Ruptured Arteriovenous Malformation Complicating Thrombolytic Therapy With Tissue Plasminogen Activator Jacqueline Proner, MD: Bruce R. Rosenblum, MD; Allen Rothman, MD \s=b\ It is thought that the clot-specific activity of tissue plasminogen activator, used in the treatment of acute myocardial infarction, makes bleeding complications less common than does the use of either streptokinase or urokinase. The incidence of intracerebral hemorrhage complicating the use of tissue plasminogen activator has been estimated to be 0.68%. This is a report of the rupture of an intracranial arteriovenous malformation complicating the use of tissue plasminogen activator therapy. Theories for the mechanism of hemorrhage in this instance are presented, as are suggestions for future use of the enzyme. (Arch Neurol. 1990;47:105-106) Tissue plasminogen activator is a clot-selective enzyme that has largely supplanted nonspecific strep¬ tokinase and urokinase in the treat¬ ment of acute myocardial infarction. Its greater specificity is thought to contribute to its lower incidence of bleeding complications, especially cen¬ tral nervous system hemorrhage.12 De¬ tailed analysis of intracranial bleeding during treatment with tissue plasmin¬ ogen activator has only been carried out in one previous study, to our knowledge.3 We report a case of cere¬ bral hemorrhage that occurred sec¬ ondary to a ruptured arteriovenous malformation during intercurrent tis¬ sue plasminogen activator treatment. Accepted for publication May 22, 1989. From the Department of Internal Medicine, New Rochelle (NY) Hospital Medical Center (Dr Proner), and the Department of Neurosurgery, Mount Sinai Medical Center, New York, NY (Drs Rosenblum and Rothman). Reprint requests to 1160 Fifth Ave, Suite 106, New York, NY 10029 (Dr Rosenblum). REPORT OF A CASE A 65-year-old man with a history of intermittent angina and controlled hyper¬ tension was admitted with substernal chest pain radiating into the left arm and elec¬ trocardiographic evidence of an acute infe¬ rior wall myocardial infarction. His initial blood pressure reading was 180/100 mm Hg. Nitrates and morphine sulfate were admin¬ istered, without relief. Subsequently the patient received a 6-mg bolus of tissue plasminogen activator fol¬ lowed by an infusion of 54 mg/h for 1 hour and then 20 mg/h for 2 subsequent hours. A 5000-U bolus of heparin was given during the first hour, followed by a 1000-U/h infu¬ sion. Seven hours after initiation of the proto¬ col, the patient developed a left hemiplegia and became unresponsive. Computed to¬ mography revealed a massive intracerebral hematoma (Fig 1). After administration of protamine and fresh-frozen plasma, the patient underwent a right frontal craniot¬ omy and evacuation of the hematoma. In the base of the cavity, an arteriovenous malformation with signs of recent hemor¬ rhage was discovered and excised using a microsurgical technique. A postoperative arteriogram demonstrated no residual mal¬ formation. A subsequent computed tomo¬ graphic scan showed the right frontal cav¬ ity containing the clips used to excise the arteriovenous malformation (Pig 2). Patho¬ logic analysis revealed the characteristic features of an arteriovenous malformation (Fig 3). The patient made an uneventful recovery despite his left hemiplegia. Comment The incidence of intracerebral hem¬ orrhage in a pooled worldwide review of clinical protocols utilizing tissue plasminogen activator has been re¬ ported as 0.68% .3 Recent protocols have suggested the use of a lower ree- Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/16/2015 ommended maximum dose of tissue plasminogen activator, recognizing that this may diminish the occurrence of intracranial hemorrhage.4 This in¬ clination is based on studies demon¬ strating the production of a systemic fibrinolytic state with higher doses, longer infusion times, and higher in¬ fusion rates.5·6 An association between these fibrinolytic disorders and bleed¬ ing complications, including central nervous system hemorrhage, has been reported.7 In general, tissue plasminogen acti¬ vator is relatively clot specific due to its high affinity for the fibrin-plasminogen complex.5·8·9 Cerebral arterio¬ venous malformations are congenital Fig 1.—Noncontrast computed tomogram of the head reveals a massive right frontal hem¬ orrhage extending to, and distorting, the ven¬ tricular system. This is characteristic of bleed¬ ing secondary to a ruptured arteriovenous malformation. Fig 2.—Postoperative computed tomogram shows no residual blood and a low-density cavity where the previous clot was evacuated. Clips, used to lígate the vessels of the arterio¬ venous malformation, are seen within this region. Fig 3.—Photomicrograph demonstrates the thin-walled dilated arteries and veins characteristic of an arteriovenous malformation with evidence of recent hemorrhage from the vessels (hematox¬ ylin-eosin, X100). anomalies composed of localized con¬ geries of arteries and veins with de¬ system neoplasms may be particularly ranged and premature connections. Although they are generally asymp¬ tomatic and predisposed to spontane¬ ous rupture, with resultant intracere¬ bral hemorrhage, episodes of repeated thrombosis within the lesion are prob¬ ably more common, as are subclinical episodes of microhemorrhage.10 These have been attributed to both the ab¬ normal fragility of the arteriovenous malformation vessels and the dra¬ matic turbulence within the arterio¬ venous shunts." Spontaneous clots or those formed in response to small bleeding occurrences might be quite susceptible to dissolution by tissue plasminogen activator. Patients harboring asymptomatic arteriovenous malformations, as in the present case, or central nervous prone to hemorrhage when they are given the fibrinolytic enzyme. Tissue plasminogen activator may lyse fibrin clots within these lesions and result in massive intracerebral hemorrhage. As part of the entry criteria for in¬ troduction into a tissue plasminogen activator protocol, it may be useful to obtain both noncontrast and contrastenhanced computed tomograms of the head. Identification of an unsuspected intracranial lesion prior to induction of therapy may alter the plan of action. The presence of such an intracranial entity may dissuade one from the use of tissue plasminogen activator in an individual case. If such use is deemed necessary, the evidence in our case may further support the use of lower dose protocols in some patients. In ad¬ dition, intensive neurologic monitor- ing should be implemented in all pa¬ tients receiving tissue plasminogen ac¬ tivator therapy. Finally, it should be emphasized that the risk of cerebral hemorrhage may be equally inherent in the use of other thrombolytic therapies, includ¬ ing streptokinase. If time constraints during an acute myocardial infarction mandate that thrombolytic therapy must be initiated immediately, before a computed tomogram can be obtained, a thorough neurologic history and physical examination should be per¬ formed to screen for patients with un¬ derlying intracranial lesions. Subse¬ quently, the patients can be followed up on clinical grounds, and further di¬ agnostic testing may be carried out when time permits. References 1. Sloan M. Thrombolysis and stroke, past and future. Arch Neurol. 1987;44:748-768. 2. Aldrich MS, Sherman SA, Greenberg HS. Cerebrovascular complications of streptokinase infusion. JAMA. 1985;253:1777-1779. 3. Carlson SE, Aldrich MS, Greenberg HS, Topol EJ. Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment. Arch Neurol. 1988;45:1070-1073. 4. Thrombolysis in Acute Myocardial Infarction Operations Committee. Announcements of protocol change in thrombolysis in myocardial infarction trial. J Am Coll Cardiol. 1987;9:467. 5. Topol EJ, Bell WR, Weisfeldt ML. Coronary thrombolysis with recombinant tissue-type plasminogen activator. Ann Intern Med. 1985;103:837\x=req-\ 843. 6. Collen D, Topol EJ, Tiefeubrunn AJ, et al. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation. 1984;70:1012-1017. 7. Califf RM, Stump D, Thorton D, et al. Hemorrhagic complications after tissue plasminogen activator (t-PA) therapy for acute myocardial infarction. Circulation. 1987;76(suppl):IV-1. 8. Grossbard EB. Genentech experience with rt-PA (activase). J Am Coll Cardiol. 1987;9:467. Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/16/2015 9. Bergmann SR, Fox KA, Ter-Pogossian MM, Sobel BE, Collen D. Clot-selective coronary thrombolysis with tissue plasminogen activator. Science. 1983;220:1181-1183. 10. Rosenblum B. Pathophysiology of cerebral arteriovenous malformations: recent advances in analysis and therapy. In: Rosenblum B, ed. State of the Art Reviews in Neurosurgery: Cerebral and Spinal Arteriovenous Malformations. Philadelphia, Pa: Hanley & Belfus Inc; 1988:1-12. 11. Rosenblum B, Bonner RF, Oldfield EH. Intraoperative measurement of cortical blood flow adjacent to cerebral AVM using laser Doppler velocimetry. J Neurosurg. 1987;66:396-399.