(Stroke. 2001;32:883.)
© 2001 American Heart Association, Inc.
Original Contributions |
Hemostatic Activation in Spontaneous Intracerebral Hemorrhage
From the Departments of Neurosurgery and Integrated Neuroscience, Brain Research Institute, University of Niigata, Niigata, Japan.
Correspondence to Yukihiko Fujii, MD, PhD, Department of Integrated Neuroscience, Brain Research Institute, University of Niigata, 1 Asahimachi, Niigata, 951-8585 Japan. E-mail yfujii{at}bri.niigata-u.ac.jp
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Abstract |
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Background and Purpose—There is no in-depth information available on the changes in hemostatic systems in patients in the acute phase of spontaneous intracerebral hemorrhage (ICH). This study was conducted to assess the relationships between the changes in hemostatic systems and clinical parameters in patients in acute-phase ICH.
Methods—The records of 358 patients admitted within 6 hours of onset of ICH were reviewed to examine the relationships between changes in hemostatic systems and computed tomographic findings and clinical parameters.
Results—The white blood cell counts and the levels of thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer in patients with intraventricular extension (IVE) or subarachnoid hemorrhage (SAH) were significantly (P<0.05) higher than those in patients without IVE or SAH. Most of the hemostatic system parameters in patients without IVE or SAH showed no significant differences compared with normal subjects. Multiple linear regression analysis revealed that the levels of thrombin-antithrombin complex significantly increased with an increase in the amount of SAH (P<0.001) and IVE (P<0.001). The levels of thrombin-antithrombin complex were not significantly associated with the volume of intraparenchymal hematoma. The level of the complex, however, was significantly (P<0.001) and independently associated with the presence of IVE or SAH (multiple logistic regression analysis).
Conclusions—The systemic activation of hemostatic systems in ICH patients seems to take place only when blood reaches the subarachnoid space. The intraparenchymal hematoma itself seems unlikely to activate hemostatic systems in peripheral blood, although the hematoma is expected to cause local activation of hemostatic systems.
Key Words: blood coagulation • cerebral ventricles • hemostasis • intracerebral hemorrhage • subarachnoid hemorrhage
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionsReferences |
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Stroke patients are at high risk for coagulopathies, such as disseminated intravascular coagulation1 and deep vein thrombosis.2 These patients, especially subarachnoid hemorrhage (SAH) patients, also show a high likelihood for the physiological activation of hemostatic systems in the ultraacute stage of stroke,3 4 5 6 7 8 9 although the mechanism for this activation remains unclear. On the other hand, to the best of our knowledge, no study has reported in detail a relationship between hemostatic activation and spontaneous intracerebral hemorrhage (ICH) in a large series of ICH patients, although a number of reports indicated impaired hemostasis as a risk factor for ICH.10 11 12 It is necessary to understand the physiological activation of hemostatic systems in ICH patients in both diagnosing coagulopathies and assessing the mechanism of hemostatic activation for stroke patients. These circumstances prompted this study.
The purpose of this study was to assess systemic hemostatic activation in patients in the acute phase of ICH. For this purpose, we reviewed the records of patients admitted within 6 hours of onset and examined relationships between the computed tomographic (CT) findings of ICH and hemostatic parameters, including sensitive markers, to detect the activation of hemostatic systems, such as thrombin-antithrombin complex.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionsReferences |
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Patient Population
This study was performed according to the human research guidelines of the Internal Review Board of University of Niigata. Informed consent for this study was obtained from all participants (patients or their families). Between January 1990 and December 1996, 779 patients having nontraumatic intracerebral hematoma on the initial CT were admitted to our hospital. Of these, ICH was diagnosed in 559 patients, excluding 220 patients (196 with a secondary intracerebral hematoma and 24 receiving anticoagulation or antiplatelet therapy), as shown in Figure 1
. Of the 559 patients, 201 who were admitted after 6
hours of onset or whose appearance of symptoms was uncertain were
excluded. Thus, 358 patients (212 men and 146 women) were admitted to
our hospital within 6 hours of onset of ICH
(Figure 1). The time of onset was determined from the
appearance of symptoms. Only patients admitted within 6 hours of onset
were studied for the following reasons: to assess the hemostatic
condition of patients in the acute stage of
ICH6 and to minimize the
possibility of involvement of patients with hemorrhagic transformation
of cerebral infarction.
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In addition to plain CT and contrast medium–enhanced CT, all patients underwent either magnetic resonance angiography or conventional cerebral angiography to exclude hemorrhages caused by definite intracranial disease, such as cerebral aneurysms. This series of patients did not include those having ischemic stroke underlying intracerebral hemorrhage. None of the 358 ICH patients presented a marked reduction in fibrinogen levels or platelet counts, which indicated that our series included no ICH caused by disseminated intravascular coagulation (DIC).
We reviewed the records of these 358 patients. The
hematoma sites were as follows: the putamen in 159 (including 37 with
large hematomas involving the thalamus), thalamus in 90, brain stem in
45, cerebellum in 34, subcortex in 26, and caudate head in 4
(Table 1).
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For comparison, 106 age-matched healthy subjects having no liver dysfunction, no diagnosis of stroke or heart disease, and no history of antiplatelet or anticoagulate therapy were hematologically examined.
CT Findings
All patients underwent a CT scan within 30 minutes of
arrival. CT scans were performed on 5-mm-thick slices in all patients,
and the intraparenchymal hematoma volume (hematoma volume in mL) was
determined with the use of an area calculation program built into the
CT scanner.9 The severity of
intraventricular extension (IVE) on initial CT was
classified into the following 3 mutually exclusive groups: (1) none, no
evidence of clots in the ventricles; (2) mild, massive hematoma in 1
ventricle (bilateral lateral ventricles, third ventricle, and fourth
ventricle); and (3) severe, massive hematoma in 
2 of the 4
ventricles. The severity of SAH on initial CT was graded into the
following 3 mutually exclusive groups: (1) none, no evidence of clots
in the subarachnoid space; (2) mild, thin clots in the
subarachnoid space; and (3) severe, massive clots in the
subarachnoid space. Readers were blinded from patients’
records.
Data Collection
Immediately after admission, the patients’
neurological findings were assessed, and their systemic blood pressures
was measured. The time of onset and medical history, including alcohol
intake, were ascertained from the patient or family. The amount of
daily alcohol consumption was calculated with the following formula:
the volume (cm3) of the drink multiplied by
the alcohol concentration (g/cm3) of the
drink. All stroke patients routinely had 20 mL of blood taken for
laboratory studies within an hour of admission. Blood was carefully
drawn for laboratory examination with a multiple-syringe technique to
avoid any artificial activation of the hemostatic
system.6 The first 1 mL of
blood was used for a blood cell count with the S-PLUS JR (Coulter). The
next 4.5 mL was carefully placed into a plastic tube containing 0.5 mL
of 3.1% citrated buffer and used to determine platelet
aggregability within an hour of blood collection. The last 9 mL was
transferred into a prechilled plastic tube containing 1 mL of 3.1%
citrated buffer, and the plasma was used to determine prothrombin time,
activated partial thromboplastin time, and fibrinogen level.
The remaining plasma was stored frozen at -70°C until it was used
for batch analyses of other hemostatic parameters.
To evaluate the activation of hemostatic systems, the levels of
thrombin-antithrombin complex (Enzygnost TAT, Behringwerke),
plasmin-antiplasmin complex (
2PI Complex,
Teijin), and D-dimer (LPIA, Iatron) were determined through enzyme
immunoassays. All assays were completed within 1 month of blood
collection. To assess the platelet aggregability, we determined
levels of enhancement of platelet sensitivity using the modified
method reported by Fishman et
al.13 Enhancement of
platelet sensitivity was defined as the lowest concentration of ADP
that produces complete second-wave aggregation.
Statistical Analysis
Scheffé’s multiple comparison, Student’s
t test, or Welch’s
t test was used to test the
differences in clinical and hematological parameters among
normal subjects and patients with and without IVE or SAH. A
2 analysis was used to test the
difference in incidence between patients with and without IVE or SAH.
An analysis of variance in linear regression was used to assess
the relationships between hematological parameters and
severity of IVE or SAH. Multiple linear regression analysis was
used to test the correlation between levels of thrombin-antithrombin
complex and other parameters. Multiple logistic regression
analysis was used to assess the relationship between the
presence of IVE or SAH and other parameters. Values are
expressed as mean±SD. For all tests, statistical significance was
taken as a 2-tailed value of
P<0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionsReferences |
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CT Findings and Clinical Parameters
Table 1
shows relationships among ICH sites and the
presence of IVE or SAH on the initial CT. Of the 358 patients, 190
(53.1%) had IVE or SAH; ie, 179 patients had IVE, 60 had SAH, and 46
had both IVE and SAH. The severity of IVE was none in 179, mild in 113,
and severe in 66 patients. The severity of SAH was none in 298, mild in
49, and severe in 11. The age of ICH patients with IVE or SAH
(64.3±12.7 years) was significantly higher than that of ICH patients
without IVE or SAH (61.3±11.8 years). The systolic blood
pressure at admission in the patients with IVE or SAH (185±34
mm Hg) was significantly higher than in those without IVE or SAH
(177±32 mm Hg). The hematoma volume in the patients with IVE or
SAH (37±40 mL) was significantly greater than that in those without
IVE or SAH (16±19 mL). Consciousness disturbance was observed
in 195 of the 358 patients (54.5%). The incidence of consciousness
disturbance (69.5%) in the patients with IVE or SAH was
significantly higher than that (37.5%) in those without IVE or SAH. No
significant difference was found in the distribution of sex and the
amount of habitual alcohol intake between the patients with and without
IVE or SAH. For the time interval from onset to arrival, no significant
difference was seen between patients with and without IVE or
SAH.
Hematological Parameters
The mean values of white blood cell counts and the
levels of thrombin-antithrombin complex, plasmin-antiplasmin complex,
and D-dimer in ICH patients were significantly higher than in normal
subjects
(Table 2). There were no significant differences in the
other parameters, including platelet counts and
fibrinogen levels, between ICH patients and normal
subjects.
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The white blood cell count in the patients with IVE or SAH
was significantly higher than in those without IVE or SAH
(Table 2). The platelet count, level of hemoglobin,
enhancement of platelet sensitivity, fibrinogen level, and
prothrombin and activated partial thromboplastin times showed
no significant difference between the patients with and without IVE or
SAH. The levels of the thrombin-antithrombin complex (an indicator of
the activation of blood coagulation system), plasmin-antiplasmin
complex (an indicator of the activation of fibrinolytic system), and
D-dimer (an indicator of the activation of blood coagulation and
fibrinolytic systems) in the patients with IVE or SAH were
significantly higher than in those without IVE or SAH. No significant
difference was found in the hematological parameters
examined, excluding the white blood cell count, between the patients
without IVE or SAH and normal subjects.
Figure 2 shows the distribution of the levels of
thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer
in individual patients with or without IVE or SAH. Multiple logistic
regression analysis revealed that the level of
thrombin-antithrombin complex and white blood cell count were
significantly and independently
(P<0.001 and
P<0.005, respectively)
associated with the presence of IVE or SAH
(Table 3). White blood cell counts and levels of
thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer
significantly increased with an increase in the amount of IVE. They
also significantly increased with a greater degree of SAH
(Table 4).
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) were significantly higher than in those without IVE or SAH (•).
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Multiple linear regression analysis was performed to
determine independent factors associated with the activation of the
blood coagulation system
(Table 5). For this analysis, the level of
thrombin-antithrombin complex was selected as a response variable
because of the closest association between the complex levels and the
presence of IVE or SAH
(Table 3). In the 190 patients with IVE or SAH, the levels
of thrombin-antithrombin complex significantly and independently rose
with an increase in the amount of IVE (standard ß coefficient, 0.352;
P<0.001) and SAH (ß=0.309,
P<0.001) and age (ß=0.141,
P<0.05). In the 168 patients
without IVE or SAH, the levels of thrombin-antithrombin complex were
not significantly associated with the (intraparenchymal) hematoma
volume. Multiple logistic regression analysis revealed that the
levels of thrombin-antithrombin complex were significantly
(P<0.001) and independently
associated with the presence of IVE or SAH, although the
(intraparenchymal) hematoma volume was not significantly associated
with the presence of IVE or SAH
(Table 3).
Figure 3, which demonstrates the relationship between the
levels of thrombin-antithrombin complex and hematoma volume in
individual patients with and without IVE or SAH, shows that the levels
of thrombin-antithrombin complex in patients with IVE or SAH were
higher than in those without IVE or SAH, regardless of hematoma
volume.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionsReferences |
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The present study provides 2 important pieces of information. First, it indicates the hemostatic condition of patients in the acute stage of ICH. To date, there has been no detailed research regarding physiological changes in the hemostatic system associated with ICH. Second, this study provides us with clues to elucidate the mechanism of hemostatic activation in hemorrhagic strokes, including SAH.
The definition of hemorrhagic stroke in the present study did not include hemorrhagic transformation of cerebral infarction. Hemorrhagic transformation, a serious problem in the clinical care of patients with acute cerebral infarction, has been extensively studied from clinical and experimental standpoints.14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 There is, however, a significant difference in the hemostatic condition between ICH and the hemorrhagic transformation. The hemorrhagic transformation hemostatic systems in patients in the setting of ischemic stroke are in a systemically and markedly activated state before its occurrence,33 34 35 36 37 38 which may be attributable to ischemic injury to a large area of brain tissue or residual thrombi in the heart. On the other hand, in ICH patients, those systems are not expected to be in a significantly activated state before onset. Thus, in this study, we tried to exclude patients with hemorrhagic transformation using strict exclusion criteria. We believe our series of ICH patients included none with hemorrhagic transformation, although it is not possible to completely exclude all of them. Hence, we will discuss the hemostatic condition in patients with ICH excluding hemorrhagic transformation of cerebral infarction.
Hemostatic Activation in Spontaneous
Intracerebral Hemorrhage
The white blood cell count and levels of
thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer
in ICH patients with IVE or SAH were much more elevated than in those
without IVE or SAH. In ICH patients showing neither IVE nor SAH, the
mean levels of hematological parameters examined here, with
the exception of the white blood cell count, were not significantly
different from those in normal subjects. An increase in white blood
cell count indicates various conditions, such as infection, trauma, and
stress. However, an increase in the levels of thrombin-antithrombin
complex, plasmin-antiplasmin complex, and D-dimer indicates the
activation of the blood coagulation system, the fibrinolytic system,
and both these systems, respectively. Thus, in ICH patients, IVE or SAH
seemed much more responsible for the systemic activation of hemostatic
systems than intracerebral (intraparenchymal) hematoma.
The intraparenchymal hematoma itself does not seem to systemically
activate hemostatic systems to a great degree, although it may
activate the surrounding hemostatic systems in the brain.
Hence, in patients having neither IVE nor SAH, an increase in the
levels of thrombin-antithrombin complex, plasmin-antiplasmin complex,
and D-dimer seems to indicate that they may have coagulopathy, such as
DIC or deep venous thrombosis. On the other hand, in patients having
either IVE or SAH, an increase in those hemostatic
parameters possibly indicates a
physiological reaction, ie, their having no
coagulopathy such as DIC. Hence, when coagulopathy is diagnosed in ICH
patients, it should be noted that there is a significant difference in
the activation of hemostatic systems between the patients with and
without IVE or SAH.
A lack of the above-mentioned information results in misinterpretation of the activation of the hemostatic systems in ICH patients. In a study regarding the relationship between hemostatic systems and ICH,39 those authors reported that the thrombin-antithrombin complex values significantly increased with an increase in hematoma volume and that patients with an insufficient elevation of the thrombin-antithrombin complex values had a high risk of hematoma enlargement. However, they carried out a univariate analysis on a small number of patients without any consideration of the presence of IVE or SAH, with a resulting misinterpretation of the data and the presentation of misinformation to readers.
Mechanisms of Hemostatic Activation in
Hemorrhagic Stroke
The mechanism responsible for hemostatic activation in
patients with hemorrhagic stroke remains uncertain. In our previous
study of
SAH,3 4 5 6
we proposed the following mechanisms for hemostatic activation in
patients with SAH: (1) systemic activation of hemostatic systems by
rapidly increased intracranial pressure or severe meningeal stimulation
through unknown neurogenic and/or humoral mechanisms; (2) systemic
activation by entry of a dissolved clot into the systemic blood
circulation with or without cerebrospinal flow; and (3) local
activation by damaged brain tissue, including cortical vessels. In the
present study, investigations into hemostatic changes in ICH
patients provided us with clues to elucidate the mechanism of
hemostatic activation in hemorrhage strokes.
The (intraparenchymal) hematoma volume itself did not correlate with the level of thrombin-antithrombin complex, ie, the activation severity of the blood coagulation system. Thus, increased intracranial pressure, as a result of an increase in the hematoma volume itself, does not appear to systemically activate hemostatic systems. Meningeal stimulation through unknown neurogenic or humoral mechanisms is unlikely to be responsible for such severe systemic activation of hemostatic systems, as we observed in this study.
In our previous study, we reported that the levels of thrombin-antithrombin complex dramatically dropped 3 days after onset, regardless of the volume of residual clot in the subarachnoid space.5 Thus, although dissolved clots enter the systemic blood circulation with or without cerebrospinal flow and promote coagulant activity, the clots are unlikely to activate the systemic hemostatic systems to such a great degree as observed in this study.
The levels of thrombin-antithrombin complex in patients with ICH were independently associated with the severity of IVE and SAH, although the levels of the complex had no significant association with hematoma volume. The clot in the ventricles can easily enter the subarachnoid space. These facts support the hypothesis that the entry of blood into the subarachnoid space is much more responsible for the systemic activation of hemostatic systems than the intraparenchymal hematoma. Although the intraparenchymal hematoma is expected to cause local activation of hemostatic systems to a limited degree, it seems unlikely to activate hemostatic systems in peripheral blood.
These findings provide us with clues to elucidate the mechanism of systemic activation of hemostatic systems in hemorrhagic strokes. However, it remains unclear how the entry of blood into the subarachnoid space systemically activates hemostatic systems. Acute severe brain trauma, which usually accompanies traumatic SAH and injury to superficial brain tissue, most frequently results in tissue factor release and the generation of transient DIC.40 41 42 43 44 Tissue factor is the principal procoagulant serving as the cofactor for factor VIIa–dependent factor X activation. Its content has been reported to be greater in the cortical gray matter than in the white matter.45 46 47 It has also been reported to be associated with noncapillary microvessels in the cerebral cortex47 and with the adventitia, as seen in superficial cerebral vessels.45 Thus, the entry of blood into the subarachnoid space may cause a considerable amount of tissue factor to release into systemic circulation through injury to superficial brain tissues, including superficial cerebral arteries, resulting in systemic hemostatic activation.
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Conclusions |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConclusionsReferences |
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The systemic activation of hemostatic systems in ICH patients seems to take place only when blood reaches the subarachnoid space. The intraparenchymal hematoma itself seems unlikely to activate hemostatic systems in peripheral blood, although the hematoma is expected to cause local activation of hemostatic systems to a limited degree.
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Acknowledgments |
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We express our sincere gratitude to Dr Naohito Tanabe, Department of Public Health, University of Niigata, for assistance with statistical analyses. We also thank Noriko Sakai, Kuwana Hospital, for laboratory assistance and Chikako Shiino, Kuwana Hospital, for help in retrieving patient records.
Received September 14, 2000; revision received December 14, 2000; accepted January 4, 2001.
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