Nancy B. Beamer

Chronic blood hyperviscosity in subjects with acute stroke, transient ischemic attack, and risk factors for stroke.

The origin and significance of blood hyperviscosity in subjects with acute stroke has been controversial. It has been argued that viscous abnormalities simply reflect either elevated hematocrit or an acute-phase response to the stroke itself. To address these issues, we measured the factors that determine blood viscosity in a cross-sectional study of 430 subjects, including 135 with acute stroke, 89 with acute transient ischemic attacks of the brain, 115 with recognized risk factors for stroke, and 91 healthy controls. The at-risk group was balanced with the acute stroke group for types of risk factors and medication usage, and all four groups were balanced for age. The viscosity of whole blood at low rates of shear and the plasma viscosity were significantly elevated in both groups with cerebrovascular symptoms and in the at-risk group compared with the healthy controls. The severity of hyperviscosity was stroke group greater than transient ischemic attack group greater than at-risk group greater than healthy controls. Increased viscosity of whole blood was associated with an elevated plasma fibrinogen concentration and with a decreased albumin/globulin ratio. This study provides evidence that blood hyperviscosity is present not only in subjects with acute brain infarction, but also in those with risk factors for stroke, and that these abnormalities are, to a considerable degree, chronic.

Enhanced in vivo platelet activation in subtypes of ischemic stroke.

It remains uncertain whether platelet activation in ischemic stroke is contributory or secondary to brain ischemia. The efficacy of aspirin (ASA) in stroke prevention suggests that platelet activation contributes to the occurrence of stroke. On the other hand, platelet activation may be simply a generalized consequence of cerebral ischemic damage. To examine this issue, plasma levels of the platelet specific proteins beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were measured in fifty-eight patients with various defined types of acute ischemic strokes. beta-TG was a broader indicator of platelet activation than PF4. Compared with an age-matched control group, thromboembolic and cardioembolic stroke patients had significantly elevated beta-TG levels (p less than 0.001). Also, beta-TG levels in these stroke categories were significantly higher in samples drawn within the first week after the event than in those drawn later (p less than 0.001). In contrast, beta-TG levels in lacunar stroke patients and in most TIA patients were normal. beta-TG levels did not correlate with the volume of cerebral infarction as measured by planimetry from CT scans. Moreover, beta-TG levels in patients on chronic ASA therapy at the time of stroke did not differ from those in patients of the same diagnostic categories not taking aspirin. These data indicate that platelet activation may be important in some, but not all, subtypes of ischemic stroke and that platelet activation can occur in stroke even though the platelet cyclooxygenase pathway is suppressed.

Persistent inflammatory response in stroke survivors

objective Goals were to determine how long acute-phase markers remain elevated after ischemic stroke and how marker levels relate to stroke risk factors, stroke mechanism, and subsequent vascular events. Methods Fibrinogen (FIB), C-reactive protein (CRP), leukocytes (WBC), neutrophils (PMN), interleukin-6, and interleukin-1 receptor antagonist were measured at stroke onset and at 6 weeks, 6 months, and 1 year after enrollment, or until a vascular event occurred in 136 acute ischemic stroke patients, 76 patients with comparable risk factors for stroke, and 48 age-balanced healthy subjects. Results Multivariate logistic analysis showed that prior stroke and FIB level predicted new events in stroke patients (p < 0.04 for both), whereas congestive heart failure (p < 0.02) and creatinine level (p < 0.006) were predictive in at-risk patients. After controlling for infection, FIB, CRP, and PMN levels at baseline were higher in at-risk but not in stroke patients with recurrent events (p < 0.05 for all). At 1 year, FIB levels remained elevated in event-free stroke survivors compared with levels in the risk and control groups (p < 0.001 for both). FIB also remained higher in stroke survivors who had atheroembolism (AE) compared with non-AE stroke survivors (381 ± 72 versus 342 ± 78 mg/dL, p < 0.02). Peripheral vascular disease was an independent predictor (p < 0.0001) of longitudinal FIB in stroke survivors. Of note, both WBC and PMN levels were chronically elevated in patients with stroke risk factors and in stroke survivors (p < 0.0001 for both) compared with healthy elderly subjects. Conclusions Most acute-phase markers decline gradually after stroke, but FIB remains significantly elevated and is associated with increased risk for recurrent vascular events.

Ischemic Stroke in the Elderly Role of the Common Factor V Mutation Causing Resistance to Activated Protein C

BACKGROUND AND PURPOSE A common missense mutation in coagulation factor V (Arg 506 Gln) creates phenotypic resistance to the anticoagulant effects of activated protein C and predisposes carriers to venous thrombosis. To assess a correlation between this common hypercoagulable state and ischemic cerebrovascular disease, we have compared the prevalence of this mutation in a group of stroke patients with that in several control patient groups. METHODS The presence of the factor V Arg 506 Gln mutation was determined by a direct polymerase chain reaction-based assay on peripheral blood leukocytes from 161 elderly patients with acute ischemic stroke, 116 elderly patients with stroke risk factors but without acute stroke, 54 healthy elderly control subjects, and 287 younger control individuals (197 blood donors and 90 neonates). RESULTS The prevalence of the heterozygous Arg 506 Gln factor V mutation was not significantly different in the elderly stroke patients (2.5%) compared with either of the age-matched control groups (2% to 4%). The prevalence of this mutation was significantly higher in each of two younger control groups (approximately 8%) than in the elderly stroke patients (2.5%). CONCLUSIONS The common factor V Arg 506 Gln mutation predisposing to venous thrombosis is not a significant genetic risk factor for ischemic stroke in the elderly.

Prostacyclin infusion in acute cerebral infarction

We gave prostacyclin infusions to seven patients with acute cerebral infarction. Patients without CT evidence of infarction improved, but those who already had hypodensities on CT did not benefit. Increased platelet activity, measured by plasma beta-thromboglobulin, decreased significantly (p < 0.01) during prostacyclin administration to normal levels, but rose again after the infusion. These results indicate that prostacyclin can be given safely in doses adequate to suppress platelet function. Our findings encouraged us to proceed with a controlled trial of its clinical efficacy.

Spontaneous echo contrast and hemorheologic abnormalities in cerebrovascular disease.

Background and Purpose Spontaneous echo contrast (SEC) is thought to represent a risk factor for cardioembolic stroke. In vitro studies suggest that SEC results from interaction between red cells and fibrinogen. To better understand the relation between SEC and stroke and to investigate the in vivo genesis of SEC, we examined the relation between SEC, the constituents of the blood, and plasma and serum viscosity in patients with acute stroke or chronic cerebrovascular disease. Methods Fifty patients with acute stroke or chronic cerebrovascular disease referred for transesophageal echocardiogram (TEE) were studied by transthoracic echocardiography and TEE. Complete blood count, fibrinogen, albumin, γ-globulin, and plasma and serum viscosity determinations were made. Left atrial SEC was graded as absent, mild, or marked by means of TEE. Results SEC was absent in 31 patients, mild in 10 patients, and marked in 9 patients. Higher grade of SEC was associated with a significantly greater percentage of patients with atrial fibrillation and larger left atrial dimension. Atrial fibrillation was present in 23% of the patients in the SEC absent group, 50% of the patients in the mild SEC group, and 78% of the patients in the marked SEC group (P<.01). Left atrial diameter averaged 3.8±0.6 cm in the SEC absent group, 4.3±1.1 in the mild SEC group, and 4.9±0.7 in the marked SEC group (P<.001). Hematocrit, white blood cell count, and platelet count did not differ among the three groups. Fibrinogen, γ-globulin, plasma viscosity, and serum viscosity values were all significantly higher in the presence of SEC (P<.05). Fibrinogen values were 361 ±97 mg/dL in the SEC absent group and 427±135 mg/dL in the marked SEC group. γ-Globulin levels were 0.75±0.23 g/dL in the SEC absent group and 1.06±0.48 g/dL in the marked SEC group. Both plasma viscosity (1.97 cp) and serum viscosity (1.64 cp) were higher in the marked SEC group than in the SEC absent group (1.77 and 1.50 cp, respectively). Conclusions In patients with acute stroke or chronic cerebrovascular disease, the severity of SEC was not related to albumin, hematocrit, white cell count, or platelet count but rather to elevated fibrinogen levels and concomitant increases in both plasma and serum viscosity. Moreover, increasing grade of SEC was associated with significantly increased left atrial diameter and a higher percentage of patients in atrial fibrillation.

Fibrinogen and the albumin-globulin ratio in recurrent stroke.

Background and Purpose In following patients initially recruited for a cross-sectional study of blood viscosity in ischemic cerebrovascular disease, it was noted that those having a low albumin-globulin ratio appeared to experience the majority of subsequent vascular events. Accordingly, a prospective study in which subjects were assigned to a high or low albumin-globulin cohort was undertaken to examine the relation between a low albumin-globulin ratio, the presence of clinical risk factors for stroke, and the occurrence of subsequent stroke, myocardial infarction, or vascular death. Methods Three groups of subjects were followed for an average of 1.5±0.8 years to ascertain vascular end points. Group 1 consisted of 126 patients with acute ischemic stroke; group 2 included 109 subjects matched with group 1 for age, medications, and recognized clinical risk factors for stroke; and group 3 was composed of 84 healthy volunteers, matched for age with groups 1 and 2. The median albumin-globulin ratio for group 1 at enrollment, 1.45, was used to dichotomize patients into two cohorts: all subjects with an albumin-globulin ratio of 1.45 or less were assigned to the “low” albumin-globulin cohort; those whose ratio was greater than 1.45 were assigned to the “high” albumin-globulin cohort. The occurrence of vascular end points was verified during subsequent hospitalizations and outpatient clinic visits and by telephone interviews of patients and providers. Results A total of 51 vascular events occurred, including 39 in group 1, 8 in group 2, and 4 in group 3. Subjects in either group 1 or 2 who were in the low albumin-globulin cohort had at least double the risk for a subsequent vascular event compared with their counterparts in the high albumin-globulin cohort (P<.01 and P<.03, respectively). In comparison with the high albumin-globulin cohort, significantly more patients in the low albumin-globulin cohort in group 1 had a history of prior stroke (P<.03). When groups 1 and 2 were combined, both a low albumin-globulin ratio and diabetes had a significant independent association with increased risk for subsequent vascular events in a Cox proportional-hazards model (P<.01 and P<.03, respectively). Conclusions The results of this study indicate that significantly increased risk for subsequent vascular events in stroke patients and in subjects with clinical risk factors for stroke is associated with a shift in the concentrations of blood proteins to a prothrombotic environment characterized by lower levels of albumin and an increased concentration of globulins and fibrinogen.

Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.

The initial acute phase response predicts long-term stroke recovery

Indicators of an acute phase response (APR) in acute ischemic stroke have been shown to correlate with infarct size and predict stroke recurrence. In this study, we examined how well the APR indicators predicted long-term stroke recovery compared with standard clinical predictors of recovery. Plasma levels of interleukin-6 (IL-6), fibrinogen, white blood cells (WBCs), and serum albumin were measured within 4+/-2 days of onset in 131 stroke patients who were free of apparent infections. Standard clinical predictors included initial National Institutes of Health Stroke Scale (NIHSS), infarct size on computed tomography (CT), and Glasgow scale. The individual correlations with 6-month Glasgow outcome were IL-6, 0.42; fibrinogen, 0.24; WBC, 0.35; albumin, 0.47; NIHSS, 0.53; infarct size, 0.19; and initial Glasgow, 0.57. (all P<.005). Multiple regression analysis yielded an adjusted R(2) of .31 for the APR indicators, compared with .38 for the clinical variables. These results indicate that the initial APR is highly correlated with 6-month stroke recovery and that this correlation approaches that observed with standard clinical predictors.

Diabetes, Hypertension and Erythrocyte Aggregation in Acute Stroke

Elevated erythrocyte (RBC) aggregation (RBC-A) may contribute to the pathogenesis of stroke and stroke recurrence. We measured RBC-A at low shear in 55 patients with acute ischemic stroke and in 24 ag