Case Reports
Depressed Platelet Status in an Elderly Patient With
Hemorrhagic Stroke After Thrombolysis for Acute
Myocardial Infarction
Victor L. Serebruany, MD, PhD; Paul A. Gurbel, MD; Andrew R. Shustov, MD;
Margaret R. Dalesandro, PhD; Cindy I. Gumbs, BS; Laura B. Grabletz, BS; Raymond D. Bahr, MD;
E. Magnus Ohman, MD; Eric J. Topol, MD; for the GUSTO-III Investigators
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 mmol/L of ADP, by 10 mmol/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. (Stroke. 1998;29:235-238.)
Key Words: hemorrhagic stroke n myocardial infarction n platelets n thrombolysis

P

latelets 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 vitro5–7 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).

Received August 8, 1997; final revision received September 8, 1997; accepted September 26, 1997.
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@aol.com
© 1998 American Heart Association, Inc.

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Platelets, Stroke, and Thrombolysis

236

Selected Abbreviations and Acronyms
AMI 5 acute myocardial infarction

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 mmol/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 (264%),
IIb(225%), IIIa(239%), IIb/IIIa (272%), and the vitronectin receptor (255%). 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.

Baseline Platelet Status in Patient With Stroke Compared With the Rest of AMI Population and
Healthy Controls*
Parameter

Control Subjects (n510)

AMI Patients (n522)

Patients With Stroke

Aggregation, %
1. ADP 5 mmol/L

52.066.7 (39-61)

66.3611.4 (47-82)

42

2. ADP 10 mmol/L

59.267.2 (45-67)

73.8612.0 (54-90)

49

3. Collagen 1 mg/mL

66.265.9 (58-74)

64.766.9 (49-72)

66

4. Thrombin 1 mg/mL

60.566.9 (49-71)

75.8610.9 (59-94)

54

5. Ristocetin 1.25 mg/mL

71.367.4 (59-84)

92.567.8 (72-100)

84

1. CD9 (p24)

41.07611.40 (20.37-58.11)

55.12617.23 (18.12-79.04)

2. GP Ib

133.7667.96 (124.43-148.21)

103.62629.89 (39.28-161.02)

37.18

3. GP IIb

37.1961.73 (34.28-40.03)

28.4262.52 (24.44-33.21)

22.76

4. GP IIIa

320.29625.20 (278.90-361.00)

326.97651.78 (211.56-418.22)

201.06

5. GP IIb/IIIa

53.0266.95 (40.29-61.27)

59.24616.3 (18.12-79.04)

16.39

6. VLA-2

41.3662.14 (38.78-45.13)

40.1864.66 (33.03-51.19)

45.18

7. P-Selectin

25.1162.56 (20.67-29.95)

31.5464.96 (22.18-40.04)

27.90

8. PECAM-1

44.4763.75 (38.18-49.14)

56.84617.69 (26.28-81.07)

61.12

9. Vitronectin

59.7666.00 (44.96-65.05)

60.16625.56 (29.24-129.40)

27.15

1. P-selectin

10.2461.07 (9.06-11.60)

26.13612.93 (10.35-57.24)

9.82

2. PECAM-1

27.7466.49 (20.29-36.80)

35.1969.66 (18.55-48.19)

19.20

Surface Receptor Expression, log fluorescence
51.44

Soluble Receptors, ng/mL

AMI indicates acute myocardial infarction; GP, glycoprotein; VLA, very late antigen; and PECAM, platelet-endothelial cell adhesion
molecule.
*Results are expressed as mean6SD. Ranges are given in parentheses.

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Serebruany et al

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. E represents patient with future stroke; M represents the rest of the AMI population.

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 –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 con-

237

trolled 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.

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.

References
1. Becker RC, Bovill EG, Corrao JM, Ball SP, Ault K, Mann K, Tracy RP.
Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q-wave
myocardial infarction. J Thromb Thrombolys. 1994;1:95–100.
2. Shah AB, Beamer N, Coull BM. Enhanced in vivo platelet activation in
subtypes of ischaemic stroke. Stroke. 1985;16:643– 647.
3. The GUSTO Investigators. An international randomized trial comparing
four thrombolytic strategies for acute myocardial infarction. N Engl J Med.
1993;329:673– 682.
4. The International Study Group. In-hospital mortality and clinical course of
20,891 patients with suspected acute myocardial infarction randomized
between alteplase and streptokinase with or without heparin. Lancet. 1990;
336:71–75.

Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016

238

Platelets, Stroke, and Thrombolysis

5. Cronberg S. Effect of fibrinolysis on adhesion and aggregation of human
platelets. Thromb Diath Haemorrh. 1968;19:474 – 482.
6. Terres W, Unmus S, Mathey DG, Bleifeld W. Effects of streptokinase,
urokinase, and tissue plasminogen activator on platelet aggregability and
stability of platelet aggregates. Cardiovasc Res. 1990;67:1175–1181.
7. Torr SR, Winters KJ, Santoro SA, Sobel BE. The nature of interactions
between tissue-type plasminogen activators and platelets. Thromb Res.
1990;59:279 –293.
8. Golino P, Ashton JH, Glas-Greenwalt P, McNatt J, Buja LM, Willerson
JT. Mediation of reocclusion by thromboxane with tissue type plasminogen activator in a canine preparation of coronary thrombosis. Circulation.
1988;77:678 – 684.
9. Nicolini FA, Lee P, Rios G, Kottke-Merchant K, Topol EJ. Combination
of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at
low doses markedly improves thrombolysis. Circulation. 1994;89:
1802–1809.
10. Gurbel PA, Navetta FI, Bates ER, Muller DW, Tenaglia AN, Miller MJ,
Muhlstein B, Hermiller JB, Davidson CJ, Aguirre FV, Beauman GJ,
Berdan LG, Leimberger JD, Bovill EG, Christenson RH, Ohman EM.
Lesion-directed administration of tissue plasminogen activator with intracoronary heparin in patients with unstable angina and coronary thrombus
undergoing angioplasty. Cathet Cardiovasc Diagn. 1996;37:382–391.

11. O’Connor CM, Meese RB, McNulty S, Lucas KD, Carney RJ,
LeBoeuf RM, Maddox W, Bethea CF, Shadoff N, Trahey TF,
Heinsimer JA, Burks JM, O’Donnell G, Krucoff MW, Califf RM, the
DUCCS-II Investigators. A randomized factorial trial of reperfusion
strategies and aspirin dosing in acute myocardial infarction. Am J
Cardiol. 1996;77:791–797.
12. Smalling RW, Bode C, Kalbfleisch J, Sen S, Limbourg P, Forycki F, Habib
G, Feldman R, Hohnloser S, Seals A, RAPID Investigators. More rapid,
complete, and stable coronary thrombolysis with bolus administration of
reteplase compared with alteplase infusion in acute myocardial infarction.
Circulation. 1995;91:2725–2732.
13. Uchiyama S, Yamazaki M, Maruyama S, Handa M, Ikeda Y, Fukuyama M,
Itagaki I. Shear-induced platelet aggregation in cerebral ischemia. Stroke.
1994;25:1547–1551.
14. Toghi H, Suzuki H, Tamura K, Kimura B. Platelet volume, aggregation
and adenosine triphosphate release in cerebral thrombosis. Stroke. 1991;22:
17–21.
15. Sobel BE. Intracranial bleeding, fibrinolysis, and anticoagulation: causal
connections and clinical implications. Circulation. 1994;90:2147–2152.
16. Olson JD. Mechanisms of hemostasis: effect on intracerebral hemorrhage.
Stroke. 1993;24(suppl 12):109 –114.

Downloaded from http://stroke.ahajournals.org/ by guest on June 24, 2016

Depressed Platelet Status in an Elderly Patient With Hemorrhagic Stroke After
Thrombolysis for Acute Myocardial Infarction
Victor L. Serebruany, Paul A. Gurbel, Andrew R. Shustov, Margaret R. Dalesandro, Cindy I.
Gumbs, Laura B. Grabletz, Raymond D. Bahr, E. Magnus Ohman and Eric J. Topol
for the GUSTO-III Investigators
Stroke. 1998;29:235-238
doi: 10.1161/01.STR.29.1.235
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1998 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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