬ rhages.29·31-32 We cannot definitely rule out the remote possibility that intracerebral hemorrhages were already present when fibrinolytic therapy was initi¬ ated, since pretreatment CT scans were not done. Large intracerebral and subarachnoid hemorrhages can cause secondary myocardial damage and cardiac arrhythmias in animal models and in patients.33 However, our patients would have had to have asymptomatic, small intracerebral hemorrhages at presentation, and resultant myocardial injury would be unlikely from such a small lesion. Despite the retrospective nature of our article, several conclusions can be drawn. Serious central nervous sys¬ tem hemorrhagic complications may occur with tissue plasminogen activa¬ tor treatment, which appear to have an overall incidence of between 0.3% and 1.2%. Although this incidence is similar to that previously reported with intravenous streptokinase,4·17 a direct assessment of risk of intracere¬ bral hemorrhage with these two thrombolytic agents cannot be made because equal fibrinolytic doses are not known. Such comparisons would also involve the incidences from patients in several different proto¬ cols. While accepted risks for intracere¬ bral hemorrhage such as hyperten¬ sion, age, diabetes, recent stroke, brain tumor, recent head injury, or recent craniotomy are important con¬ siderations in patient selection for thrombolytic therapy, an additional concern is the potential development of a systemic fibrinolytic state. The optimum intravenous dosage to achieve effective coronary recanalization and prevent rethrombosis, yet minimize the risk of a systemic thrombolytic state, has not yet been defined. It appears that the lowest dose required for intracoronary clot lysis, given for the shortest period of time, may result in a lower incidence of central nervous system hemor- rhagic complications. A complete review of all hemorrhages following tissue plasminogen activator use may provide further information concern¬ ing the risk of central nervous system hemorrhage during tissue plasmino¬ gen activator thrombolysis. Tissue plasminogen activator (Acti¬ vase) has recently been accepted by the Food and Drug Administration for general use in the management of acute myocardial infarction. The rec¬ ommended dose is 100 mg (60 mg in the first hour with 6 to 10 mg as a bolus, 20 mg over the second hour, and 20 mg over the third hour), or 1.25 mg/kg over three hours. 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