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Platelet count and function in spontaneous intracerebral hemorrhage
Platelet Count and Function in Spontaneous Intracerebral Hemorrhage Wendy C. Ziai, MD,*,‡,§ Michel T. Torbey, MD, MPH,*,‡,§ Thomas S. Kickler, MD,† Sangjin Oh, MD,‡ Anish Bhardwaj, MD,*,‡,§ and Robert J. Wityk, MD‡
Impaired platelet function has been associated with an increased propensity for intracerebral hemorrhage (ICH). The role of platelet count and dysfunction in spontaneous ICH (SICH) is poorly understood. We tested the hypotheses that patients with SICH have subtle platelet dysfunction associated with ICH progression and larger ICH size. In a retrospective case series, we compared platelet counts in patients with SICH with age-matched controls with neuromuscular disorders admitted to a Neurosciences Critical Care Unit (NCCU). In a subset of patients, platelet function was measured within one week of ICH. Computerized tomography (CT) scans were performed within 24 hours of the event and ICH volume determined by the ABC/2 method. Comparison of 43 patients with SICH and 35 age-matched controls with neuromuscular disease demonstrated significant decreases in platelet counts over the first few days of admission to the NCCU (Nadir: 149 ⫾ 9 vs 202 ⫾ 12 IU/mm3; P ⫽ .001). There was a significant correlation between a fall in platelet count and change in hematoma size in 28 patients (P ⫽ .01). Seventeen patients were enrolled prospectively to study platelet function. Patients were divided into 2 groups based on ICH volume: ⱕ 30cc and ⬎ 30cc. There was an association of low platelet count at a median of 4 days with larger ICH volume (P ⫽ .01). Platelet function abnormalities, including aggregation to arachidonic acid, collagen, and ADP and ATP release reactions to thrombin and collagen, and a prolonged bleeding time were common findings in ICH patients compared to standardized controls. Platelet dysfunction was more common in large versus small ICH (80% vs 50%). Two patients with significant (⬎15%) hematoma enlargement within the first 24 hours had significant early decreases in platelet counts and extensive platelet dysfunction. In conclusion, platelet dysfunction is common among patients with SICH. Low platelet count and platelet dysfunction may be factors in expansion of ICH volume. Further prospective studies with larger sample size are needed to assess this association. Key Words: Coagulopathy— hematoma—intracerebral hemorrhage—platelets. Copyright © 2003 by National Stroke Association
From the *Division of Neurosciences Critical Care and the Departments of †Hematology, ‡Neurology, and §Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Received April 5, 2003; revised June 29, 2003; accepted July 2, 2003. Supported in part by the Johns Hopkins Fund for Medical Discovery. Dr Bhardwaj is supported in part by the Established Investigator Grant from the American Heart Association. Address reprint requests to Wendy C. Ziai, MD, Johns Hopkins Hospital, Division of Neurosciences Critical Care, 600 N. Wolfe Street/ Meyer 8-140, Baltimore, MD 21287. E-mail: [email protected] Copyright © 2003 by National Stroke Association 1052-3057/03/1204-0000$30.00/0 doi:10.1016/S1052-3057(03)00075-2
Intracerebral hemorrhage (ICH) accounts for 10% to 15% of strokes in the United States.1 Despite a decline in the incidence of ICH over the past few decades, shortterm mortality remains high, ranging from 20% to 50%.1,2 Two clinical predictors appear to be associated with poor outcome: a depressed level of consciousness on admission and hematoma size.3,4 Volumetric studies of hematoma size show a robust correlation with 30-day mortality, with over 80% survival in patients with hematomas ⬍ 30 cc, 35% survival for hematomas between 30 and 60 cc, and 19% survival in patients with hematomas ⬎ 60 cc in size.3 Equally important is the finding that 38% of patients presenting within 6 hours of symptom onset have
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substantial enlargement of ICH within the first 24 hours.5 Platelets are essential for the maintenance of hemostasis, and platelet hypofunction leads to deranged coagulation and hemorrhage.6 The determinants of ICH volume and expansion, particularly the role of platelets, are poorly understood at this time. A few small studies have suggested that patients with ICH may have underlying platelet dysfunction.7-9 These studies were limited by the extent of testing for platelet dysfunction and assessment of hematoma volume. The aims of this study were to test the hypotheses that: (1) patients with ICH have platelet dysfunction, as assessed by bleeding time and in vitro assays of platelet function, and (2) the presence of platelet dysfunction correlates with ICH volume and expansion.
ICH Volume Determination Non-enhanced baseline head CT scan performed within 24 hours of symptom onset (34 available studies) and follow-up CT study performed within 24 to 72 hours (28 available studies) were analyzed for hematoma location, volume, and expansion by two reviewers blinded to the platelet function results (R.W. and M.T.). ICH location was classified as basal ganglionic, thalamic, or lobar. ICH volume was determined by the A⫻B⫻C/2 method.3,13,14 Volume of intraventricular hemorrhage was not included in the analysis of ICH volume. Patients were dichotomized into two groups based on ICH volume: ⱕ 30 cc and ⬎ 30 cc. Patients were also grouped into those with stable ICH size and patients with hematoma enlargement (defined as an increase in hematoma size of ⬎ 15% from the first to the second CT scans).
Materials and Methods Patient Selection Adult patients admitted with supratentorial spontaneous ICH (SICH) to a Neurosciences Critical Care Unit (NCCU) of a university teaching hospital were included. We excluded patients: (1) who died within 24 hours of admission; (2) with known bleeding disorder or anticoagulant use; (3) who were pregnant; (4) with intracranial neoplasm, arteriovenous malformation, aneurysm, or cavernous angioma; and (5) with a known history of intravenous drug abuse.
Retrospective Case-control Series We retrospectively reviewed the medical records of 43 consecutive patients admitted with SICH to a NCCU of a university teaching hospital between September 1996 and August 1999. Data collected included age, sex, race, and history of hypertension, diabetes, coronary artery disease, hyperlipidemia, renal or liver dysfunction, smoking, alcohol or drug abuse, previous stroke, current antiplatelet drug or cyclo-oxygenase inhibitor use, and other medications. Platelet counts were reported on admission and daily for 10 days. Prothrombin (PT) and partial thromboplastin time (PTT) were also followed serially. All patients were treated in the NCCU using a standardized protocol of frequent neurologic assessment, supportive care, and blood pressure management. Thirty-five patients admitted with myasthenia gravis (MG) (n ⫽ 23) and Guillain-Barre´ syndrome (GBS) (n ⫽ 12) for at least 4 days to the NCCU within the same time frame of SICH patients served as controls. These patients were included to assess the effect of critical illness on platelet counts in the absence of SICH or other intracranial pathology. Patients with GBS and MG were treated with supportive care, plasma exchange, or immunoglobulin treatments as indicated. No distinction was made as to which treatment regimen was used.
Platelet Function Tests In 17/43 patients, we prospectively performed an extensive platelet function workup within 7 days of onset of ICH. The workup included platelet count with mean corpuscular volume (MCV), fibrinogen, von Willebrand factor, prothrombin factor 1.2, a platelet aggregation panel (including ADP, arachidonic acid [AA] and collagen as agonists), and ATP release studies. The coefficient of variation of platelet function tests, for our lab, are as follows: platelet counts: 2.0%; platelet function: collagen, epinephrine, ADP-induced aggregation: 5.0%; ATP release: 3.0%. Results were interpreted by a hematologist blinded to the ICH volume (T.K.). Patient consent was obtained.
Statistical Analysis Statistical analysis was performed using SPSS 10.0 statistical package. Categorical variables were compared with Pearson’s 2 test and, when necessary, Fisher’s exact 2-tailed test. Continuous variables were compared with 2-tailed t tests for comparison of means. All results are presented as mean ⫾ SEM.
Results Forty-three ICH patients were identified with mean age 62 ⫾ 2 years, (range: 40-86). Sixty-four percent were males and 60% were African American. A history of hypertension was documented in majority of patients (65%; Table 1). Hemorrhage location was equally distributed between basal ganglia and lobar areas (42% each) and thalamus in 16% of cases. Mean volume of ICH on initial CT scan was 41 ⫾ 7 cc, and on follow-up CT scan, 46 ⫾ 9 cc. Fifteen (44%) patients had an initial ICH volume ⬎ 30 cc. There were no significant differences in patient characteristics between patients with large and small hematomas, including age, aspirin use, and other
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Table 1. ICH patient demographics Characteristic
ICH patients (n ⫽ 43) (%)
Age (y) Gender Female Male Race African American White Asian Hypertension Smoking Alcohol use Liver disease Renal insufficiency Prior aspirin use
62 ⫾ 2* 15 (36) 27 (64) 26 (60) 15 (35) 2 (5) 28 (65) 5 (29) 10 (23) 1 (2) 4 (9) 8 (19)
*Mean xx SEM.
known risk factors for bleeding or ICH: a history of hypertension, liver disease, or alcohol use. Thirty-five controls were identified with mean age 57 ⫾ 3 years (range: 27-86). Although platelet count was within normal range in both groups on admission to the NCCU, it was significantly lower in ICH patients (Table 2). Platelet counts dropped in both ICH patients and controls over the first week following admission (Fig 1), but remained significantly lower in ICH patients (Table 2). The mean decrease in platelet number (admission to nadir) was 55 ⫾ 11 IU/mm3 in patients with small hematoma volume, compared to 74 ⫾ 16 IU/mm3 in those with ICH size ⬎ 30 cc (P ⫽ NS). In 6 patients with significant increase in hematoma size, the mean platelet count decreased by 106 ⫾ 24 IU/mm3, compared with 22 patients with stable hematoma size whose platelet count fell by 65 ⫾ 9 IU/mm3 (P ⫽ NS). Medication usage before admission or during the period of platelet monitoring which may potentially have contributed to decrease in platelet counts was as follows: heparin (ICH patients: 0; controls: 35); zantac (42; 34); antiplatelet agents (7; 6); antiepileptics (dilantin, valproate: 19; 0); antibiotics (vancomycin, erythromycin: 2; 4); prednisone (1; 18); azathioprine (0; 5); FK506 (0; 1);
Figure 1. Changes in mean platelet counts over first 10 days of hospital stay. Mean platelet counts decreased in both control and ICH patients, but remained significantly lower in ICH patients (*) for the first week, and were significantly lower in ICH patients with hematoma expansion compared to those without on days 6 and 7 (**).
lasix (4; 4); captopril (1; 1); digoxin (1; 2); and allopurinol (1; 2). Platelet function tests (Table 3) were performed at 4.5 ⫾ 0.5 days (range: 1-7) following ICH. At this time, 9 (53%) patients had a low platelet count (range: 76-149 IU/mm3), compared to only 3 patients on admission. This included all 5 (100%) patients with initial large ICHs (⬎30cc; P ⫽ .01). Platelet dysfunction, either in aggregation responses or ATP release, was found in 10 of 17 (59%) patients; this included 80% of large hematoma patients and 50% of those with small ICH (P ⫽ NS). Platelet aggregation in response to arachidonic acid was impaired in 33% of small ICH patients and 80% of large ICHs (P ⫽ .08). The degree of impairment was greater in patients with large compared to small ICHs (2.8 ⫾ 2.5% vs 20.3 ⫾ 4.9% aggregation; P ⫽ .009). Both patients with significant ICH expansion had absent aggregation response to AA. Four of 7 patients with impaired aggregation to AA were taking aspirin; the other 3 patients had no reported history of antiplatelet drug use. Platelet aggregation response to all agonists was lower in aspirin users compared to non-users (AA response: 8.6 ⫾ 4.1% vs 16.0 ⫾ 5.1%). However, 2 of the 7 aspirin users by history had no laboratory evidence of platelet hypofunction and 4 had normal bleeding times. Percent platelet aggregation to ADP and collagen was also lower in patients with large versus small ICH. ATP release reaction was lower for
Table 2. Comparison of mean platelet counts in ICH and control patients
Age (y) Admission platelet count (IU/mm3) Nadir platelet count (IU/mm3) Day of nadir platelet count (days) Thrombocytopenia (⬍ 150 IU/mm3); (%)
ICH (n ⫽ 43)
Control (n ⫽ 35)
P value
62 ⫾ 2 220 ⫾ 12 149 ⫾ 9 3.3 ⫾ 0.3 55
57 ⫾ 3 273 ⫾ 12 202 ⫾ 12 4.0 ⫾ 0.5 11
.14 .006 .001 .26 ⬍.001
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Table 3. Platelet function abnormalities
Platelet function test Platelet count: [IU/mm3] Elevated MPV [fL] Platelet aggregation to collagen [5 g/ml] (%) Platelet aggregation to AA [0.5/mM] (%) Platelet aggregation to ADP [20 l] (%) ATP release to collagen [5 g/ml] (%) ATP release to thrombin [1 g/ml] (%) Bleeding time (increased)
ICH patients (n ⫽ 17) 223 ⫾ 19 9.8 ⫾ 0.2 52.9 ⫾ 5.4 12.9 ⫾ 3.5‡ 15.1 ⫾ 2.8 14.5 ⫾ 2.5‡ 26.9 ⫾ 3.6‡
Control subjects* (n ⫽ 10)
50.2 ⫾ 2.9 21.4 ⫾ 2.4 20.6 ⫾ 2.3 28.6 ⫾ 3.6 55.6 ⫾ 6.1
Number (%) abnormal (n ⫽ 17) 9 (53)† 14 (82) 8 (47) 7 (41) 4 (24) 9 (53) 3 (18) 3 (18)
AA, arachidonic acid; MPV, mean platelet volume. *Normal control subjects used to ensure agonists are active †Less than 150 IU/mm3. ‡Significant at the P ⬍ .05 level.
large ICH in response to thrombin, but higher in response to collagen versus patients with small ICH. Fibrinogen levels were mildly elevated in both groups. PT and PTT were normal on admission in all patients and showed no elevation over time. Prothrombin factor 1.2 was elevated in 4 of 6 patients in the large ICH group, and both von Willebrand factor antigen and mean platelet volumes were elevated in both groups (15/17 and 14/17 patients, respectively). The ten healthy “standards” for PFT analysis all had normal platelet aggregation studies. The clinical characteristics and platelet test results of the two patients with ICH expansion are as follows: patient 1 had hypertension, alcohol abuse, and a mildly decreased platelet count at the time of the platelet function tests (decrease from admission: 255 to 143 IU/mm3) with abnormal platelet aggregation and ATP release reactions (no history of aspirin use). Patient 2, with hypertension and ASA use, had a very large ICH and had the lowest platelet count at time of platelet function tests (decrease from admission: 246 to 76 IU/mm3) in addition to abnormalities of all platelet function tests performed, including a prolonged bleeding time. No other noncranial sites of bleeding were apparent in this group of patients.
Discussion The major findings of this study are that (A) patients with SICH are more likely to have low platelet counts compared to ICU patients without brain pathology; (B) the association between SICH and falling platelet counts suggests that platelet abnormalities may be a consequence of the hemorrhage; (C) platelet dysfunction is common in patients with ICH and may extend beyond ASA effect; and (D) low platelet count and platelet dysfunction may be factors in expansion of ICH volume. We found that platelet function abnormalities were common in patients with ICH as compared to healthy
“standards.” The pattern of platelet dysfunction was variable, with depression of multiple platelet aggregation characteristics. Certain abnormalities (aggregation to arachidonic acid) could be explained, in some cases, by previous ASA use. There was an association of low platelet count (nadir) with larger ICH size and with ICH expansion. Platelet counts also decreased in an agematched control group of critically ill patients with neuromuscular disease, but thrombocytopenia (platelet count ⬍ 150 IU/mm3) was observed less frequently. No clear association was seen with ICH size and specific platelet aggregation agonists, although significant reductions in mean aggregation response to arachidonic acid and ADP stimulation was found in patients with larger ICH size. Two patients with ICH volume expansion within the first 24 hours had extensive platelet dysfunction and absent aggregation response to arachidonic acid. Abnormal platelet function has been implicated in the pathophysiology of both ischemic and hemorrhagic stroke.7,9,19 In a study of ADP-induced platelet release reactions in acute stroke patients, Mulley et al7 found evidence of platelet hyperactivity in thromboembolic stroke while patients with either primary ICH or subarachnoid hemorrhage had hyporeactive platelets. Liu et al19 reported platelet hyperfunction in both ischemic stroke and stroke with hemorrhagic transformation, as determined by significantly increased platelet aggregation rates induced by ADP or epinephrine, and elevated plasma levels of beta-thromboglobulin. This suggests that hemorrhagic stroke, like ischemic stroke, may reflect a hypercoagulable state, while spontaneous ICH, not associated with infarction, may represent a hypocoagulable state in terms of platelet function. It is not understood whether the association between ICH and platelet dysfunction is caused by a preexisting factor, which may enhance the likelihood of hemorrhage, or is a consequence of ICH and related to the severity of brain injury. Our study cannot make this distinction,
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based on the delay in performance of PFTs and lack of follow-up PFTs beyond the acute hospital course. Brain trauma secondary to ICH, like systemic trauma, may be a precipitant to decreased platelet function or number. Disruptive brain injury, studied in patients with gunshot wounds and blunt brain injury, exposes circulating blood to released tissue thromboplastin, which activates the extrinsic coagulation pathway and produces fibrin clot and vigorous fibrinolysis, causing consumption of coagulation factors with risk of further bleeding.21 This is usually associated with the depletion of fibrinogen, but not a decline in platelet counts, unlike other forms of DIC. Secondly, consumption of platelets during hemostasis is known to occur after massive bleeding in trauma.22 The volume of hemorrhage required to produce this effect, however, is usually significantly larger than that seen in non-traumatic ICH. Platelet dysfunction after trauma may also be associated with other factors such as low hematocrit (⬍20%) which decreases platelet adhesion, dilutional thrombocytopenia secondary to massive transfusion, hypothermia-induced platelet dysfunction, and use of colloids and dextran solutions which can impair hemostasis by interfering with the factor VIIIvon Willebrand complex, and fibrin formation seen in ICH.23 In a retrospective study of patients with spontaneous putaminal hemorrhage, Niizuma et al8 reported significantly larger hematoma size in regular alcohol consumers, and patients with liver dysfunction and low platelet counts. Six patients in our study were regular alcohol users, although none had significant abnormalities of liver function tests or altered coagulation parameters and only 2 had admission platelet counts ⬍ 150 IU/mm3 (but ⬎ 100 IU/mm3). The possibility of drug reaction, especially to cytoprotective agents (H2 blockers) for peptic ulcer prevention, which all patients are placed on initially, was unlikely because of the short time interval for drug-induced thrombocytopenia to have developed. Other medications such as antibiotics, subcutaneous heparin (in control patients), and antiepileptics may have contributed to thrombocytopenia although the widespread occurrence of falling platelet counts would not have been expected from medications alone. Studies of primary stroke prevention with ASA have demonstrated that prolonged use of aspirin is associated with a small risk of ICH.24-26 Aspirin use has also been found to have a higher propensity for lobar hematoma compared with other common locations for SICH.27 We found no correlation between hematoma location and platelet hypofunction in our study. There was a trend for patients with larger ICH to have abnormal platelet aggregation to arachidonic acid, which could be accounted for by ASA use in 4/7 patients. However, 2 “aspirin users” had no platelet dysfunction suggesting aspirin history is not always reliable, and similar aggregation defects were seen in non-ASA users. Impaired response
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to arachidonic acid, for instance, has been attributed to several reported defects in the prostaglandin synthetic pathway.18 Our study was limited by small sample size and by few patients with large ICH. Future studies should follow changes in platelet function from immediately after onset of ICH, through the acute phase, and at long-term follow-up to determine the cause and effect relationship of platelet dysfunction in ICH.
References 1. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, American Heart Association, 2001, 1-3. 2. Dennis M, Burn J, Sandercock P, et al. Long-term survival after first ever stroke: The Oxfordshire Community Stroke Project. Stroke 1993;24:796-800. 3. Broderick JP, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage: A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987-993. 4. Helweg-Larsen S, Sommer W, Strange P, et al. Prognosis for patients treated conservatively for spontaneous intracerebral hematomas. Stroke 1984;15:1045-1048. 5. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1-5. 6. Boldt J, Menges T, Wollbruck M, et al. Platelet function in critically ill patients. Chest 1994;106:899-903. 7. Mulley GP, Heptinstall S, Taylor PM, et al. ADP-induced platelet release reaction in acute stroke. Thromb Haemost 1983;50:524-526. 8. Niizuma H, Shimizu Y, Nakasato N, et al. Influence of liver dysfunction on volume of putaminal hemorrhage. Stroke 1988;19:987-990. 9. Serebruany VL, Gurbel PA, Shustov AR, et al. Depressed platelet status in an elderly patient with hemorragic stroke after thrombolysis for acute myocardial infarction. Stroke 1998;29:235-238. 10. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81-84. 11. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-607. 12. Russell-Smith NC, Flower RJ, Cardinal DC. Measuring platelet and leukocyte aggregation/adhesion responses in very small volumes of whole blood. J Pharmacol Methods 1981;6:315-333. 13. Lisk DR, Pasteur W, Rhoades H. Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology 1994;44:133-139. 14. Kazui S, Naritomi H, Yamamoto H, et al. Enlargement of spontaneous intracerebral hemorrhage. Stroke 1996;27: 1783-1787. 15. Berndt MC, Ward CM, De Luca M, et al. The molecular mechanism of platelet adhesion. Aust N Z J Med 1995; 25:822-830. 16. Andrews RK, Lopez JA, Berndt MC. Molecular mechanisms of platelet adhesion and activation. Int J Biochem Cell Biol 1997;29:91-105. 17. Weiss HJ. Platelet physiology and abnormalities of platelet function (first of two parts). N Engl J Med 1975;293: 531-541.
206 18. Weiss H. Platelets: Pathophysiology and antiplatelet drug therapy. New York, Alan R. Liss, Inc, 1982. 19. Liu L, Lin Z, Shen Z, et al. Platelet hyperfunction exists in both acute non-hemorrhagic and hemorrhagic stroke. Thrombosis Res 1994;75:485-490. 20. Bick RL. Platelet function defects: A clinical review. Semin Thromb Haemost 1992;18:167-185. 21. Hulka F, Mullins RJ, Frank EH. Blunt brain injury activates the coagulation process. Arch Surg 1996;131:923927. 22. Thompson CB. Selective consumption of large platelets during massive bleeding. Br Med J (Clin Res Ed) 1985; 291:95-96.
W.C. ZIAI ET AL. 23. Samana CM. Traumatic emergencies and hemostasis. Cah Anesthesiol 1995;43:479-482. 24. Buring JE, Bogousslavsky J, Dyken M. Aspirin and stroke. Stroke 1998;29:885-886. 25. He J, Whelton PK, Vu B, et al. Aspirin and risk of hemorrhagic stroke: A meta-analysis of randomized controlled trials. JAMA 1998;280:1930-1935. 26. Mayo NE, Levy AR, Goldberg MS. Aspirin and hemorrhagic stroke. Stroke 1991;22:1213-1214. 27. Wong KS, Mok V, Lam WW, et al. Aspirin-associated intracerebral hemorrhage: Clinical and radiologic features. Neurology 2000;54:2298-2301.
Impaired platelet function has been associated with an increased propensity for intracerebral hemorrhage (ICH). The role of platelet count and dysfunction in spontaneous ICH (SICH) is poorly understood. We tested the hypotheses that patients with SICH have subtle platelet dysfunction associated with ICH progression and larger ICH size. In a retrospective case series, we compared platelet counts in patients with SICH with age-matched controls with neuromuscular disorders admitted to a Neurosciences Critical Care Unit (NCCU). In a subset of patients, platelet function was measured within one week of ICH. Computerized tomography (CT) scans were performed within 24 hours of the event and ICH volume determined by the ABC/2 method. Comparison of 43 patients with SICH and 35 age-matched controls with neuromuscular disease demonstrated significant decreases in platelet counts over the first few days of admission to the NCCU (Nadir: 149 ⫾ 9 vs 202 ⫾ 12 IU/mm3; P ⫽ .001). There was a significant correlation between a fall in platelet count and change in hematoma size in 28 patients (P ⫽ .01). Seventeen patients were enrolled prospectively to study platelet function. Patients were divided into 2 groups based on ICH volume: ⱕ 30cc and ⬎ 30cc. There was an association of low platelet count at a median of 4 days with larger ICH volume (P ⫽ .01). Platelet function abnormalities, including aggregation to arachidonic acid, collagen, and ADP and ATP release reactions to thrombin and collagen, and a prolonged bleeding time were common findings in ICH patients compared to standardized controls. Platelet dysfunction was more common in large versus small ICH (80% vs 50%). Two patients with significant (⬎15%) hematoma enlargement within the first 24 hours had significant early decreases in platelet counts and extensive platelet dysfunction. In conclusion, platelet dysfunction is common among patients with SICH. Low platelet count and platelet dysfunction may be factors in expansion of ICH volume. Further prospective studies with larger sample size are needed to assess this association. Key Words: Coagulopathy— hematoma—intracerebral hemorrhage—platelets. Copyright © 2003 by National Stroke Association
From the *Division of Neurosciences Critical Care and the Departments of †Hematology, ‡Neurology, and §Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Received April 5, 2003; revised June 29, 2003; accepted July 2, 2003. Supported in part by the Johns Hopkins Fund for Medical Discovery. Dr Bhardwaj is supported in part by the Established Investigator Grant from the American Heart Association. Address reprint requests to Wendy C. Ziai, MD, Johns Hopkins Hospital, Division of Neurosciences Critical Care, 600 N. Wolfe Street/ Meyer 8-140, Baltimore, MD 21287. E-mail: [email protected] Copyright © 2003 by National Stroke Association 1052-3057/03/1204-0000$30.00/0 doi:10.1016/S1052-3057(03)00075-2
Intracerebral hemorrhage (ICH) accounts for 10% to 15% of strokes in the United States.1 Despite a decline in the incidence of ICH over the past few decades, shortterm mortality remains high, ranging from 20% to 50%.1,2 Two clinical predictors appear to be associated with poor outcome: a depressed level of consciousness on admission and hematoma size.3,4 Volumetric studies of hematoma size show a robust correlation with 30-day mortality, with over 80% survival in patients with hematomas ⬍ 30 cc, 35% survival for hematomas between 30 and 60 cc, and 19% survival in patients with hematomas ⬎ 60 cc in size.3 Equally important is the finding that 38% of patients presenting within 6 hours of symptom onset have
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substantial enlargement of ICH within the first 24 hours.5 Platelets are essential for the maintenance of hemostasis, and platelet hypofunction leads to deranged coagulation and hemorrhage.6 The determinants of ICH volume and expansion, particularly the role of platelets, are poorly understood at this time. A few small studies have suggested that patients with ICH may have underlying platelet dysfunction.7-9 These studies were limited by the extent of testing for platelet dysfunction and assessment of hematoma volume. The aims of this study were to test the hypotheses that: (1) patients with ICH have platelet dysfunction, as assessed by bleeding time and in vitro assays of platelet function, and (2) the presence of platelet dysfunction correlates with ICH volume and expansion.
ICH Volume Determination Non-enhanced baseline head CT scan performed within 24 hours of symptom onset (34 available studies) and follow-up CT study performed within 24 to 72 hours (28 available studies) were analyzed for hematoma location, volume, and expansion by two reviewers blinded to the platelet function results (R.W. and M.T.). ICH location was classified as basal ganglionic, thalamic, or lobar. ICH volume was determined by the A⫻B⫻C/2 method.3,13,14 Volume of intraventricular hemorrhage was not included in the analysis of ICH volume. Patients were dichotomized into two groups based on ICH volume: ⱕ 30 cc and ⬎ 30 cc. Patients were also grouped into those with stable ICH size and patients with hematoma enlargement (defined as an increase in hematoma size of ⬎ 15% from the first to the second CT scans).
Materials and Methods Patient Selection Adult patients admitted with supratentorial spontaneous ICH (SICH) to a Neurosciences Critical Care Unit (NCCU) of a university teaching hospital were included. We excluded patients: (1) who died within 24 hours of admission; (2) with known bleeding disorder or anticoagulant use; (3) who were pregnant; (4) with intracranial neoplasm, arteriovenous malformation, aneurysm, or cavernous angioma; and (5) with a known history of intravenous drug abuse.
Retrospective Case-control Series We retrospectively reviewed the medical records of 43 consecutive patients admitted with SICH to a NCCU of a university teaching hospital between September 1996 and August 1999. Data collected included age, sex, race, and history of hypertension, diabetes, coronary artery disease, hyperlipidemia, renal or liver dysfunction, smoking, alcohol or drug abuse, previous stroke, current antiplatelet drug or cyclo-oxygenase inhibitor use, and other medications. Platelet counts were reported on admission and daily for 10 days. Prothrombin (PT) and partial thromboplastin time (PTT) were also followed serially. All patients were treated in the NCCU using a standardized protocol of frequent neurologic assessment, supportive care, and blood pressure management. Thirty-five patients admitted with myasthenia gravis (MG) (n ⫽ 23) and Guillain-Barre´ syndrome (GBS) (n ⫽ 12) for at least 4 days to the NCCU within the same time frame of SICH patients served as controls. These patients were included to assess the effect of critical illness on platelet counts in the absence of SICH or other intracranial pathology. Patients with GBS and MG were treated with supportive care, plasma exchange, or immunoglobulin treatments as indicated. No distinction was made as to which treatment regimen was used.
Platelet Function Tests In 17/43 patients, we prospectively performed an extensive platelet function workup within 7 days of onset of ICH. The workup included platelet count with mean corpuscular volume (MCV), fibrinogen, von Willebrand factor, prothrombin factor 1.2, a platelet aggregation panel (including ADP, arachidonic acid [AA] and collagen as agonists), and ATP release studies. The coefficient of variation of platelet function tests, for our lab, are as follows: platelet counts: 2.0%; platelet function: collagen, epinephrine, ADP-induced aggregation: 5.0%; ATP release: 3.0%. Results were interpreted by a hematologist blinded to the ICH volume (T.K.). Patient consent was obtained.
Statistical Analysis Statistical analysis was performed using SPSS 10.0 statistical package. Categorical variables were compared with Pearson’s 2 test and, when necessary, Fisher’s exact 2-tailed test. Continuous variables were compared with 2-tailed t tests for comparison of means. All results are presented as mean ⫾ SEM.
Results Forty-three ICH patients were identified with mean age 62 ⫾ 2 years, (range: 40-86). Sixty-four percent were males and 60% were African American. A history of hypertension was documented in majority of patients (65%; Table 1). Hemorrhage location was equally distributed between basal ganglia and lobar areas (42% each) and thalamus in 16% of cases. Mean volume of ICH on initial CT scan was 41 ⫾ 7 cc, and on follow-up CT scan, 46 ⫾ 9 cc. Fifteen (44%) patients had an initial ICH volume ⬎ 30 cc. There were no significant differences in patient characteristics between patients with large and small hematomas, including age, aspirin use, and other
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Table 1. ICH patient demographics Characteristic
ICH patients (n ⫽ 43) (%)
Age (y) Gender Female Male Race African American White Asian Hypertension Smoking Alcohol use Liver disease Renal insufficiency Prior aspirin use
62 ⫾ 2* 15 (36) 27 (64) 26 (60) 15 (35) 2 (5) 28 (65) 5 (29) 10 (23) 1 (2) 4 (9) 8 (19)
*Mean xx SEM.
known risk factors for bleeding or ICH: a history of hypertension, liver disease, or alcohol use. Thirty-five controls were identified with mean age 57 ⫾ 3 years (range: 27-86). Although platelet count was within normal range in both groups on admission to the NCCU, it was significantly lower in ICH patients (Table 2). Platelet counts dropped in both ICH patients and controls over the first week following admission (Fig 1), but remained significantly lower in ICH patients (Table 2). The mean decrease in platelet number (admission to nadir) was 55 ⫾ 11 IU/mm3 in patients with small hematoma volume, compared to 74 ⫾ 16 IU/mm3 in those with ICH size ⬎ 30 cc (P ⫽ NS). In 6 patients with significant increase in hematoma size, the mean platelet count decreased by 106 ⫾ 24 IU/mm3, compared with 22 patients with stable hematoma size whose platelet count fell by 65 ⫾ 9 IU/mm3 (P ⫽ NS). Medication usage before admission or during the period of platelet monitoring which may potentially have contributed to decrease in platelet counts was as follows: heparin (ICH patients: 0; controls: 35); zantac (42; 34); antiplatelet agents (7; 6); antiepileptics (dilantin, valproate: 19; 0); antibiotics (vancomycin, erythromycin: 2; 4); prednisone (1; 18); azathioprine (0; 5); FK506 (0; 1);
Figure 1. Changes in mean platelet counts over first 10 days of hospital stay. Mean platelet counts decreased in both control and ICH patients, but remained significantly lower in ICH patients (*) for the first week, and were significantly lower in ICH patients with hematoma expansion compared to those without on days 6 and 7 (**).
lasix (4; 4); captopril (1; 1); digoxin (1; 2); and allopurinol (1; 2). Platelet function tests (Table 3) were performed at 4.5 ⫾ 0.5 days (range: 1-7) following ICH. At this time, 9 (53%) patients had a low platelet count (range: 76-149 IU/mm3), compared to only 3 patients on admission. This included all 5 (100%) patients with initial large ICHs (⬎30cc; P ⫽ .01). Platelet dysfunction, either in aggregation responses or ATP release, was found in 10 of 17 (59%) patients; this included 80% of large hematoma patients and 50% of those with small ICH (P ⫽ NS). Platelet aggregation in response to arachidonic acid was impaired in 33% of small ICH patients and 80% of large ICHs (P ⫽ .08). The degree of impairment was greater in patients with large compared to small ICHs (2.8 ⫾ 2.5% vs 20.3 ⫾ 4.9% aggregation; P ⫽ .009). Both patients with significant ICH expansion had absent aggregation response to AA. Four of 7 patients with impaired aggregation to AA were taking aspirin; the other 3 patients had no reported history of antiplatelet drug use. Platelet aggregation response to all agonists was lower in aspirin users compared to non-users (AA response: 8.6 ⫾ 4.1% vs 16.0 ⫾ 5.1%). However, 2 of the 7 aspirin users by history had no laboratory evidence of platelet hypofunction and 4 had normal bleeding times. Percent platelet aggregation to ADP and collagen was also lower in patients with large versus small ICH. ATP release reaction was lower for
Table 2. Comparison of mean platelet counts in ICH and control patients
Age (y) Admission platelet count (IU/mm3) Nadir platelet count (IU/mm3) Day of nadir platelet count (days) Thrombocytopenia (⬍ 150 IU/mm3); (%)
ICH (n ⫽ 43)
Control (n ⫽ 35)
P value
62 ⫾ 2 220 ⫾ 12 149 ⫾ 9 3.3 ⫾ 0.3 55
57 ⫾ 3 273 ⫾ 12 202 ⫾ 12 4.0 ⫾ 0.5 11
.14 .006 .001 .26 ⬍.001
W.C. ZIAI ET AL.
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Table 3. Platelet function abnormalities
Platelet function test Platelet count: [IU/mm3] Elevated MPV [fL] Platelet aggregation to collagen [5 g/ml] (%) Platelet aggregation to AA [0.5/mM] (%) Platelet aggregation to ADP [20 l] (%) ATP release to collagen [5 g/ml] (%) ATP release to thrombin [1 g/ml] (%) Bleeding time (increased)
ICH patients (n ⫽ 17) 223 ⫾ 19 9.8 ⫾ 0.2 52.9 ⫾ 5.4 12.9 ⫾ 3.5‡ 15.1 ⫾ 2.8 14.5 ⫾ 2.5‡ 26.9 ⫾ 3.6‡
Control subjects* (n ⫽ 10)
50.2 ⫾ 2.9 21.4 ⫾ 2.4 20.6 ⫾ 2.3 28.6 ⫾ 3.6 55.6 ⫾ 6.1
Number (%) abnormal (n ⫽ 17) 9 (53)† 14 (82) 8 (47) 7 (41) 4 (24) 9 (53) 3 (18) 3 (18)
AA, arachidonic acid; MPV, mean platelet volume. *Normal control subjects used to ensure agonists are active †Less than 150 IU/mm3. ‡Significant at the P ⬍ .05 level.
large ICH in response to thrombin, but higher in response to collagen versus patients with small ICH. Fibrinogen levels were mildly elevated in both groups. PT and PTT were normal on admission in all patients and showed no elevation over time. Prothrombin factor 1.2 was elevated in 4 of 6 patients in the large ICH group, and both von Willebrand factor antigen and mean platelet volumes were elevated in both groups (15/17 and 14/17 patients, respectively). The ten healthy “standards” for PFT analysis all had normal platelet aggregation studies. The clinical characteristics and platelet test results of the two patients with ICH expansion are as follows: patient 1 had hypertension, alcohol abuse, and a mildly decreased platelet count at the time of the platelet function tests (decrease from admission: 255 to 143 IU/mm3) with abnormal platelet aggregation and ATP release reactions (no history of aspirin use). Patient 2, with hypertension and ASA use, had a very large ICH and had the lowest platelet count at time of platelet function tests (decrease from admission: 246 to 76 IU/mm3) in addition to abnormalities of all platelet function tests performed, including a prolonged bleeding time. No other noncranial sites of bleeding were apparent in this group of patients.
Discussion The major findings of this study are that (A) patients with SICH are more likely to have low platelet counts compared to ICU patients without brain pathology; (B) the association between SICH and falling platelet counts suggests that platelet abnormalities may be a consequence of the hemorrhage; (C) platelet dysfunction is common in patients with ICH and may extend beyond ASA effect; and (D) low platelet count and platelet dysfunction may be factors in expansion of ICH volume. We found that platelet function abnormalities were common in patients with ICH as compared to healthy
“standards.” The pattern of platelet dysfunction was variable, with depression of multiple platelet aggregation characteristics. Certain abnormalities (aggregation to arachidonic acid) could be explained, in some cases, by previous ASA use. There was an association of low platelet count (nadir) with larger ICH size and with ICH expansion. Platelet counts also decreased in an agematched control group of critically ill patients with neuromuscular disease, but thrombocytopenia (platelet count ⬍ 150 IU/mm3) was observed less frequently. No clear association was seen with ICH size and specific platelet aggregation agonists, although significant reductions in mean aggregation response to arachidonic acid and ADP stimulation was found in patients with larger ICH size. Two patients with ICH volume expansion within the first 24 hours had extensive platelet dysfunction and absent aggregation response to arachidonic acid. Abnormal platelet function has been implicated in the pathophysiology of both ischemic and hemorrhagic stroke.7,9,19 In a study of ADP-induced platelet release reactions in acute stroke patients, Mulley et al7 found evidence of platelet hyperactivity in thromboembolic stroke while patients with either primary ICH or subarachnoid hemorrhage had hyporeactive platelets. Liu et al19 reported platelet hyperfunction in both ischemic stroke and stroke with hemorrhagic transformation, as determined by significantly increased platelet aggregation rates induced by ADP or epinephrine, and elevated plasma levels of beta-thromboglobulin. This suggests that hemorrhagic stroke, like ischemic stroke, may reflect a hypercoagulable state, while spontaneous ICH, not associated with infarction, may represent a hypocoagulable state in terms of platelet function. It is not understood whether the association between ICH and platelet dysfunction is caused by a preexisting factor, which may enhance the likelihood of hemorrhage, or is a consequence of ICH and related to the severity of brain injury. Our study cannot make this distinction,
PLATELET FUNCTION AND INTRACEREBRAL HEMORRHAGE
based on the delay in performance of PFTs and lack of follow-up PFTs beyond the acute hospital course. Brain trauma secondary to ICH, like systemic trauma, may be a precipitant to decreased platelet function or number. Disruptive brain injury, studied in patients with gunshot wounds and blunt brain injury, exposes circulating blood to released tissue thromboplastin, which activates the extrinsic coagulation pathway and produces fibrin clot and vigorous fibrinolysis, causing consumption of coagulation factors with risk of further bleeding.21 This is usually associated with the depletion of fibrinogen, but not a decline in platelet counts, unlike other forms of DIC. Secondly, consumption of platelets during hemostasis is known to occur after massive bleeding in trauma.22 The volume of hemorrhage required to produce this effect, however, is usually significantly larger than that seen in non-traumatic ICH. Platelet dysfunction after trauma may also be associated with other factors such as low hematocrit (⬍20%) which decreases platelet adhesion, dilutional thrombocytopenia secondary to massive transfusion, hypothermia-induced platelet dysfunction, and use of colloids and dextran solutions which can impair hemostasis by interfering with the factor VIIIvon Willebrand complex, and fibrin formation seen in ICH.23 In a retrospective study of patients with spontaneous putaminal hemorrhage, Niizuma et al8 reported significantly larger hematoma size in regular alcohol consumers, and patients with liver dysfunction and low platelet counts. Six patients in our study were regular alcohol users, although none had significant abnormalities of liver function tests or altered coagulation parameters and only 2 had admission platelet counts ⬍ 150 IU/mm3 (but ⬎ 100 IU/mm3). The possibility of drug reaction, especially to cytoprotective agents (H2 blockers) for peptic ulcer prevention, which all patients are placed on initially, was unlikely because of the short time interval for drug-induced thrombocytopenia to have developed. Other medications such as antibiotics, subcutaneous heparin (in control patients), and antiepileptics may have contributed to thrombocytopenia although the widespread occurrence of falling platelet counts would not have been expected from medications alone. Studies of primary stroke prevention with ASA have demonstrated that prolonged use of aspirin is associated with a small risk of ICH.24-26 Aspirin use has also been found to have a higher propensity for lobar hematoma compared with other common locations for SICH.27 We found no correlation between hematoma location and platelet hypofunction in our study. There was a trend for patients with larger ICH to have abnormal platelet aggregation to arachidonic acid, which could be accounted for by ASA use in 4/7 patients. However, 2 “aspirin users” had no platelet dysfunction suggesting aspirin history is not always reliable, and similar aggregation defects were seen in non-ASA users. Impaired response
205
to arachidonic acid, for instance, has been attributed to several reported defects in the prostaglandin synthetic pathway.18 Our study was limited by small sample size and by few patients with large ICH. Future studies should follow changes in platelet function from immediately after onset of ICH, through the acute phase, and at long-term follow-up to determine the cause and effect relationship of platelet dysfunction in ICH.
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