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Aspirin Response Test role in platelet transfusion following intracerebral hemorrhage
Clinical Neurology and Neurosurgery 137 (2015) 12–14
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Aspirin Response Test role in platelet transfusion following intracerebral hemorrhage夽 Einat Engel-Haber a,∗ , Anat Horev b , Priyanka Chablani c , Natan M. Bornstein d , Ashutosh Jadhav b , Tudor G. Jovin b , Vivek Reddy b , Maxim D. Hammer b a
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel University of Pittsburgh Medical Center, Department of Neurology, Pittsburgh, PA, United States c Ohio State University College of Medicine, Columbus, OH, United States d Tel Aviv Sourasky Medical Center, Department of Neurology, Tel Aviv University, Tel Aviv, Israel b
a r t i c l e
i n f o
Article history: Received 12 May 2015 Received in revised form 7 June 2015 Accepted 10 June 2015 Available online 12 June 2015 Keywords: Aspirin Aspirin Response Test Intracerebral hemorrhage Platelets Platelet response test Platelet transfusion Reduced platelet activity
a b s t r a c t Objectives: Spontaneous intracerebral hemorrhage (ICH) results in high morbidity and mortality. A target for therapy might be hematoma expansion, which occurs in a significant proportion of patients, and can be exacerbated by antiplatelet medications, such as aspirin. It is not clear whether platelet transfusion neutralizes aspirin. The Aspirin Response Test (ART) is commonly ordered in this patient population, but it is not clear whether the results of this test can help select patients for transfusion of platelets. The aim of our study is to investigate whether a selected group of ICH patients, those with reduced platelet activity (“aspirin responders”), will benefit from platelet transfusion. Materials and methods: This retrospective study included 63 patients who were taking aspirin but no other antithrombotic medication prior to the ICH. For each patient, we measured hematoma size by head CT on admission and compared with follow-up head CT 1 day later. Results: In the general cohort, 41% of transfused patients and 29% of non-transfused patients had a hematoma expansion. In the “aspirin responders” group, 46% of transfused patients and 22% of nontransfused patients had an expansion. Conclusions: Our data suggest that platelet transfusion following an ICH in “aspirin responders” does not reduce hematoma expansion rates in those patients. A larger prospective study is needed. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Intracerebral hemorrhage (ICH) comprises 4–15% of acute stroke cases and is the most fatal form of all stroke subtypes [1], with mortality at least 40% after 1 month [2]. Volume and growth of hemorrhage were shown to be strong predictors of mortality and functional outcome [3,4]. Patients presenting with spontaneous ICH are often on antiplatelet therapy. The significant correlations [5,6] between aspirin use and poor outcome following ICH, probably due to hematoma expansion, suggest that minimizing hematoma growth should be a primary aim in the treatment of patients with aspirin associated ICH.
夽 This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University. ∗ Corresponding author at: 8 Dunash St, Ramat Gan 5228558, Israel. Tel.: +972 584 058442. E-mail addresses: [email protected], [email protected] (E. Engel-Haber). http://dx.doi.org/10.1016/j.clineuro.2015.06.007 0303-8467/© 2015 Elsevier B.V. All rights reserved.
Several studies reported that platelet transfusion for reversing antiplatelet therapy does not have a significant impact on the clinical outcome and does not prevent hematoma expansion [6,7]. The authors suggest that in the majority of these cases, hemorrhage expansion had already occurred before platelets were transfused. Another reason that platelet transfusion has not been found to have a significant impact on clinical outcome may be because it is not selectively given to those patients who will benefit the most. If there was a way to predict whether a hemorrhage might expand due to aspirin intake, then perhaps platelet transfusion could be given selectively to those who would therefore receive the most benefit from this treatment. The Aspirin Response Test (ART; VerifyNow aspirin assay) is a blood test that assesses the efficacy of aspirin treatment. The ART measures the effect of aspirin on its target, Cyclooxygenase-1 (COX1). A serum ARU (Aspirin Response Units) < 550 is considered as reduced platelet activity and indicates that aspirin is working – these are the “aspirin responders”. ARU ≥ 550 indicates that the aspirin is not working and the patient is a non-responder. The ART
E. Engel-Haber et al. / Clinical Neurology and Neurosurgery 137 (2015) 12–14
13
Table 1 Demographic table. Demographic
General cohort Patients without a transfusion (n = 24) Mean
Age, y (SD) Gender (% male) Clinical (on admission) Systolic BP (mm Hg) (SD) Diastolic BP (mm Hg) (SD) Platelets, 103 /L (SD) Aspirin Response Units (ARU, n = 45, SD) Imaginga ICH volume imaging#1 (mL) (SD) ICH volume imaging#2 (mL) (SD) ICH expansion (%) ICH growth (mL) Process measure Time from symptoms to initial CT (h) (SD) Time between CT scans (h) (SD) a
Aspirin responders Transfused patients (n = 39) Mean
Patients without a transfusion (n = 18) Mean
Transfused patients (n = 24) Mean
71.4 (12) 42
74.0 (13.7) 51
70.1 (12.0) 44
74.3 (13.0) 46
167.4 (39.0) 93.2 (27.9) 210.2 (44.1) 473.3 (44.4)
173.6 (31.7) 90.0 (20.7) 210.5 (52.8) 457.8 (50.4)
166.7 (44.3) 95.2 (31.6) 203.1 (44.6) 467.6 (37.7)
170.1 (30.4) 86.7 (18.8) 219.0 (53.9) 447.6 (28.2)
27.7 (31.1) 34.6 (44.0) 27 7.0
32.0 (31.2) 38.2 (40.1) 23 6.22
25.7 (26.7) 28.9 (31.0) 17 3.25
31.5 (35.5) 40.1 (46.7) 31 8.6
2.3 (1.3) 13.1 (9.3)
2.4 (1.7) 17.1 (15.8)
2.1 (1.1) 13.5 (8.1)
2.3 (1.9) 20.6 (19.1)
Within the ICH volume measurements, one patient was classified as an outlier and was removed from that analysis.
has been shown to have a sensitivity of 100% and a specificity of 96% for aspirin induced platelet inhibition [8]. A recent study showed that in patients with acute ICH, reduced platelet activity on admission predicts hemorrhage growth and poor outcomes. A substantial number of patients had reduced platelet activity consistent with aspirin use but were not known to take aspirin. The authors suggested that measurement of platelet activity may be more important than known antiplatelet medication use [9]. The study also demonstrated that platelet transfusion in patients with a reduced platelet activity increases the ARU as expected. The aim of our study is to investigate whether patients of this selected group, the “aspirin responders”, will benefit from a platelet transfusion and show a reduction in the expansion of the hematoma. 2. Materials and methods This retrospective study was approved by the hospital’s Institutional Review Board. The study population comprised all patients with ICH presenting to our institution between 2009 and 2011. Included were only those patients taking aspirin but no other antithrombotic medication prior to the ICH. Excluded were any patients that developed ICH due to trauma, ruptured vascular malformation or aneurysm, hemophilic condition or hemorrhagic transformation of infarction. Aspirin usage was extracted from the patient charts. We also included patients that demonstrated a reduced platelet activity (ARU < 550) and a high-level of suspicion for aspirin usage, though it was not specifically documented in their records. It was either implied from their chart, or was based on age, comorbid conditions, and their inability to provide history due to poor mental status. Data collected included demographic information, blood pressure, serum platelet concentration, and result of serum ART. Two neurologists, who were blinded to the ART results, measured hematoma volumes using the ABC/2 formula, and expansion was defined as a relative growth of more than 33% from the initial CT or
an absolute growth greater than 6 mL [10,11]. A few patients had a follow-up MRI instead of a CT, and the adjusted formula ABC*0.8/2 was used to measure the ICH [12]. Serum ART was not available for all of the patients for various reasons. First of all, several patients were transfers from other hospitals in the area and were already transfused on arrival – therefore measuring ART in that case was ineffective. In addition, ART measures were not mandatory at the hospital and were performed per physician discretion and thus were not performed in all cases. Platelet transfusion was also given per physician discretion, as there was no specific protocol. In general, transfused patients received 4–10 units of platelets, however many records did not specify the amount given. The Chi Square and Fisher’s Exact Test were used, where appropriate. A standard p = 0.05 was used to indicate a statistically significant difference between comparison groups. SAS 9.2 for Windows was used to perform the analysis. 3. Results A total of 63 patients were identified that met inclusion criteria. There were no significant differences between transfused and nontransfused patients. Demographic data are displayed in Table 1. In the whole cohort, 16 of the 39 (41%) patients that received a transfusion had a hematoma expansion. Among the 24 that were not transfused, 7 (29%) had an expansion. By Chi-Square test (Table 2) there was no statistical correlation between platelet transfusion and hematoma expansion (2 = 0.90, p = .42). Within the whole cohort, 45 of 63 patients had serum ART measured – 30 with a documented aspirin use and 15 that had suspected use with ART indicative of reduced platelet activity (ARU < 550). 42/45 (93%) were “aspirin responders”. Among the 42 “aspirin responders”, whose demographic data are also displayed in Table 1: 11 out of 24 patients that received a platelet transfusion had a hematoma expansion (46%). Of the remaining 18 patients that did not receive a transfusion, only four patients had an expansion (22%). By Fisher’s Exact Test
Table 2 In the whole cohort, hematoma expansion rate in treated vs untreated patients. No increase in hematoma volume (n = 40) No treatment (n = 24) Treatment with platelet transfusion (n = 39)
71% (17/24) 59% (23/39)
Increase in hematoma volume (n = 23)
Chi Square p value
29% (7/24) 41% (16/39) .42
14
E. Engel-Haber et al. / Clinical Neurology and Neurosurgery 137 (2015) 12–14
Table 3 Among aspirin “responders”, the hematoma expansion rate in treated vs untreated. No increase in hematoma volume (n = 27) No treatment (n = 18) Treatment with platelet transfusion (n = 24)
78% (14/18) 54% (13/24)
Increase in hematoma volume (n = 15)
Fisher’s Exact Test p value
22% (4/18) 46% (11/24) .19
(Table 3) there was no statistical correlation between transfusion and hematoma expansion among “aspirin responders” (p = .19). 4. Discussion The ART (VerifyNow aspirin assay) is routinely used in order to assess platelet function in patients with ICH previously taking aspirin. Although this is a commonly ordered test, it is unknown whether using it to identify “aspirin responders” can either predict hemorrhage expansion, or response to platelet transfusion. We confirmed the results of previous studies [6,7] that demonstrated that platelet transfusion does not have a significant impact in preventing hematoma expansion, among patients taking aspirin. Of the patients that did not receive a transfusion, 29% of patients had an expansion, while 41% had an expansion following a transfusion. This result clearly shows that transfusion does not prevent hematoma expansion. Our next step was to investigate a sub-group of patients, the “aspirin responders”. Our original hypothesis was that transfused “aspirin responders” will show a lower expansion rate than the non-transfused “aspirin responders”. However, our data suggest that “aspirin responders” do not seem to benefit from platelet transfusion. 22% of those who did not receive a transfusion had an expansion while 46% of those that received a transfusion had an expansion. The transfused patients did not have a lower rate of hemorrhage expansion than those who did not receive a transfusion. On the contrary, our study showed a trend of a higher rate of hematoma expansion within the group that received the platelets; however, we found those results to be statistically insignificant. These findings may also be partially explained by the fact that on average transfused patients were 4 years older than non-transfused (74.3 vs 70.1), however this difference is statistically insignificant (p value = .293). Another explanation could be due to the fact that transfused patients underwent the second imaging on average 20.6 h after the first one while non-transfused only waited 13.5 h on average – however, it is estimated that hematoma expansion occurs mostly within the first 6 h therefore this is probably not the reason for these differences [13]. Several studies previously assessed the role of platelet function tests in predicting ICH outcomes. However, there is no existing literature that discusses the correlation between ART, platelet transfusion and ICH expansion, making our study an important step in understanding this relationship. Our analysis has several limitations. The primary one is small sample size, affecting the validity of statistical analysis. In addition, due to the high accuracy of the ART test and because of the relatively small sample size, we have included patients with a suspected aspirin use (as noted in Section 2). In conclusion, the purpose of this study was to investigate whether the ART can be used to determine whether patients with ICH, who were previously on daily aspirin therapy, would benefit from platelet transfusion to prevent worsening of the hemorrhage.
According to our findings, “aspirin responders” do not seem to derive benefit from platelet transfusion. The study is limited by small sample size, but provides new evidence which should foster a larger, prospective study to more reliably determine the clinical utility of ART in patients with ICH. Conflict of interest None of the authors have conflicts of interest that in any way pertain to the content of this study. Dr. Bornstein has performed consultation work for Pfizer Israel, Bayer Israel, Rafa Laboratories Ltd., Ever Neuro Pharma, Brainsgate Ltd., and D-Pharm. Dr. Bornstein has received honoraria from Takeda Pharmaceuticals International, General Electric, and Covden-Healthcare Products. Source of funding None of the authors have received any funding or salary and products or services are related to the subject matter of this article. References [1] J.N. Goldstein, S.H. Thomas, V. Frontiero, et al., Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage, Stroke 37 (2006) 151–155. [2] M.S. Dennis, Outcome after brain hemorrhage, Cerebrovasc. Dis. 16 (Suppl. 1) (2003) 9–13. [3] S. Juvela, Risk factors for impaired outcome after spontaneous intracerebral hemorrhage, Arch. Neurol. 52 (1995) 1193–1200. [4] S.M. Davis, J. Broderick, M. Hennerici, et al., Hematoma growth is a determinant of mortality and poor outcome after intracereral hemorrhage, Neurology 66 (2006) 1175–1181. [5] P. Saloheimo, M. Ahonen, S. Juvela, J. Pyhtinen, E.R. Savolainen, M. Hillbom, Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death, Stroke 37 (2006) 129–133. [6] C.J. Creutzeldt, J.R. Weinstein, W.T. Longstreth Jr., K.J. Becker, T.O. McPharlin, D.L. Tirschwell, Prior antiplatelet therapy, platelet infusion therapy and outcome after intracerebral hemorrhage, J. Stroke Cerebrovasc. Dis. 18 (2009) 221–228. [7] A.F. Ducruet, Z.L. Hickman, B.E. Zacharia, et al., Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage, Neurol. Res. 32 (2010) 706–710. [8] N. Blais, C. Pharand, M. Lordkipanidze, Y.K. Sia, Y. Merhi, J.G. Diodati, Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2), Thromb. Haemost. 102 (2009) 404–411. [9] A.M. Naidech, B. Jovanovic, S. Liebling, et al., Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage, Stroke 40 (2009) 2398–2401. [10] T. Brott, J. Broderick, R. Kothari, et al., Early hemorrhage growth in patients with intracerebral hemorrhage, Stroke 28 (1997) 1–5. [11] R. Wada, R.I. Aviv, A.J. Fox, et al., CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage, Stroke 38 (2007) 1257–1262. [12] R.E. Burgess, S. Warach, T.J. Schaewe, et al., Development and validation of a simple conversion model for comparison of intracerebral hemorrhage volumes measured on CT and gradient recalled echo MRI, Stroke 39 (2008) 2017–2020. [13] Y. Fujii, S. Takeuchi, O. Sasaki, T. Minakawa, R. Tanaka, Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage, Stroke 29 (1998) 1160–1166.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Aspirin Response Test role in platelet transfusion following intracerebral hemorrhage夽 Einat Engel-Haber a,∗ , Anat Horev b , Priyanka Chablani c , Natan M. Bornstein d , Ashutosh Jadhav b , Tudor G. Jovin b , Vivek Reddy b , Maxim D. Hammer b a
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel University of Pittsburgh Medical Center, Department of Neurology, Pittsburgh, PA, United States c Ohio State University College of Medicine, Columbus, OH, United States d Tel Aviv Sourasky Medical Center, Department of Neurology, Tel Aviv University, Tel Aviv, Israel b
a r t i c l e
i n f o
Article history: Received 12 May 2015 Received in revised form 7 June 2015 Accepted 10 June 2015 Available online 12 June 2015 Keywords: Aspirin Aspirin Response Test Intracerebral hemorrhage Platelets Platelet response test Platelet transfusion Reduced platelet activity
a b s t r a c t Objectives: Spontaneous intracerebral hemorrhage (ICH) results in high morbidity and mortality. A target for therapy might be hematoma expansion, which occurs in a significant proportion of patients, and can be exacerbated by antiplatelet medications, such as aspirin. It is not clear whether platelet transfusion neutralizes aspirin. The Aspirin Response Test (ART) is commonly ordered in this patient population, but it is not clear whether the results of this test can help select patients for transfusion of platelets. The aim of our study is to investigate whether a selected group of ICH patients, those with reduced platelet activity (“aspirin responders”), will benefit from platelet transfusion. Materials and methods: This retrospective study included 63 patients who were taking aspirin but no other antithrombotic medication prior to the ICH. For each patient, we measured hematoma size by head CT on admission and compared with follow-up head CT 1 day later. Results: In the general cohort, 41% of transfused patients and 29% of non-transfused patients had a hematoma expansion. In the “aspirin responders” group, 46% of transfused patients and 22% of nontransfused patients had an expansion. Conclusions: Our data suggest that platelet transfusion following an ICH in “aspirin responders” does not reduce hematoma expansion rates in those patients. A larger prospective study is needed. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Intracerebral hemorrhage (ICH) comprises 4–15% of acute stroke cases and is the most fatal form of all stroke subtypes [1], with mortality at least 40% after 1 month [2]. Volume and growth of hemorrhage were shown to be strong predictors of mortality and functional outcome [3,4]. Patients presenting with spontaneous ICH are often on antiplatelet therapy. The significant correlations [5,6] between aspirin use and poor outcome following ICH, probably due to hematoma expansion, suggest that minimizing hematoma growth should be a primary aim in the treatment of patients with aspirin associated ICH.
夽 This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University. ∗ Corresponding author at: 8 Dunash St, Ramat Gan 5228558, Israel. Tel.: +972 584 058442. E-mail addresses: [email protected], [email protected] (E. Engel-Haber). http://dx.doi.org/10.1016/j.clineuro.2015.06.007 0303-8467/© 2015 Elsevier B.V. All rights reserved.
Several studies reported that platelet transfusion for reversing antiplatelet therapy does not have a significant impact on the clinical outcome and does not prevent hematoma expansion [6,7]. The authors suggest that in the majority of these cases, hemorrhage expansion had already occurred before platelets were transfused. Another reason that platelet transfusion has not been found to have a significant impact on clinical outcome may be because it is not selectively given to those patients who will benefit the most. If there was a way to predict whether a hemorrhage might expand due to aspirin intake, then perhaps platelet transfusion could be given selectively to those who would therefore receive the most benefit from this treatment. The Aspirin Response Test (ART; VerifyNow aspirin assay) is a blood test that assesses the efficacy of aspirin treatment. The ART measures the effect of aspirin on its target, Cyclooxygenase-1 (COX1). A serum ARU (Aspirin Response Units) < 550 is considered as reduced platelet activity and indicates that aspirin is working – these are the “aspirin responders”. ARU ≥ 550 indicates that the aspirin is not working and the patient is a non-responder. The ART
E. Engel-Haber et al. / Clinical Neurology and Neurosurgery 137 (2015) 12–14
13
Table 1 Demographic table. Demographic
General cohort Patients without a transfusion (n = 24) Mean
Age, y (SD) Gender (% male) Clinical (on admission) Systolic BP (mm Hg) (SD) Diastolic BP (mm Hg) (SD) Platelets, 103 /L (SD) Aspirin Response Units (ARU, n = 45, SD) Imaginga ICH volume imaging#1 (mL) (SD) ICH volume imaging#2 (mL) (SD) ICH expansion (%) ICH growth (mL) Process measure Time from symptoms to initial CT (h) (SD) Time between CT scans (h) (SD) a
Aspirin responders Transfused patients (n = 39) Mean
Patients without a transfusion (n = 18) Mean
Transfused patients (n = 24) Mean
71.4 (12) 42
74.0 (13.7) 51
70.1 (12.0) 44
74.3 (13.0) 46
167.4 (39.0) 93.2 (27.9) 210.2 (44.1) 473.3 (44.4)
173.6 (31.7) 90.0 (20.7) 210.5 (52.8) 457.8 (50.4)
166.7 (44.3) 95.2 (31.6) 203.1 (44.6) 467.6 (37.7)
170.1 (30.4) 86.7 (18.8) 219.0 (53.9) 447.6 (28.2)
27.7 (31.1) 34.6 (44.0) 27 7.0
32.0 (31.2) 38.2 (40.1) 23 6.22
25.7 (26.7) 28.9 (31.0) 17 3.25
31.5 (35.5) 40.1 (46.7) 31 8.6
2.3 (1.3) 13.1 (9.3)
2.4 (1.7) 17.1 (15.8)
2.1 (1.1) 13.5 (8.1)
2.3 (1.9) 20.6 (19.1)
Within the ICH volume measurements, one patient was classified as an outlier and was removed from that analysis.
has been shown to have a sensitivity of 100% and a specificity of 96% for aspirin induced platelet inhibition [8]. A recent study showed that in patients with acute ICH, reduced platelet activity on admission predicts hemorrhage growth and poor outcomes. A substantial number of patients had reduced platelet activity consistent with aspirin use but were not known to take aspirin. The authors suggested that measurement of platelet activity may be more important than known antiplatelet medication use [9]. The study also demonstrated that platelet transfusion in patients with a reduced platelet activity increases the ARU as expected. The aim of our study is to investigate whether patients of this selected group, the “aspirin responders”, will benefit from a platelet transfusion and show a reduction in the expansion of the hematoma. 2. Materials and methods This retrospective study was approved by the hospital’s Institutional Review Board. The study population comprised all patients with ICH presenting to our institution between 2009 and 2011. Included were only those patients taking aspirin but no other antithrombotic medication prior to the ICH. Excluded were any patients that developed ICH due to trauma, ruptured vascular malformation or aneurysm, hemophilic condition or hemorrhagic transformation of infarction. Aspirin usage was extracted from the patient charts. We also included patients that demonstrated a reduced platelet activity (ARU < 550) and a high-level of suspicion for aspirin usage, though it was not specifically documented in their records. It was either implied from their chart, or was based on age, comorbid conditions, and their inability to provide history due to poor mental status. Data collected included demographic information, blood pressure, serum platelet concentration, and result of serum ART. Two neurologists, who were blinded to the ART results, measured hematoma volumes using the ABC/2 formula, and expansion was defined as a relative growth of more than 33% from the initial CT or
an absolute growth greater than 6 mL [10,11]. A few patients had a follow-up MRI instead of a CT, and the adjusted formula ABC*0.8/2 was used to measure the ICH [12]. Serum ART was not available for all of the patients for various reasons. First of all, several patients were transfers from other hospitals in the area and were already transfused on arrival – therefore measuring ART in that case was ineffective. In addition, ART measures were not mandatory at the hospital and were performed per physician discretion and thus were not performed in all cases. Platelet transfusion was also given per physician discretion, as there was no specific protocol. In general, transfused patients received 4–10 units of platelets, however many records did not specify the amount given. The Chi Square and Fisher’s Exact Test were used, where appropriate. A standard p = 0.05 was used to indicate a statistically significant difference between comparison groups. SAS 9.2 for Windows was used to perform the analysis. 3. Results A total of 63 patients were identified that met inclusion criteria. There were no significant differences between transfused and nontransfused patients. Demographic data are displayed in Table 1. In the whole cohort, 16 of the 39 (41%) patients that received a transfusion had a hematoma expansion. Among the 24 that were not transfused, 7 (29%) had an expansion. By Chi-Square test (Table 2) there was no statistical correlation between platelet transfusion and hematoma expansion (2 = 0.90, p = .42). Within the whole cohort, 45 of 63 patients had serum ART measured – 30 with a documented aspirin use and 15 that had suspected use with ART indicative of reduced platelet activity (ARU < 550). 42/45 (93%) were “aspirin responders”. Among the 42 “aspirin responders”, whose demographic data are also displayed in Table 1: 11 out of 24 patients that received a platelet transfusion had a hematoma expansion (46%). Of the remaining 18 patients that did not receive a transfusion, only four patients had an expansion (22%). By Fisher’s Exact Test
Table 2 In the whole cohort, hematoma expansion rate in treated vs untreated patients. No increase in hematoma volume (n = 40) No treatment (n = 24) Treatment with platelet transfusion (n = 39)
71% (17/24) 59% (23/39)
Increase in hematoma volume (n = 23)
Chi Square p value
29% (7/24) 41% (16/39) .42
14
E. Engel-Haber et al. / Clinical Neurology and Neurosurgery 137 (2015) 12–14
Table 3 Among aspirin “responders”, the hematoma expansion rate in treated vs untreated. No increase in hematoma volume (n = 27) No treatment (n = 18) Treatment with platelet transfusion (n = 24)
78% (14/18) 54% (13/24)
Increase in hematoma volume (n = 15)
Fisher’s Exact Test p value
22% (4/18) 46% (11/24) .19
(Table 3) there was no statistical correlation between transfusion and hematoma expansion among “aspirin responders” (p = .19). 4. Discussion The ART (VerifyNow aspirin assay) is routinely used in order to assess platelet function in patients with ICH previously taking aspirin. Although this is a commonly ordered test, it is unknown whether using it to identify “aspirin responders” can either predict hemorrhage expansion, or response to platelet transfusion. We confirmed the results of previous studies [6,7] that demonstrated that platelet transfusion does not have a significant impact in preventing hematoma expansion, among patients taking aspirin. Of the patients that did not receive a transfusion, 29% of patients had an expansion, while 41% had an expansion following a transfusion. This result clearly shows that transfusion does not prevent hematoma expansion. Our next step was to investigate a sub-group of patients, the “aspirin responders”. Our original hypothesis was that transfused “aspirin responders” will show a lower expansion rate than the non-transfused “aspirin responders”. However, our data suggest that “aspirin responders” do not seem to benefit from platelet transfusion. 22% of those who did not receive a transfusion had an expansion while 46% of those that received a transfusion had an expansion. The transfused patients did not have a lower rate of hemorrhage expansion than those who did not receive a transfusion. On the contrary, our study showed a trend of a higher rate of hematoma expansion within the group that received the platelets; however, we found those results to be statistically insignificant. These findings may also be partially explained by the fact that on average transfused patients were 4 years older than non-transfused (74.3 vs 70.1), however this difference is statistically insignificant (p value = .293). Another explanation could be due to the fact that transfused patients underwent the second imaging on average 20.6 h after the first one while non-transfused only waited 13.5 h on average – however, it is estimated that hematoma expansion occurs mostly within the first 6 h therefore this is probably not the reason for these differences [13]. Several studies previously assessed the role of platelet function tests in predicting ICH outcomes. However, there is no existing literature that discusses the correlation between ART, platelet transfusion and ICH expansion, making our study an important step in understanding this relationship. Our analysis has several limitations. The primary one is small sample size, affecting the validity of statistical analysis. In addition, due to the high accuracy of the ART test and because of the relatively small sample size, we have included patients with a suspected aspirin use (as noted in Section 2). In conclusion, the purpose of this study was to investigate whether the ART can be used to determine whether patients with ICH, who were previously on daily aspirin therapy, would benefit from platelet transfusion to prevent worsening of the hemorrhage.
According to our findings, “aspirin responders” do not seem to derive benefit from platelet transfusion. The study is limited by small sample size, but provides new evidence which should foster a larger, prospective study to more reliably determine the clinical utility of ART in patients with ICH. Conflict of interest None of the authors have conflicts of interest that in any way pertain to the content of this study. Dr. Bornstein has performed consultation work for Pfizer Israel, Bayer Israel, Rafa Laboratories Ltd., Ever Neuro Pharma, Brainsgate Ltd., and D-Pharm. Dr. Bornstein has received honoraria from Takeda Pharmaceuticals International, General Electric, and Covden-Healthcare Products. Source of funding None of the authors have received any funding or salary and products or services are related to the subject matter of this article. References [1] J.N. Goldstein, S.H. Thomas, V. Frontiero, et al., Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage, Stroke 37 (2006) 151–155. [2] M.S. Dennis, Outcome after brain hemorrhage, Cerebrovasc. Dis. 16 (Suppl. 1) (2003) 9–13. [3] S. Juvela, Risk factors for impaired outcome after spontaneous intracerebral hemorrhage, Arch. Neurol. 52 (1995) 1193–1200. [4] S.M. Davis, J. Broderick, M. Hennerici, et al., Hematoma growth is a determinant of mortality and poor outcome after intracereral hemorrhage, Neurology 66 (2006) 1175–1181. [5] P. Saloheimo, M. Ahonen, S. Juvela, J. Pyhtinen, E.R. Savolainen, M. Hillbom, Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death, Stroke 37 (2006) 129–133. [6] C.J. Creutzeldt, J.R. Weinstein, W.T. Longstreth Jr., K.J. Becker, T.O. McPharlin, D.L. Tirschwell, Prior antiplatelet therapy, platelet infusion therapy and outcome after intracerebral hemorrhage, J. Stroke Cerebrovasc. Dis. 18 (2009) 221–228. [7] A.F. Ducruet, Z.L. Hickman, B.E. Zacharia, et al., Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage, Neurol. Res. 32 (2010) 706–710. [8] N. Blais, C. Pharand, M. Lordkipanidze, Y.K. Sia, Y. Merhi, J.G. Diodati, Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2), Thromb. Haemost. 102 (2009) 404–411. [9] A.M. Naidech, B. Jovanovic, S. Liebling, et al., Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage, Stroke 40 (2009) 2398–2401. [10] T. Brott, J. Broderick, R. Kothari, et al., Early hemorrhage growth in patients with intracerebral hemorrhage, Stroke 28 (1997) 1–5. [11] R. Wada, R.I. Aviv, A.J. Fox, et al., CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage, Stroke 38 (2007) 1257–1262. [12] R.E. Burgess, S. Warach, T.J. Schaewe, et al., Development and validation of a simple conversion model for comparison of intracerebral hemorrhage volumes measured on CT and gradient recalled echo MRI, Stroke 39 (2008) 2017–2020. [13] Y. Fujii, S. Takeuchi, O. Sasaki, T. Minakawa, R. Tanaka, Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage, Stroke 29 (1998) 1160–1166.