Does Platelet Administration Affect Mortality in Elderly Head-Injured Patients Taking Antiplatelet Medications?

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Abstract
A significant portion of patients sustaining traumatic brain injury (TBI) take antiplatelet medications (aspirin or clopidogrel), which have been associated with increased morbidity and mortality. In an attempt to alleviate the risk of increased bleeding, platelet transfusion has become standard practice in some institutions. This study was designed to determine if platelet transfusion reduces mortality in patients with TBI on antiplatelet medications. Databases from two Level I trauma centers were reviewed. Patients with TBI 50 years of age or older with documented preinjury use of clopidogrel or aspirin were included in our cohort. Patients who received platelet transfusions were compared with those who did not to assess outcome differences between them. Demographics and other patient characteristics abstracted included Injury Severity Score, Glasgow Coma Scale, hospital length of stay, and warfarin use. Three hundred twenty-eight patients comprised the study group. Of these patients, 166 received platelet transfusion and 162 patients did not. Patients who received platelets had a mortality rate of 17.5 per cent (29 of 166), whereas those who did not receive platelets had a mortality rate of 16.7 per cent (27 of 162) (P = 0.85). Transfusion of platelets in patients with TBI using antiplatelet therapy did not reduce mortality.
Does Platelet Administration Affect Mortality
in Elderly Head-Injured Patients Taking
Antiplatelet Medications?
DOUGLAS M. DOWNEY, M.D.,* BENJAMIN MONSON, M.D.,* KARYN L. BUTLER, M.D.,† GERALD R. FORTUNA,JR., M.D.,‡
JONATHAN M. SAXE, M.D.,§ JAMES P. DOLAN, M.D.,kRONALD J. MARKERT, PH.D.,* MARY C. MCCARTHY, M.D.§
From the *Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio; the
†Department of Surgery, Hartford Hospital, Hartford, Connecticut; the ‡Department of Surgery, University
of Cincinnati School of Medicine, Cincinnati, Ohio; the §Division of Trauma, Department of Surgery, Wright
State University Boonshoft School of Medicine, Dayton, Ohio; and the kDepartment of Surgery, Oregon
Health Sciences University, Portland, Oregon
A significant portion of patients sustaining traumatic brain injury (TBI) take antiplatelet
medications (aspirin or clopidogrel), which have been associated with increased morbidity and
mortality. In an attempt to alleviate the risk of increased bleeding, platelet transfusion has become
standard practice in some institutions. This study was designed to determine if platelet trans-
fusion reduces mortality in patients with TBI on antiplatelet medications. Databases from
two Level I trauma centers were reviewed. Patients with TBI 50 years of age or older with docu-
mented preinjury use of clopidogrel or aspirin were included in our cohort. Patients who received
platelet transfusions were compared with those who did not to assess outcome differences
between them. Demographics and other patient characteristics abstracted included Injury
Severity Score, Glasgow Coma Scale, hospital length of stay, and warfarin use. Three hundred
twenty-eight patients comprised the study group. Of these patients, 166 received platelet trans-
fusion and 162 patients did not. Patients who received platelets had a mortality rate of 17.5 per cent
(29 of 166), whereas those who did not receive platelets had a mortality rate of 16.7 per cent (27 of
162) (P50.85). Transfusion of platelets in patients with TBI using antiplatelet therapy did not
reduce mortality.
TRAUMATIC BRAIN INJURY (TBI) is responsible for
more than one million hospital visits, over
200,000 hospital admissions, and approximately
50,000 deaths in the United States annually.
1
With the
aging of our population, reports now show that these
injuries are most prevalent among persons older than
75 years of age. In this population, motor vehicle
crashes and falls were the two leading causes asso-
ciated with TBI-related hospitalizations.
1
Over the past decade, there has been a significant
increase in the use of antiplatelet agents after percuta-
neous cardiac interventions, stroke prevention, and
cardiac prophylaxis. Many elderly patients taking anti-
platelet agents such as aspirin and clopidogrel are at risk
for intracranial bleeding after trauma. In an attempt to
reduce the increased morbidity and mortality associated
with TBI in patients on antiplatelet or anticoagulant
medications, some centers frequently treat platelet
dysfunction with platelet transfusion. A recent study
showed that rapid warfarin reversal with fresh-frozen
plasma leads to reduction in mortality from 48 to 10 per
cent in patients with intracranial hemorrhage (P<
0.001).
2
However, the reversal of platelet dysfunction in
patients with TBI on antiplatelet medications has not
been fully investigated.
Two studies published in the past 5 years have
demonstrated a significant increase in mortality among
patients with TBI taking antiplatelet agents. A retro-
spective review in patients with TBI comparing
aspirin, warfarin, and no anticoagulation showed sig-
nificantly elevated mortality in those patients taking
aspirin or warfarin. However, there was no difference
in mortality between patients taking aspirin and
patients taking warfarin.
3
Another retrospective study
investigating patients with TBI who were taking
aspirin and clopidogrel showed an increased mortality
in patients taking these antiplatelet medications.
4
Address correspondence and reprint requests to Jonathan M.
Saxe, M.D., Department of Surgery, Wright State University
Boonshoft School of Medicine, Weber Center for Health Educa-
tion, Suite 7000, Miami Valley Hospital, One Wyoming Street,
Dayton, OH 45409. E-mail: jonathan.m.saxe@wright.edu.
1100
Jones et al. found that patients with TBI receiving
antiplatelet therapy have increased morbidity (more
cranial operations and reoperations and greater blood
product transfusion needs). Interestingly, the study did
not show an increase in mortality.
5
There is a paucity of data in the literature regarding
the clinical impact of reversing the action of anti-
platelet medications. A recent publication demon-
strated, in an ex vivo model, that normalization of
platelet function occurred after the equivalent trans-
fusion of 12.5 units of platelets in average-sized
patients with steady-state levels of clopidogrel.
6
In
this study, platelet function was considered normal
if platelet function normalized by analysis on a
Platelet Function Analyzer (PFA-100; Dade-Behring,
Miami, FL).
Frequently used to assess platelet activity, the PFA-
100 functions by passing a blood specimen through a
perforation in a membrane coated with collagen and
either adenosine diphosphate (ADP) or epinephrine.
Platelets spontaneously adhere to collagen and aggre-
gate because of stimulation by ADP or epinephrine.
The closure time (time required for a platelet plug to
occlude the aperture and stop flow) is taken as a
measure of platelet aggregation and function. How-
ever, as a result of the characteristics of the mechanism
of the assay, PFA-100 analysis is inaccurate in identi-
fying platelet dysfunction resulting from clopidogrel
use.
7
Furthermore, in a study comparing trauma
patients with and without TBI, it was found that
patients with brain injury had greater platelet activa-
tion (measured by increases in levels of expression
of p-selectin, glycoprotein IIb–IIIa activated con-
formation, and platelet microparticles) but lower pla-
telet function (increased collagen/epinephrine closure
times) as measured with the PFA-100. It was also
reported that this combination of increased platelet
activation with decreased function was associated with
increased mortality.
8
The purpose of this present study
was to determine whether platelet transfusion for
patients with TBI taking antiplatelet agents reduces
mortality.
Materials and Methods
With Institutional Review Board approval from
Miami Valley Hospital (MVH) and University Hospi-
tal in Cincinnati (UC), a review of two Level I trauma
center databases was performed for the period between
January 1, 2003, and December 31, 2006. Three hun-
dred twenty-eight patients with TBI who were re-
ceiving preinjury antiplatelet therapy were identified
to assess the effects of platelet transfusion. Patients
included in the study were older than 50 years of age
with documented ongoing use of antiplatelet therapy
(aspirin and/or clopidogrel) before injury with radio-
logically confirmed intracranial hemorrhage (epidural,
subdural, subarachnoid, or intraparenchymal hemor-
rhages). Twenty-seven patients being treated with
warfarin, in addition to antiplatelet therapy, were
transfused with fresh-frozen plasma in addition to
platelets. One hundred ninety-two patients were iden-
tified in the MVH registry and 136 were identified in
the UC database. MVH physicians routinely transfuse
patients on antiplatelet therapy who demonstrate pla-
telet dysfunction on PFA-100 screening. Transfusion
of platelets was documented in 135 of 192 patients
(70%) in the MVH trauma database. UC transfuses
patients with TBI only when warranted; thus, only 31
of 136 patients (23%) received platelet transfusion at
this center.
Both facilities confirmed platelet transfusion by
crossreferencing medical record numbers with their
respective blood bank registries. Those patients who
received platelets (n 4166) were compared with those
who did not (n 4162) to determine the difference in
mortality between the two populations.
Baseline demographic and clinical characteristics
included in the study were: age, sex, presenting Glas-
gow Coma Scale (GCS), presenting Injury Severity
Score (ISS), hospital length of stay, clopidogrel use,
and warfarin use. The ttest for independent samples
was used to compare groups on continuous variables,
and Pearson’s x
2
test was used to compare categorical
variables. In addition to the univariate comparison
of mortality between the two groups, multivariable
logistic regression was used to adjust for significant
baseline characteristics. Inferences were made at the
0.05 level of significance.
Results
Three hundred twenty-eight patients with TBI were
included in the study. One hundred sixty-six patients
with TBI received platelet transfusions (135 at MVH
and 31 at UC), whereas 162 did not (57 at MVH and
105 at UC). The two groups did not differ with respect
to sex (P40.058), presenting ISS (P40.43), pre-
senting GCS (P40.96), or length of hospital stay
(P40.22). The platelet group was older (77.4 vs 73.0
years, P< 0.001). Also, the group that received pla-
telets had a higher rate of warfarin use (89 vs 80%,
P40.038) and clopidogrel use (45 vs 14%, P< 0.001)
(Table 1).
The mortality rate for the transfused patients
was 17.5 per cent (29 of 166), whereas mortality for
those who did not receive platelet transfusions was
16.7 per cent (27 of 162, P40.85). Additionally, the
relationship between transfusion and mortality was
nearly unchanged after adjusting for the baseline
No. 11 PLATELET ADMINISTRATION’S EFFECT ON MORTALITY ?Downey et al. 1101
characteristics that were significant on univariate
analysis (i.e., age, warfarin, and clopidogrel; P4
0.79).
Surviving patients did not differ from those who died
with regard to age (74.9 vs 76.9 years, P40.21) or
sex (51 male vs 54% male, P40.74). Patients taking
concomitant warfarin anticoagulation had a higher
mortality rate than those not taking warfarin (14 or 51
[27.5%] vs 42 of 277 [15.2%], P40.032). Those
taking and not taking clopidogrel did not differ in
mortality rate (15 of 97 [15.5%] vs 41 of 231 [17.7%],
P40.62). Not surprisingly, both ISS and GCS were
predictive of mortality. Patients who died had a
higher mean ISS and lower mean GCS (ISS 425.7 vs
19.8, P< 0.001; GCS 48.8 vs 13.7, P< 0.001).
Discussion
In this study from two Level I trauma centers, we
found that platelet transfusion did not predict mortality
in elderly trauma patients with TBI who were on pre-
existing antiplatelet therapy. In addition, in keeping
with what others have found, our results indicate that
the GCS and ISS were predictive of mortality.
9, 10
There are a number of limitations to this study. First,
using data from two institutions with different trans-
fusion protocols may introduce selection bias. MVH
had a more liberal policy for platelet transfusion than
UC, where laboratory evidence of platelet dysfunction
was needed before transfusion was ordered. However,
we believe that patients at these two medical centers
received sufficiently similar care otherwise. Thus,
comparisons involving the outcome of mortality are
justified. Second, the timing of platelet transfusion was
not standardized at either medical center. Because
platelets contribute to hemostasis immediately after an
injury, earlier transfusion, perhaps even transfusion on
arrival to the hospital during the initial evaluation,
would have limited the extensiveness of the hemor-
rhage. At MVH, the average time from the trauma
surgeon’s order for platelets and their arrival was 34
minutes. Additional time was needed to complete
laboratory studies testing for abnormal platelet func-
tion. Furthermore, we did not examine the impact of
time to platelet administration on mortality nor did we
investigate the relationship between the time of the last
dose of the antiplatelet agent and the time of platelet
transfusion. The serum excretion half-life of aspirin is
3.5 to 4.5 hours after administration, although its pla-
telet effect is evident for the lifetime of the platelets
affected. Clopidogrel’s dose-dependent half-life is
2 hours, but its platelet effects, like aspirin, extend
to the lifetime of the affected platelet. The mecha-
nism of platelet inactivation by aspirin is through the
cyclo-oxygenase pathway inhibition, which leads to
inhibition of thromboxane A2 synthesis and thus
dysfunction of platelet aggregation.
11
Clopidogrel, on
the other hand, works by covalently binding the ADP
receptor on the platelet cell membrane, which inhibits
fibrinogen binding and results in dysfunction of pla-
telet aggregation. At steady-state levels, 40 to 60 per
cent of platelets are inactivated, leading to a functional
thrombocytopenia.
12
In our sample, we routinely gave
six units of concentrated platelets, which is essentially
equivalent to what would have been a 10-unit trans-
fusion of platelet products in the past. In some studies
that have investigated the performance of the PFA-100
in vitro platelet test, it was reported that an average
platelet volume of 12.5 units was required to achieve
normalization of platelet activity.
6
It is unclear if our
dosing guidelines had an impact on mortality rate in
the current study. Future prospective studies should
address the three limitations identified in our retro-
spective analysis.
Intuitively, platelet transfusion for patients taking
antiplatelet therapy should lead to a reduction in mor-
tality and morbidity. However, our two-center chart
review of 328 patients with TBI older than 50 years of
age who were taking antiplatelet medication before
their injury did not reach this conclusion. If platelet
transfusion is to be justified in this population, a pro-
spective, randomized, protocol-based trial is necessary
to test for a beneficial effect.
REFERENCES
1. Centers for Disease Control and Prevention (CDC). Rates of
hospitalization related to traumatic brain injury—nine states, 2003.
MMWR Morb Mortal Wkly Rep 2007;56:167–70.
TABLE 1. Baseline Characteristics for Patients with Traumatic Brain Injury on Anitplatelet Medication at the Time of Injury
Characteristic Platelets (n 4166) No Platelets (n 4162) PValue
Age, years 77.4 ± 10.4* 73.0 ± 10.8 <0.001
Sex: male, n and (%) 83 (50) 86 (53) 0.58
Glasgow Coma Score 12.8 ± 4.0 12.8 ± 3.9 0.96
Injury Severity Score 20.5 ± 7.5 21.2 ± 8.9 0.43
Length of hospital stay, days 7.5 ± 8.7 6.4 ± 7.6 0.22
Clopidogrel yes, no (%) 74 (45) 23 (14) <0.001
Warfarin: yes, no (%) 147 (89) 130 (80) 0.038
* Mean ± standard deviation.
THE AMERICAN SURGEON November 20091102 Vol. 75
2. Ivascu FA, Howells GA, Junn FS, et al. Rapid warfarin
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3. Mina AA, Knipfer JF, Park DY, et al. Intracranial compli-
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4. Ohm C, Mina A, Howells G, et al. Effects of antiplatelet
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    • "However, platelet transfusion was shown not beneficial in terms of mortality among patients older than 50 years old with pre-injury antiplatelets who suffered from TBI with ICH [41]. Routine platelet transfusion may even be harmful. "
    [Show abstract] [Hide abstract] ABSTRACT: Traumatic brain injury in elderly patients is a neglected global disease burden. The main cause is fall, followed by motor vehicle accidents. This review article summarizes different aspects of geriatric traumatic brain injury, including epidemiology, pathology, and effects of comorbidities and pre-injury medications such as antiplatelets and anticoagulants. Functional outcome with or without surgical intervention, cognitive outcome, and psychiatric complications are discussed. Animal models are also reviewed in attempt to explain the relationship of aging and outcome, together with advances in stem cell research. Though elderly people in general did fare worse after traumatic brain injury, certain "younger elderly" people, aged 65-75 years, could have a comparable outcome to younger adults after minor to moderate head injury.
    Full-text · Article · Sep 2012
    • "A study on patients with spontaneous ICH receiving antiplatelet agents showed no reduction of the frequency of hematoma expansion through platelet transfusion [34], but early transfusion of platelets within 12 hours of ictus resulted in improved platelet activity assays as well as smaller final haemor­ rhage size and more independence at 3 months [35]. Downey and colleagues retrospectively analysed patients on antiplatelet medication at their institution who underwent platelet transfusion (n = 166) to those patients on antiplatelet medication who did not (n = 162) [36]. No differences regarding mortality were observed between both groups. "
    [Show abstract] [Hide abstract] ABSTRACT: As the population ages, emergency physicians are confronted with a growing number of trauma patients receiving antithrombotic and antiplatelet medication prior to injury. In cases of traumatic brain injury, pre-injury treatment with anticoagulants has been associated with an increased risk of posttraumatic intracranial haemorrhage. Since high age itself is a well-recognised risk factor in traumatic brain injury, this population is at special risk for increased morbidity and mortality. The effects of antiplatelet medication on coagulation pathways in posttraumatic intracranial haemorrhage are not well understood, but available data suggest that the use of these agents increases the risk of an unfavourable outcome, especially in cases of severe traumatic brain injury. Standard laboratory investigations are insufficient to evaluate platelet activity, but new assays for monitoring platelet activity have been developed. Commonly used interventions to restore platelet activity include platelet transfusion and application of haemostatic drugs. Nevertheless, controlled clinical trials have not been carried out and, therefore, clinical practice guidelines are not available. In addition to the risks of the acute trauma, patients are at risk for cardiac events such as life-threatening stent thrombosis if antiplatelet therapy is withdrawn. In this review article, we summarize the pathophysiologic mechanisms of the most commonly used antiplatelet agents and analyse results of studies on the effects of this treatment on patients with traumatic brain injury. Additionally, we focus on opportunities to counteract antiplatelet effects in those patients as well as on considerations regarding the withdrawal of antiplatelet therapy. In those chronically ill patients, an interdisciplinary approach involving intensivists, neurosurgeons as well as cardiologists is often mandatory.
    Full-text · Article · Jul 2012
    • "Th ese platelet transfusions do not reverse antiplatelet agents such as clopidogrel and there is no evidence to support use of platelet transfusions to improve outcomes in patients who have recently taken antiplatelet agents [80]. Retrospective studies in both trauma patients and nontrauma patients with intracranial hemorrhage have found no benefi t from platelet transfusions given to patients who are taking antiplatelet agents818283. "
    [Show abstract] [Hide abstract] ABSTRACT: In June 2011 the Canadian National Advisory Committee on Blood and Blood Products sponsored an international consensus conference on transfusion and trauma. A panel of 10 experts and two external advisors reviewed the current medical literature and information presented at the conference by invited international speakers and attendees. The Consensus Panel addressed six specific questions on the topic of blood transfusion in trauma. The questions focused on: ratio-based blood resuscitation in trauma patients; the impact of survivorship bias in current research conclusions; the value of nonplasma coagulation products; the role of protocols for delivery of urgent transfusion; the merits of traditional laboratory monitoring compared with measures of clot viscoelasticity; and opportunities for future research. Key findings include a lack of evidence to support the use of 1:1:1 blood component ratios as the standard of care, the importance of early use of tranexamic acid, the expected value of an organized response plan, and the recommendation for an integrated approach that includes antifibrinolytics, rapid release of red blood cells, and a foundation ratio of blood components adjusted by results from either traditional coagulation tests or clot viscoelasticity or both. The present report is intended to provide guidance to practitioners, hospitals, and policy-makers.
    Article · Dec 2011
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