The Coagulation-Fibrinolysis System in Patients with Leukoaraiosis and Binswanger Disease

ORIGINAL CONTRIBUTION The Coagulation-Fibrinolysis System in Patients With Leukoaraiosis and Binswanger Disease Hidekazu Tomimoto, MD; Ichiro Akiguchi, MD; Ryo Ohtani, MD; Hideo Yagi, MD; Masutaro Kanda, MD; Hiroshi Shibasaki, MD; Yasumasa Yamamoto, MD Background: Hypercoagulability is observed in vascu- and XDP levels and an increased ventricular area– lar dementia, including Binswanger disease. However, the cranial space area ratio, as compared with the patients correlation between hypercoagulability, leukoaraiosis, and with other neurological diseases (PϽ.001). The index of dementia remains unclear. cognitive impairment in patients at a deteriorating stage showed a decreasing trend vs that of patients in the stable Objective: To examine how activation of the coagula- stage. Among the variables that were significantly asso- tion fibrinolysis correlates with leukoaraiosis and de- ciated with a hypercoagulable condition (ie, age, scores mentia. on Mini-Mental State Examination or the Hasegawa De- mentia Rating Scale, Revised [MMSE/HDRS], white mat- Patients and Methods: Thrombin-antithrombin com- ter lesions, ventricular area–cranial space area ratio, and plex (TAT), prothrombin fragment1+2 (F1+2) and cross- C-reactive protein), age (odds ratio [OR], 2.82) and linked D-dimer (XDP) were measured consecutively in MMSE/HDSR scores (OR, 0.43) survived as predictors 18 subjects without dementia and with leukoaraiosis, and for coagulation activation, and C-reactive protein sur- in 29 subjects with subcortical vascular dementia and se- vived for fibrinolysis activation (OR, 4.63) in multivar- vere leukoaraiosis (Binswanger disease) at either stable iate analysis. or deteriorating stages. They were compared with 19 patients with old lacunar infarctions and 24 patients with Conclusion: Hypercoagulability in a subgroup of pa- other neurological diseases. We also examined the indi- tients with Binswanger disease and with more severe cog- ces of cognitive impairment and brain atrophy. In each nitive impairment and brain atrophy does not support a group, the ventricular area–cranial space area ratio was triggering role for a coagulation-fibrinolysis system, al- measured by an image analyzer. though it may contribute to worsening of neurological deficits. Results: Patients with Binswanger disease who were ex- clusively at deteriorating stages showed increased TAT Arch Neurol. 2001;58:1620-1625 INSWANGER DISEASE (BD) is tem is also activated,5 especially in those a form of vascular demen- with vascular dementia.6 Although there tia characterized by diffuse has been no established therapy until re- white matter lesions and a cently, these observations may open a new varying degree of lacunar in- avenue for the treatment of vascular de- farction in the basal ganglia and white mat- mentia with antiplatelet or antithrombin B1 7,8 ter. Its pathogenesis still remains uncer- drugs. tain, but fibrohyalinosis of the medullary White matter lesions in small-artery arteries resulting from long-standing hy- diseases have previously been shown to pertension has been thought to cause the correlate with von Willebrand factor ac- white matter lesions.2,3 tivity, but inversely with antithrombin III, From the Department of Previous investigations have re- an inhibitory factor of the coagulation sys- Neurology, Faculty of vealed hematological disorders in pa- tem regardless of cognitive impairment.9 Medicine, Kyoto University, tients with BD. ␤-Thromboglobulin, a In our previous study,10 the coagulation Kyoto, Japan (Drs Tomimoto, marker of platelet activation, increases in markers were increased at the later stages Akiguchi, Ohtani, Yagi, Kanda, and Shibasaki), and blood samples obtained from the inter- of BD; however, it remains unclear whether the Department of Neurology, nal jugular veins of patients with BD, in- white matter lesions without cognitive im- Kyoto Second Red Cross dicating the activation of platelets in the pairment are also associated with hyper- Hospital, Kyoto cerebral circulation.4 In patients with de- coagulability. Our hypothesis is that there (Dr Yamamoto). mentia, the coagulation-fibrinolysis sys- may be a causal relationship between hy- (REPRINTED) ARCH NEUROL / VOL 58, OCT 2001 WWW.ARCHNEUROL.COM 1620 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 PATIENTS AND METHODS INVESTIGATIONS The psychometric assessment consisted of CDR and Mini- PATIENTS AND CONTROL SUBJECTS Mental State Examination administered in Japanese or the Hasegawa Dementia Rating Scale, Revised (MMSE/HDSR). The study population consisted of 90 patients who were Peripheral blood samples were drawn from the antecubital treated at our institute and at affiliated hospitals from March vein of the nonparalyzed arm, with minimal stasis, by means 1997 to December 1999 (Table 1). These patients in- of a clean venipuncture. The blood samples were collected cluded 18 individuals without dementia with diffuse white into siliconized tubes that contained one-tenth volume of 3.8% matter lesions (leukoaraiosis without dementia group) and trisodium citrate, and were then centrifuged at 2300g for 15 29 patients with BD who had been assigned to this study minutes at room temperature. These plasma samples were consecutively. The inclusion for the leukoaraiosis with- stored at −70°C until used. The concentration of thrombin- out dementia group was based on the results of the clini- antithrombin complex (TAT), prothrombin fragment1+2 (F1+2), cal dementia rating (CDR) scale11 and magnetic reso- and cross-linked D-dimer (XDP) was measured by enzyme- nance imaging (MRI) scans. All subjects in the leukoaraiosis linked immunosorbent assays. Samples with TAT values above without dementia group had grade 2 or grade 3 white mat- the detection limit of the assays (60 ng/mL) were excluded ter lesions irrespective of the number of lacunar infarc- from further analysis because they were considered to be likely tions. The diagnosis of BD was based on the clinical diag- artifacts. In each patient, brain MRI scans were performed nostic criteria proposed by Bennett et al.12 Briefly, all of the to measure the size of the brain. patients had dementia, bilateral diffuse subcortical hyper- intense lesions (grade 3) on T2-weighted MRI scans, and IMAGE ANALYSIS at least 2 of the following 3 clinical findings: (1) a vascular Using computer-assisted image analysis of the MRI, the ven- risk factor or evidence of systemic vascular disease; (2) evi- tricular area–cranial space area ratio was measured as an in- dence of focal cerebrovascular disease; and (3) evidence of dex of brain atrophy as previously described.14 Briefly, mono- “subcortical” cerebral dysfunction such as gait disorders, chromatic photo images of the MRI at the level of the basal parkinsonism, or incontinence. According to the neuro- ganglia and thalamus were digitized on a Macintosh com- logical status, the patients with BD were classified into ei- puter (PC7500; Apple Computers, Cupertino, Calif) with ther the stable or deteriorating group. If there had been fo- an LS-1000 film scanner (Nikon, Tokyo, Japan) at a reso- cal or subcortical cerebral dysfunction, as described earlier, lution of 1350 dots per inch. The images were stored as 8-bit within the previous 3 months, then those patients were de- gray scale JPEG files (256 shades of gray), and the image files fined as “deteriorating” based on their history, clinical pro- were analyzed using National Institutes of Health image ana- files, and a follow-up of their neurological findings. lyzer software (National Institutes of Health, Bethesda, Md). The lacunar infarction group consisted of 15 symp- tomatic patients at the chronic stage and 4 asymptomatic STATISTICAL ANALYSIS patients. The other neurological disease (OND) group consisted of 24 age-matched patients, excluding those with ce- The statistical significance of the intergroup differences rebrovascular diseases (6 patients with cervical spondylo- was assessed by the ␹2 test for categorical variables and by sis: 3 each with vasovagal syncope and neurosis; 2 each with the Kruskal-Wallis and Mann-Whitney U tests for continu- dizziness, depression, essential tremor, and peripheral neu- ous variables using StatView II software (version 5.0 for ropathy; and 1 each with migraine, brain tumor, restless Macintosh; SAS Institute, Cary, NC). The association leg syndrome, and epilepsy). No one in the lacunar infarc- between the hemostatic markers and other variables was tion or OND groups had significant white matter lesions first tested by a univariate logistic regression analysis. Co- classified as grade 2 or grade 3 by the scale devised by variates significant at the PϽ.05 critical level were entered Schmidt et al.13 into the multivariate model. percoagulability and dementia. To understand whether was mild to severe, with CDR scores ranging from 1 to 3 this may be a trigger or epiphenomenon during cogni- and with MMSE/HDSR scores between 8/30 and 22/30. tive decline, it is important to assess the coagulation- Other abnormal neurological findings included abulia, fibrinolysis system during the preclinical or early stages unsteady gait, dysarthria, incontinence, sensory defi- of subcortical vascular dementia. In the present study, cits, and hemiparesis. None of the patients with BD ful- we determined the causes of coagulation-fibrinolysis sys- filled the modified version of the clinical criteria on dis- tem activation in patients with white matter lesions, mani- seminated

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