To the Editor:
I read with great interest the above-titled article by Serebruany and colleagues.1 This report is special because prospective data are available regarding the changes of platelet functions before the occurrence of hemorrhagic stroke following thrombolysis.1 I would like to make the following comments and report the case of an elderly Chinese man who developed a cerebellar hematoma after thrombolysis for acute myocardial infarction (MI) when thrombocytopenia was induced by low-molecular-weight heparin.
First, hemorrhagic stroke is a major complication of thrombolysis for acute MI, even though patients with a recent history of stroke were excluded from clinical trials on thrombolysis in acute MI.2 3 In general, hemorrhagic stroke after thrombolysis in acute MI occurs within the first 24 to 48 hours of treatment; the hematoma is commonly lobar in location and occasionally multifocal; and the risk of hemorrhagic stroke is greater with tissue plasminogen activator than streptokinase.2 3 I wonder whether the index patient of Serebruany et al1 had a history of recent transient ischemic attack or a history of stroke longer than 6 months. I also wonder whether his arterial blood pressure was high when he was treated with tissue plasminogen activator. The platelet count was normal, but the activated partial thromboplastin time was mildly prolonged at 36 hours after thrombolysis,1 and I am interested in knowing about any disturbance in his coagulation and/or platelet count immediately after the development of neurological symptoms at 44 hours.
Second, I have two concerns when reviewing the comprehensive platelet function tests. Although many platelet functions of the index patient were rather “abnormal” compared with the mean results of the group of patients with acute MI and those of the control group, the absolute results were either within or very close to the lower limit of the “normal” range provided by the two groups of subjects (see the Table1 ). It would be interesting to speculate why hemorrhagic stroke did not occur in the other patients and control subjects whose results were more abnormal than those of the index patient in some platelet function tests. In addition, the platelet functions appeared to improve spontaneously in all patients, including the index patient, after thrombolysis. Nevertheless, the hemorrhagic stroke occurred at 44 hours after thrombolysis in the index patient, when his platelet functions were improving (see the Figure1 ). While it is unfortunate that the results of platelet function tests at a later time were unavailable, I wonder whether the authors can explain the timing of hemorrhagic stroke in relation to the changes in platelet functions of the index patient.
Finally, I would like to briefly describe a 76-year-old Hong Kong Chinese man whose depressed platelet count contributed to the occurrence of hemorrhagic stroke after thrombolysis for acute MI. This patient, who had no history of stroke or transient ischemic attack, presented initially with chest pain and ECG changes indicating acute inferior MI. Streptokinase (1.5 million U IV) was given over a 1-hour period, and his chest pain subsided, together with complete resolution of the ECG changes. Subsequently, he was given subcutaneous low-molecular-weight heparin and oral aspirin (300 mg loading dose followed by 150 mg daily). Serial cardiac enzymes confirmed acute MI. Forty-six hours after his first MI, his chest pain recurred with ECG changes of acute anterior MI. A second dose of streptokinase was given, and once again his chest pain subsided, together with complete resolution of the ECG changes. Ten hours after the second dose of streptokinase, he awoke with a headache, confusion, and dizziness. Urgent CT of his brain revealed a right cerebellar hematoma 2.5 cm in diameter; blood tests revealed coagulopathy and thrombocytopenia, and his platelet count was reduced to 89 000/mL. His arterial blood pressure remained stable throughout the admission. The cerebellar hematoma was managed conservatively, together with cessation of low-molecular-weight heparin and aspirin and transfusion of fresh frozen plasma and platelet concentrate. He was discharged without neurological deficit, and his latest platelet count was 269 000/mL. The thrombocytopenia was probably induced by treatment with low-molecular-weight heparin,4 and the antiplatelet antibody was negative. I wonder whether the authors have encountered thrombocytopenia following thrombolysis and use of heparin in patients with acute MI.
- Copyright © 1998 by American Heart Association
We thank Dr Cheung for his interest and comments regarding our GUSTO-III case report.R1 Indeed, they are the only prospective data available that support the concept of platelet hypofunction as a risk factor for intracranial hemorrhage after systemic thrombolysis for MI. Dr Cheung correctly points out that known cerebrovascular disease and systemic hypertension are risk factors for intracranial hemorrhage following thrombolytic therapy with any agent. Neither of these risk factors was present in our patient. Coagulopathy, either induced or spontaneous, also can increase hemorrhagic events but was not observed significantly in the index patient. Moreover, the platelet count in our patient was stable throughout the hospital course.
Dr Cheung also correctly points out that a few of the acute MI patients exhibited slightly higher platelet aggregation than our patient in response to collagen and ristocetin; however, the index patient represented the lowest level in 7 of 14 of receptor expression and function tests. Clearly, there is heterogeneity of platelet activity in acute MI, and not all patients have highly active platelets.R2 Our major concern, and the stimulus for this report, involves the uniform dosing regimens of antiplatelet agents in many clinical trials, particularly those involving the elderly, without accounting for the variability of baseline platelet function.
Occurrence of stroke depends on multiple factors.R3 Platelet hypofunction may be just one of them. Later after thrombolysis, the pattern of platelet characteristics was similar between the described patient and the rest of the acute MI group; however, platelet function remained well below the mean. The GUSTO-III platelet study assessed platelets in a prospective manner over the first 24 hours after the start of thrombolysis.R4 It is possible that the clinical manifestations of the intracranial hemorrhage occurred well after the initial onset of bleeding.
Serebruany VL, Gurbel PA, Shustov AR, Dalesandro MR, Gumbs CI, Grabletz LB, Bahr RD, Ohman EM, Topel EJ, for the GUSTO-III Investigators. Depressed platelet status in an elderly patient with hemorrhagic stroke after thrombolysis for acute myocardial infarction. Stroke. 1998;29:235–238.
Serebruany VL, Gurbel PA, Shustov AR, Ohman EM, Topol EJ. Heterogeneity of platelet aggregation and major surface receptor expression in patients presenting with acute myocardial infarction. Am Heart J. In press.
Gore JM, Granger CB, Simoons ML, Sloan MA, Weaver WD, White HD, Barbash GI, Van de Werf F, Aylward PE, Topol EJ, Califf RM, for the GUSTO-I Investigators. Stroke after thrombolysis: mortality and functional outcomes in the GUSTO-I trial. Circulation. 1995;92:2811–2818.
Gurbel PA, Serebruany VL, Shustov AR, Bahr RD, Carpo C, Ohman EM, Topol EJ, for the GUSTO III Investigators. Effects of reteplase and alteplase on platelet aggregation and major receptor expression during the first 24 hours of acute myocardial infarction treatment: the GUSTO III Platelet Study. J Am Coll Cardiol. 1998;31:1466–1473.