From the Union Memorial Hospital, Baltimore, Md (V.L.S., P.A.G., A.R.S.);
Centocor, Inc, Malvern, Pa (M.R.D., C.I.G., L.B.G.); St Agnes Hospital,
Baltimore, Md (R.D.B.); Duke Clinical Research Institute, Durham, NC (E.M.O.);
and Cleveland Clinic, Cleveland, Ohio (E.J.T.).
Correspondence to Dr Victor L. Serebruany, Sinai Center for Thrombosis Research, 2401 W Belvedere Ave, Schapiro Research Building-R202, Baltimore, MD 21215. E-mail Heartdrug{at}aol.com
Abstract
Background—Impaired platelet
function has been reported in acute myocardial infarction (AMI) and
stroke. However, prospective data on the changes of platelet status
in patients before the occurrence of hemorrhagic stroke after
thrombolytic therapy are unavailable.
Case Description—An 86-year-old male patient was among the 23 AMI
patients enrolled in the platelet study for the GUSTO-III trial. He
received 325 mg of aspirin daily for at least 6 years, suffered an AMI,
and was successfully reperfused with alteplase, but after 44 hours
developed a large hemorrhagic stroke resulting in paraplegia.
Platelet aggregation and receptor expression were measured by flow
cytometry and ELISA before thrombolysis and at 3, 6,
12, and 24 hours thereafter. The percentage of platelet aggregation
was lower in the stroke patient at every time point when induced by
5 µmol/L of ADP, by 10 µmol/L of ADP, and by thrombin
than in the rest of the AMI group. Ristocetin and collagen-induced
aggregability were within the group range. Decreased platelet
glycoprotein Ib, IIb, IIIa, and IIb/IIIa and
vitronectin receptor expression were observed in the stroke
patient. No other differences in p24 (CD9), very late antigen-2,
P-selectin, and platelet/endothelial cell adhesion
molecule-1 expression were determined.
Conclusions—Profound depression of platelet status preceded
the occurrence of hemorrhagic stroke in an elderly long-term aspirin
user treated with thrombolytic therapy. Initial
"exhausted" platelets may be responsible for the increased risk
for hemorrhagic stroke after coronary
thrombolysis.
Platelets have been implicated as
important components in the natural history of acute myocardial
infarction (AMI)1 and stroke.2
Thrombolytic agents remain the cornerstone of treatment for
patients with AMI, whereas intracerebral bleeding is
the most serious complication of their use.3 4 There is
substantial evidence from in vitro5 6 7 and animal
studies8 9 that impaired platelet function occurs after
thrombolytic therapy and may play a role in the
occurrence of intracranial hemorrhage. However, prospective
dynamic data on the platelet status in patients before the
occurrence of hemorrhagic stroke after thrombolytic
therapy for AMI are unavailable.
We describe an elderly patient with an AMI who was enrolled in the
GUSTO-III trial and underwent serial measurements of platelet
aggregability, soluble receptor levels, and major surface receptor
expression who later developed an intracerebral
hemorrhage.
Case Report
An 86-year-old man with no prior cardiac history was admitted to
the emergency department of St Agnes Hospital with 2.5 hours of left
arm pain and chest discomfort. Blood pressure was 129/75 mm Hg,
and pulse was 85 beats per minute. The physical examination was
unremarkable. Past medical history was relevant for a hemicolectomy for
villous adenoma. There was no history of bleeding diathesis or tobacco
or alcohol use. The patient had received 325 mg of aspirin daily for
the last 6 years. There were no other concomitant medications. The
electrocardiogram demonstrated normal sinus rhythm with
Q waves in leads V1 through V3 and ST segment
elevation in leads V1 through V4, indicating an
acute anteroseptal myocardial infarction. The white blood cell count
was 8400/mL, platelet count was 196 000/mL, and the hematocrit was
44.5%. The blood urea nitrogen was 14 mg/dL, and
creatinine was 1.1 mg/dL. The activated partial
thromboplastin time was 34 seconds. The prothrombin time was 14
seconds.
The patient was treated with 325 mg of aspirin and 5000 U of
intravenous heparin, followed by a continuous infusion of
heparin as recommended in the GUSTO-III protocol. The patient was
randomized to treatment with 100 mg of alteplase (15 mg bolus followed
by 85 mg infusion over 90 minutes). Chest pain resolved within the
first hour, and there was no evidence of congestive heart failure or
arrhythmia. The peak creatine kinase (CK) was 554 IU/L, and
peak CK-MB was 51 IU/L. Heparin was discontinued after 24 hours. At 36
hours, the activated partial thromboplastin time was 40
seconds, and the platelet count was 211 000/mL.
Approximately 44 hours after admission, the patient developed
progressive confusion and left hemiplegia. A computed tomographic scan
of the head demonstrated at least three areas of focal
intracerebral hemorrhage. In light of these
findings, aspirin was discontinued. An echocardiogram demonstrated
anteroseptal hypokinesis and ejection fraction estimated at 40% to
45%, with no significant valvular heart disease. No embolic
foci were identified. The neurological status improved after a
prolonged hospitalization, and the patient was transferred to a
subacute facility for further rehabilitation.
Blood samples were obtained before thrombolysis
and at 3, 6, 12, and 24 hours thereafter. The
table summarizes the baseline
platelet aggregability in response to different agonists, flow
cytometry of platelet surface receptors, and ELISA measurements of
soluble antigens in the described patient compared with the rest of the
AMI group and healthy control subjects.
Platelet characteristics were severely depressed in this
patient compared with control subjects and the AMI group. Platelet
aggregation in response to ADP (both 5 and 10 µmol/L) and
thrombin were the lowest among the AMI patients. Collagen- and
ristocetin-induced platelet aggregability were diminished, but
within the group range. The lowest surface receptor expression among
the AMI group was observed for platelet glycoproteins
Ib (
Discussion
The present report emphasizes the potential importance of
baseline platelet characteristics in the pathogenesis of
hemorrhagic stroke after thrombolytic therapy for AMI.
We attempted to correlate antecedent platelet status by using
conventional aggregometry, ELISA, and flow cytometry techniques, with
an episode of hemorrhagic stroke in the oldest patient enrolled in the
GUSTO-III platelet study.
The major complication of thrombolytic therapy is
hemorrhagic stroke, which occurs in 1.2% to 1.9% of treated AMI
patients.10 11 12 Platelets have been implicated in both
ischemic13 14 and hemorrhagic15 16
stroke. However, all of these studies have been performed in the
relatively late phases of acute stroke and could be confounded by the
natural history of the disease and the effects of various concomitant
medications. The prospective assessment of the platelet status in
the controlled clinical trial provides us with a unique opportunity to
characterize the patient's platelets before the occurrence of
stroke.
It should be noted that none of the measured platelet aggregation
agonists, soluble antigens, or surface receptors served as a specific
marker exclusively affected in the described patient. In contrast, we
found a profound depression of multiple platelet-related
characteristics. This finding leads us to an important observation. We
can no longer hypothetically assume that platelets are necessarily
systemically activated during the initial pre-reperfusion phase
of AMI.
Another meaningful issue is the long-term use of relatively high doses
of aspirin, which was documented in the described patient. However,
there is no evidence that depressed platelet characteristics in
this patient were directly related to the antecedent aspirin
therapy.
This preliminary report also suggests that the adequate and timely
assessment of platelet activity may be critical in assessing the
risk for hemorrhagic stroke. Bleeding events after standard
thrombolytic and/or antiplatelet therapy could be
related to the decreased platelet characteristics in such patients.
It is not clear whether we should uniformly use aggressive
thrombolytic strategies without individual assessment
of platelet status in AMI patients. Based on the present case,
it is reasonable to speculate that the early bleeding complication
observed after modern therapy could be, at least in part, related to
depressed baseline platelet characteristics.
In conclusion, the ability to define patients at risk of hemorrhagic
stroke after thrombolysis in AMI cannot be overstated.
If platelets indeed are vital elements of the acute
coronary and cerebrovascular events, then their characteristics
could affect the response to thrombolytic therapy and
clinical outcome. In our case, profound depression of platelet
status preceded the occurrence of hemorrhagic stroke in an elderly
patient who was successfully reperfused. Dysfunctional platelets
may be responsible for the increased risk of provoking hemorrhagic
stroke after thrombolysis. Further analysis of
the baseline platelet status and its clinical significance during
acute vascular syndromes remains to be determined.
Selected Abbreviations and Acronyms
Acknowledgments
This work was supported, in part, by Medtronic, Inc, and by
Boehringer Mannheim GmbH. We are indebted to the staff of the
emergency departments and critical care units of the St Agnes and the
Union Memorial Hospitals. We would like to thank Kenneth A. Ault, MD,
for his advice with the flow cytometry techniques and Barry S. Coller,
MD, for his constructive comments and helpful suggestions on the
manuscript.
Received August 8, 1997;
revision received September 8, 1997;
accepted September 26, 1997.
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Case Reports
Depressed Platelet Status in an Elderly Patient With Hemorrhagic Stroke After Thrombolysis for Acute Myocardial Infarction
Key Words: hemorrhagic stroke • myocardial infarction • platelets • thrombolysis
64%), IIb(25%), IIIa(39%), IIb/IIIa (72%), and the
vitronectin receptor (55%). The patient with
intracerebral hemorrhage also had lower levels
of soluble substances indicative of platelet activation (P-selectin
and platelet–endothelial cell adhesion molecule
[PECAM]-1) before thrombolysis. Compared with
baseline, we observed some changes of the platelet status after
thrombolytic therapy. The patterns of these changes
were similar in the patient with the hemorrhagic stroke compared with
the rest of AMI group. Early in thrombolysis (3 to 6
hours), we observed minor reductions of platelet aggregation and
receptor expression together with a substantial increase of soluble
P-selectin and PECAM-1 plasma concentrations. Later in
thrombolysis (12 to 24 hours), we found a slight
elevation of platelet aggregability, an increase in specific
expression of glycoprotein IIb/IIIa, very late antigen-2,
and PECAM-1 with no further changes of soluble P-selectin and PECAM-1.
The dynamics of these receptors over 24 hours are shown in the
figure.
AMI
=
acute myocardial infarction
View larger version (15K):
[in a new window]
Figure 1. Dynamic changes of the glycoprotein IIb/IIIa
expression (A), very late antigen (VLA)-2 (B), and
platelet–endothelial cell adhesion molecule
(PECAM)-1 (C) during the first 24 hours after
thrombolysis. 
represents patient with
future stroke; 
represents the rest of the AMI
population.
View this table:
[in a new window]
Table 1. Baseline Platelet Status in Patient With Stroke Compared
With the Rest of AMI Population and Healthy Controls1
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