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Table 1. 
Clinical Profiles and Levels of Hemostatic Markers in Patients With Binswanger Disease*
Clinical Profiles and Levels of Hemostatic Markers in Patients With Binswanger Disease*
Table 2. 
Summary of the Patient Profiles and Laboratory Findings*
Summary of the Patient Profiles and Laboratory Findings*
Table 3. 
Hemostatic Markers for the Subgroups*
Hemostatic Markers for the Subgroups*
1.
Landi  GD'Angelo  ABoccardi  E  et al.  Hypercoagulability in acute stroke: prognostic significance. Neurology. 1987;371667- 1671Article
2.
Feinberg  WMBruck  DCRing  MECorrigan  JJ  Jr Hemostatic markers in acute stroke. Stroke. 1989;20592- 597Article
3.
Fisher  MFrancis  R Altered coagulation in cerebral ischemia: platelet, thrombin, and plasmin activity. Arch Neurol. 1990;471075- 1079Article
4.
Fujii  YTanaka  RTakeuchi  SKoike  TMinakawa  TSasaki  O Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg. 1994;8051- 57Article
5.
Takano  KYamaguchi  TKato  HOmae  T Activation of coagulation in acute cardioembolic stroke. Stroke. 1991;2212- 16Article
6.
Takano  KYamaguchi  TUchida  K Markers of a hypercoagulable state following acute ischemic stroke. Stroke. 1992;23194- 198Article
7.
Kilpatrick  TJMatkovic  ZDavis  SMMcGrath  CMDauer  RJ Hematologic abnormalities occur in both cortical and lacunar infarction. Stroke. 1993;241945- 1950Article
8.
Bennett  DAWilson  RSGilley  DWFox  JH Clinical diagnosis of Binswanger's disease. J Neurol Neurosurg Psychiatry. 1990;53961- 965Article
9.
Roman  GC Senile dementia of Binswanger type: a vascular form of dementia in the elderly. JAMA. 1987;2581782- 1788Article
10.
Furuta  AIshii  NNishihara  YHorie  A Medullary arteries in aging and dementia. Stroke. 1991;22442- 446Article
11.
Caplan  LR Binswanger's disease revisited. Neurology. 1995;45626- 633Article
12.
Akiguchi  ITomimoto  HSuenaga  TWakita  HBudka  H Alterations of glia and axons in the brains of Binswanger's disease patients. Stroke. 1997;281423- 1429Article
13.
Iwamoto  TKubo  HTakasaki  M Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and Binswanger's disease. Stroke. 1995;2652- 56Article
14.
Schneider  RRingelstein  EBZeumer  HKiesewetter  HJung  F The role of plasma hyperviscosity in subcortical arteriosclerotic encephalopathy (Binswanger's disease). J Neurol. 1987;23467- 73Article
15.
Ringelstein  EBMauckner  ASchneider  R  et al.  Effects of enzymatic blood defibrination in subcortical arteriosclerotic encephalopathy. J Neurol Neurosurg Psychiatry. 1988;511051- 1057Article
16.
Okumiya  KMatsubayashi  KWada  TKimura  SDoi  YOzawa  T Effects of exercise on neurobehavioral function in community-dwelling older people more than 75 years of age. J Am Geriatr Soc. 1996;44569- 572
17.
Bredbacka  SBlomback  MWiman  BPelzer  H Laboratory methods for detecting disseminated intravascular coagulation (DIC): new aspects. Acta Anaesthesiol Scand. 1993;37125- 130Article
18.
Schmidt  RFazekas  FKleinert  G  et al.  Magnetic resonance imaging signal hyperintensities in the deep and subcortical white matter: a comparative study between stroke patients and normal volunteers. Arch Neurol. 1992;49825- 827Article
19.
Wada  HOhiwa  MKaneko  T  et al.  Plasma level of tumor necrosis factor in disseminated intravascular coagulation. Am J Hematol. 1991;37147- 151Article
20.
Roman  GC From UBOs to Binswanger's disease. Impact of magnetic resonance imaging on vascular dementia research. Stroke 1996;271269- 1273Article
21.
Mast  HTatemichi  TKMohr  JP Chronic brain ischemia: the contributions of Otto Binswanger and Alois Alzheimer to the mechanisms of vascular dementia. J Neurol Sci. 1995;1324- 10Article
22.
Feigin  IPopoff  N Neuropathological changes late in cerebral edema: the relationship to trauma, hypertensive disease and Binswanger's encephalopathy. J Neuropathol Exp Neurol. 1963;22500- 511Article
23.
Tomimoto  HAkiguchi  ISuenaga  T  et al.  Alterations of the blood-brain barrier and glial cells in white matter lesions in cerebrovascular and Alzheimer's disease patients. Stroke. 1996;272069- 2074Article
24.
Akiguchi  ITomimoto  HSuenaga  TWakita  HBudka  H Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study. Acta Neuropathol. 1998;9578- 84Article
25.
Thomas  WSMori  ECopeland  BRYu  JQMorrissey  JHdel Zoppo  GJ Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke. 1993;24847- 853Article
26.
Feinberg  WMErickson  LPBruck  DKittelson  J Hemostatic markers in acute ischemic stroke: association with stroke type, severity, and outcome. Stroke. 1996;271296- 1300Article
27.
Tohgi  HTakahashi  HChiba  KTamura  K Coagulation-fibrinolysis system in poststroke patients receiving antiplatelet medication. Stroke. 1993;24801- 804Article
28.
Kario  KMatsuo  TKobayashi  HAsada  RMatsuo  M "Silent" cerebral infarction is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels in elderly Japanese. Arterioscler Thromb Vasc Biol. 1996;16734- 741Article
29.
Izumi  YTsuda  YIchihara  STakahashi  TMatsuo  H Effects of defibrination on hemorheology, cerebral blood flow velocity, and CO2 reactivity during hypocapnia in normal subjects. Stroke. 1996;271328- 1332Article
30.
Lindahl  AKSandset  PMAbildgaard  U Incidence of hypercoagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis. 1990;20253- 262
31.
Reinthaller  AMursch-Edlmayr  GTatra  G Thrombin-antithrombin III complex levels in normal pregnancy with hypertensive disorders and after delivery. Br J Obstet Gynaecol. 1990;97506- 510Article
32.
Reininger  CBGraf  JReininger  AJSpannagl  MSteckmeier  BSchweiberer  L Increased platelet and coagulatory activity indicate ongoing thrombogenesis in peripheral arterial disease. Thromb Res. 1996;82523- 532Article
33.
Oltrona  LBroccolino  MMerlini  PASpinola  APezzano  AMannucci  PM Activation of the hemostatic mechanism after pharmacological cardioversion of acute nonvalvular atrial fibrillation. Circulation. 1997;952003- 2006Article
Original Contribution
September 1999

Coagulation Activation in Patients With Binswanger Disease

Author Affiliations

From the Departments of Neurology, Faculty of Medicine, Kyoto University (Drs Tomimoto, Akiguchi, Wakita, and Osaki) and Kyoto Second Red Cross Hospital (Drs Hayashi and Yamamoto), Kyoto, Japan.

Arch Neurol. 1999;56(9):1104-1108. doi:10.1001/archneur.56.9.1104
Abstract

Background  A hypercoagulable state is often associated with an acute stroke in cerebrovascular disease (CVD). However, in Binswanger disease (BD), no information is available on the coagulation-fibrinolysis pathway except for the presence of high plasma fibrinogen levels.

Objective  To determine the association of BD and coagulation-fibrinolysis pathway activation.

Patients and Methods  We examined the levels of fibrinogen, thrombin-antithrombin complex, prothrombin fragment1+2, and cross-linked D-dimer in 17 patients with BD, 24 neurologic patients without CVD, and 26 patients with lacunar infarction in either the acute or chronic stage.

Results  As compared with the non-CVD and lacunar infarction groups, the patients with BD had significantly elevated levels of thrombin-antithrombin complex (P<.001), prothrombin fragment1+2 (P<.05), and cross-linked D-dimer (P<.01). There was also a significant increase in fibrinogen levels compared with the non-CVD group (P<.05). In the BD group, 8 patients in stable condition (ie, those without obvious neurologic deficits in the past 3 months) showed normal levels or a mild increase in their fibrinogen, thrombin-antithrombin complex, prothrombin fragment1+2, or cross-linked D-dimer levels. In contrast, 9 patients with BD with a subacute aggravation of their focal or subcortical cerebral functions (deteriorating group) showed a significant increase in their thrombin-antithrombin complex levels compared with the stable patients (P<.01). Similarly, the fibrinogen, prothrombin fragment1+2, and cross-linked D-dimer levels were elevated in the deteriorating patients, but this trend did not reach statistical significance.

Conclusions  These results indicate that the coagulation-fibrinolysis pathway is activated in patients with BD with a subacute aggravation. Coagulation activation may result in the formation of microthrombi and microcirculatory disturbances in the brains of these patients, and thus promote further biological and neurologic insults.

A HYPERCOAGULABLE state is often encountered in the acute stages of cerebrovascular disease (CVD). Studies in which hemostatic markers were used have shown a rapid activation of the coagulation-fibrinolysis pathway after a stroke.14 The degree of activation differs between different types of stroke, with cerebral embolism being the most marked followed by atherothrombotic infarction.5 However, some investigators have shown that abnormalities in the coagulation-fiblinolytic pathway are not as important in patients with penetrating artery disease.6,7

Binswanger disease (BD) is a condition characterized by prominent brain atrophy with ventricular dilation, diffuse white matter lesions, and a scattering of lacunar infarcts in the basal ganglia and white matter. Patients with BD have dementia, and often have vascular risk factors, focal cerebrovascular deficits, and subcortical cerebral dysfunction.8 Although hypertensive small artery disease and medullary artery sclerosis have been implicated in the pathogenesis of these white matter lesions, as well as multiple lacunae,912 only a few authors have addressed the alterations in the hemorheological parameters that may affect the cerebral microcirculation in BD. The release of β-thromboglobulin into the cerebral circulation, which is an indicator of platelet activation, is increased in patients with BD.13 Plasma hyperviscosity and elevated fibrinogen levels are striking abnormalities in patients with BD, and are believed to deteriorate to chronic ischemia, thus promoting the process of demyelination.11,14 However, a therapeutic approach using ancrod, a defibrinating agent, has proven ineffective.15 To our knowledge, there have been no reports on the coagulation-fibrinolysis pathway in patients with BD.

In the present investigation, we examined the plasma levels of several hemostatic markers in patients with BD and compared them with those of neurologic patients without CVD as well as patients with lacunar infarction.

PATIENTS AND METHODS
PATIENTS AND CONTROL SUBJECTS

The study population consisted of 67 patients treated at Kyoto University, Kyoto, Japan, and affiliated hospitals from March 1996 to February 1998. These included 17 patients with BD who were assigned to this study consecutively. The diagnosis of BD was based on the clinical diagnostic criteria proposed by Bennett et al.8 Briefly, all of the patients had dementia, bilateral diffuse subcortical hyperintense lesions on T2-weighted magnetic resonance imaging (MRI), and at least 2 of the following 3 clinical findings: (1) a vascular risk factor or evidence of systemic vascular disease; (2) evidence of focal CVD; and (3) evidence of subcortical cerebral dysfunction such as gait disorders, parkinsonism, or incontinence. The neurologic status of patients with BD was judged to be deteriorating or stable; ie, if there was either focal or subcortical cerebral dysfunction, as described above, within the past 3 months, the patients were classified as deteriorating based on the history of their clinical profile and a follow-up of their neurologic findings; otherwise the patient was defined as stable.

The control population consisted of 24 age-matched neurologic patients with nonvascular diseases (non-CVD group) such as cervical spondylosis, peripheral neuropathy, Parkinson disease, Alzheimer disease, spinocerebellar ataxia, depression, and essential tremor. The lacunar infarction group included 26 age-matched patients whose diagnoses were based on neurologic examination and MRI findings. All of the patients in this group showed a few lacunae but no significant white matter lesions. The interval between the stroke and the blood sampling was 1 month in 10 patients, 1 to 3 months in 3 patients, and 3 to 55 months in 13 patients.

INVESTIGATIONS

The psychometric assessment consisted of a Mini-Mental State Examination (MMSE) or a Hasegawa Dementia Rating Scale–Revised administered in Japanese.16 Brain computed tomography and MRI were performed to determine the presence of diffuse white matter lesions and lacunar infarcts. Peripheral blood samples were drawn by venipuncture from an antecubital vein of the nonparalyzed arm, with minimal stasis. They were collected in siliconized tubes that contained a one-tenth volume of 3.8% trisodium citrate, centrifuged at 2300g for 15 minutes at room temperature, and stored at −70°C until used. The concentration of the coagulation markers (thrombin-antithrombin complex [TAT] and prothrombin fragment1+2 [F1+2]) and the fibrinolytic marker (cross-linked D-dimer [XDP])17 were measured by enzyme-linked immunosorbent assays. The normal values were as follows: TAT concentration, lower than 3.0 ng/mL; F1+2, lower than 1.2 nmol/mL; and XDP, lower than 150 ng/mL.

STATISTICAL ANALYSIS

Differences between the ages of each group were determined by a 1-factor analysis of variance followed by the Fisher protected least significant difference procedure between each group using StatView II software, version 4.5, 1995 (Abacus Concepts Inc, Berkeley, Calif), for a Macintosh computer. The differences between the groups for the fibrinogen, TAT, F1+2, and XDP levels were determined by the Mann-Whitney U test. The association between the TAT values and the patient characteristics was analyzed using multiple regression analysis. A P value <.05 indicated statistical significance.

RESULTS

The 17 patients with BD all showed confluent or irregular periventricular hyperintensities on their MRI scans judged to be grade 3 by the Schmidt scale,18 with varying degrees of lacunar infarction in the basal ganglia and white matter. The severity of the dementia was mild to moderate, with the MMSE/Hasegawa Dementia Rating Scale–Revised scores ranging from 8/30 to 21/30. Other abnormal neurologic findings included abulia, an unsteady gait, dysarthria, incontinence, sensory deficits, and hemiparesis. None of the patients with BD fulfilled the modified version of the criteria established by the Research Committee on Disseminated Intravascular Coagulation (DIC) of the Japanese Ministry of Health and Welfare.19 The mean (range) prothrombin time was 12.8 (11.1-21.0) seconds; activated partial thromboplastin time, 31.0 (22.2-48.4) seconds; and platelet count, 0.21 (0.13-0.32)×109/L.

The patients with BD were subdivided into 8 neurologically stable patients (stable group) and 9 patients who showed a subacute aggravation of either focal or subcortical cerebral dysfunctions (deteriorating group). No obvious focal neurologic deficits had been noted within the past 3 months in the stable patients, whereas 4 of the 9 deteriorating patients had evidence of recent lacunar infarctions (Table 1; patients 9, 10, 15, and 16) and 3 of these patients showed mild hemiparesis. Since patients with BD usually have lacunar infarcts visible on MRI scans, the lacunae were thought to be responsible for the deterioration if the MRI studies indicated a recent infarction or the location of the lacunae corresponded to the emerging neurologic deficits or subcortical dysfunction. Antiplatelet drugs were prescribed in 3 of 8 stable patients and in 1 of 9 deteriorating patients before the aggravation. An anticoagulant was not used in either group.

There was no significant difference in age between the non-CVD, lacunar infarction, and BD groups. Although hypertension was more frequent in the lacunar infarction and BD groups than in the non-CVD group, there were no significant differences in other risk factors between these groups (Table 2). In the lacunar infarction group, there were no significant increases in the fibrinogen, TAT, F1+2, or XDP levels compared with the non-CVD group. This was also true of the patients with lacunar infarction in the acute stage who had strokes within the past month, with the mean ± SD level for fibrinogen being 326.9±74.6 mg/dL; TAT, 1.8±0.7 mg/mL; F1+2, 0.7±0.1 nmol/L; and XDP, 83.0±35.2 ng/mL.

The patients with BD showed significantly higher TAT (P<.001), F1+2 (P<.05), and XDP (P<.01) levels compared with the non-CVD and lacunar infarction groups (Mann-Whitney U test; Table 3). The association between TAT values and patient characteristics, including disease category, age, sex, smoking history, hypertension, diabetes mellitus, antiplatelet therapy, noncerebral vascular lesions, total cholesterol and triglyceride levels, hematocrit, leukocyte count, and C-reactive protein, was assessed by multiple linear regression analysis. The coefficient of determination (R2) was 0.541, and the multiple correlation coefficient was 0.735. Among the 13 explanatory variables, only the disease category correlated significantly with the TAT value (P<.05). The patients with BD also showed significantly higher fibrinogen levels than the non-CVD group (P<.05, Mann-Whitney U test). The stable patients with BD often showed slightly elevated levels of fibrinogen, TAT, F1+2, and XDP compared with the non-CVD group, but this was not significant. The deteriorating patients with BD occasionally showed abnormally high values for these 4 hemostatic markers, regardless of the presence or absence of fresh lacunar infarctions. The concentration of TAT in the deteriorating group was significantly higher than in the stable group (P<.01, Mann-Whitney U test; Table 1). Similarly, the fibrinogen, F1+2, and XDP levels were elevated in the deteriorating group, but this trend did not reach statistical significance.

COMMENT

Recent advances in radiological diagnosis have demonstrated that BD is far more common than originally thought, and increasing attention has been paid to BD not only in Europe and Japan, but also in North America.1,15,20 The pathogenesis of BD and the difference between BD and the multiple lacunar infarctions that accompany the white matter lesions remain unclear.9 However, it is likely that chronic cerebral ischemia is common to these 2 diseases.21 In addition, it has been suggested that these white matter lesions may be caused by arterial hypertension and a subsequent dysfunction of the blood-brain barrier.2224 A compromised blood-brain barrier may permit the entry of macromolecules and other blood constituents into the vascular wall and perivascular neural parenchyma,25 and these serum components may subsequently damage the myelin structures.

In the present study, the patients with BD showed significantly higher fibrinogen, TAT, F1+2, and XDP values, especially in the deteriorating group. Activation of the coagulation-fibrinolysis pathway has been observed during the acute stage of cardioembolic stroke and aneurysmal subarachnoid hemorrhage.46,26 In some studies, the levels of TAT and other molecular markers were reported to be increased in poststroke patients, suggesting a sustained enhancement of the coagulation system in the chronic stages of stroke.27,28 Activation of the coagulation-fiblinolysis pathway may have unfavorable effects on cerebral microcirculation through a hemorheological mechanism rather than clotting the vessels. This mechanism may exert particular effect on thickened small arteries, in which any form of hemostasis can easily cause microcirculatory failure.

Levels of fibrinogen, one of the major determinants of plasma viscosity, are elevated in patients with marked white matter lesions compared with those with slight abnormalities.1 The plasma viscosity also has an important hemorheological impact on the cerebral microcirculation.29 Therefore, high fibrinogen levels may contribute to the chronic cerebral ischemia observed in BD, although the neurologic deterioration seems to occur regardless of the plasma fibrinogen levels.

The hemostatic markers are also elevated in disseminated consumption coagulopathy,17 metastatic carcinoma,30 pancreatitis,30 pregnancy,31 peripheral arterial disease,32 and acute atrial fibrillation after pharmacological cardioversion.33 Although the hemostatic markers were elevated in those patients with BD with a subacute aggravation, most patients did not experience such problems. In addition, the frequency of noncerebral vascular lesions was not increased in the patients with BD compared with the other 2 groups. Although the fresh lacunar infarctions may have some effect on hemostatic markers, coagulation system activation was not observed even in the acute stages of lacunar infarction, and also was not related to their concomitant presence in deteriorating patients with BD. Therefore, the increase in hemostatic markers observed in the deteriorating patients with BD can be attributed to an activation of the coagulation-fibrinolysis pathway occurring more diffusely in the brain. Coagulation-fibrinolytic activation is presumed to have more hemorheological effect on small penetrating arteries in the white matter.

A marked increase in the TAT, F1+2, and XDP levels was observed only in the patients with BD experiencing a subacute aggravation. The prothrombotic state indicated by these hemostatic markers may be merely the result of cerebral tissue damage. Alternatively, it may play a causative role in cerebral microembolization and subsequent neurologic exacerbation.

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Article Information

Accepted for publication January 12, 1999.

This work was supported by a grant-in-aid for Scientific Research on Priority Areas from the Japanese Ministry of Education, Science and Culture (Dr Akiguchi) and a grant from Sasagawa Foundation (Dr Tomimoto), Tokyo, Japan.

The authors are grateful to Masutaro Kanda, MD (Ijinkai Takeda General Hospital, Kyoto, Japan), Satoshi Ogura, MD, and Hideo Yagi, MD (Takeda Hospital, Kyoto) for their help in sampling the data.

Reprints: Hidekazu Tomimoto, MD, Department of Neurology, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan (e-mail: tomimoto@isola.kuhp.kyoto-u.ac.jp).

References
1.
Landi  GD'Angelo  ABoccardi  E  et al.  Hypercoagulability in acute stroke: prognostic significance. Neurology. 1987;371667- 1671Article
2.
Feinberg  WMBruck  DCRing  MECorrigan  JJ  Jr Hemostatic markers in acute stroke. Stroke. 1989;20592- 597Article
3.
Fisher  MFrancis  R Altered coagulation in cerebral ischemia: platelet, thrombin, and plasmin activity. Arch Neurol. 1990;471075- 1079Article
4.
Fujii  YTanaka  RTakeuchi  SKoike  TMinakawa  TSasaki  O Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg. 1994;8051- 57Article
5.
Takano  KYamaguchi  TKato  HOmae  T Activation of coagulation in acute cardioembolic stroke. Stroke. 1991;2212- 16Article
6.
Takano  KYamaguchi  TUchida  K Markers of a hypercoagulable state following acute ischemic stroke. Stroke. 1992;23194- 198Article
7.
Kilpatrick  TJMatkovic  ZDavis  SMMcGrath  CMDauer  RJ Hematologic abnormalities occur in both cortical and lacunar infarction. Stroke. 1993;241945- 1950Article
8.
Bennett  DAWilson  RSGilley  DWFox  JH Clinical diagnosis of Binswanger's disease. J Neurol Neurosurg Psychiatry. 1990;53961- 965Article
9.
Roman  GC Senile dementia of Binswanger type: a vascular form of dementia in the elderly. JAMA. 1987;2581782- 1788Article
10.
Furuta  AIshii  NNishihara  YHorie  A Medullary arteries in aging and dementia. Stroke. 1991;22442- 446Article
11.
Caplan  LR Binswanger's disease revisited. Neurology. 1995;45626- 633Article
12.
Akiguchi  ITomimoto  HSuenaga  TWakita  HBudka  H Alterations of glia and axons in the brains of Binswanger's disease patients. Stroke. 1997;281423- 1429Article
13.
Iwamoto  TKubo  HTakasaki  M Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and Binswanger's disease. Stroke. 1995;2652- 56Article
14.
Schneider  RRingelstein  EBZeumer  HKiesewetter  HJung  F The role of plasma hyperviscosity in subcortical arteriosclerotic encephalopathy (Binswanger's disease). J Neurol. 1987;23467- 73Article
15.
Ringelstein  EBMauckner  ASchneider  R  et al.  Effects of enzymatic blood defibrination in subcortical arteriosclerotic encephalopathy. J Neurol Neurosurg Psychiatry. 1988;511051- 1057Article
16.
Okumiya  KMatsubayashi  KWada  TKimura  SDoi  YOzawa  T Effects of exercise on neurobehavioral function in community-dwelling older people more than 75 years of age. J Am Geriatr Soc. 1996;44569- 572
17.
Bredbacka  SBlomback  MWiman  BPelzer  H Laboratory methods for detecting disseminated intravascular coagulation (DIC): new aspects. Acta Anaesthesiol Scand. 1993;37125- 130Article
18.
Schmidt  RFazekas  FKleinert  G  et al.  Magnetic resonance imaging signal hyperintensities in the deep and subcortical white matter: a comparative study between stroke patients and normal volunteers. Arch Neurol. 1992;49825- 827Article
19.
Wada  HOhiwa  MKaneko  T  et al.  Plasma level of tumor necrosis factor in disseminated intravascular coagulation. Am J Hematol. 1991;37147- 151Article
20.
Roman  GC From UBOs to Binswanger's disease. Impact of magnetic resonance imaging on vascular dementia research. Stroke 1996;271269- 1273Article
21.
Mast  HTatemichi  TKMohr  JP Chronic brain ischemia: the contributions of Otto Binswanger and Alois Alzheimer to the mechanisms of vascular dementia. J Neurol Sci. 1995;1324- 10Article
22.
Feigin  IPopoff  N Neuropathological changes late in cerebral edema: the relationship to trauma, hypertensive disease and Binswanger's encephalopathy. J Neuropathol Exp Neurol. 1963;22500- 511Article
23.
Tomimoto  HAkiguchi  ISuenaga  T  et al.  Alterations of the blood-brain barrier and glial cells in white matter lesions in cerebrovascular and Alzheimer's disease patients. Stroke. 1996;272069- 2074Article
24.
Akiguchi  ITomimoto  HSuenaga  TWakita  HBudka  H Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study. Acta Neuropathol. 1998;9578- 84Article
25.
Thomas  WSMori  ECopeland  BRYu  JQMorrissey  JHdel Zoppo  GJ Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke. 1993;24847- 853Article
26.
Feinberg  WMErickson  LPBruck  DKittelson  J Hemostatic markers in acute ischemic stroke: association with stroke type, severity, and outcome. Stroke. 1996;271296- 1300Article
27.
Tohgi  HTakahashi  HChiba  KTamura  K Coagulation-fibrinolysis system in poststroke patients receiving antiplatelet medication. Stroke. 1993;24801- 804Article
28.
Kario  KMatsuo  TKobayashi  HAsada  RMatsuo  M "Silent" cerebral infarction is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels in elderly Japanese. Arterioscler Thromb Vasc Biol. 1996;16734- 741Article
29.
Izumi  YTsuda  YIchihara  STakahashi  TMatsuo  H Effects of defibrination on hemorheology, cerebral blood flow velocity, and CO2 reactivity during hypocapnia in normal subjects. Stroke. 1996;271328- 1332Article
30.
Lindahl  AKSandset  PMAbildgaard  U Incidence of hypercoagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis. 1990;20253- 262
31.
Reinthaller  AMursch-Edlmayr  GTatra  G Thrombin-antithrombin III complex levels in normal pregnancy with hypertensive disorders and after delivery. Br J Obstet Gynaecol. 1990;97506- 510Article
32.
Reininger  CBGraf  JReininger  AJSpannagl  MSteckmeier  BSchweiberer  L Increased platelet and coagulatory activity indicate ongoing thrombogenesis in peripheral arterial disease. Thromb Res. 1996;82523- 532Article
33.
Oltrona  LBroccolino  MMerlini  PASpinola  APezzano  AMannucci  PM Activation of the hemostatic mechanism after pharmacological cardioversion of acute nonvalvular atrial fibrillation. Circulation. 1997;952003- 2006Article
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