Denise C. Bruck

Hemostatic markers in acute stroke.

To assess the time course of thrombosis and fibrinolysis after acute stroke, we measured concentrations of fibrinopeptide A (FpA), B-beta 1-42 peptide (B-beta 1-42), B-beta 15-42 peptide (B-beta 15-42), and crosslinked D-dimer (XDP) in 31 patients at varying times following acute ischemic stroke and in 13 neurologically stable patients with chronic strokes. FpA levels were markedly elevated during the first week after stroke and declined slowly during the first month. Mean FpA levels were not significantly elevated in chronic stroke patients. Mean XDP levels were slightly elevated during the first week and increased during the next 2 weeks after stroke. B-beta 1-42 and B-beta 15-42 levels were not elevated at any time following acute stroke. Our data suggest that fibrin formation greatly exceeds endogenous fibrinolysis during the acute phase of ischemic stroke. Endogenous fibrinolysis develops slowly following stroke. Prolonged elevation of FpA concentration suggests that thrombin activity and fibrin formation continue for up to 4 weeks in some patients with ischemic stroke.

Hemostatic Markers in Acute Ischemic Stroke Association With Stroke Type, Severity, and Outcome

BACKGROUND AND PURPOSE Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality. METHODS We measured fibrinopeptide A, cross-linked D-dimer, and beta-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model. RESULTS The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and beta-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality. CONCLUSIONS Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Fibrinolysis after acute ischemic stroke.

Abstract Stroke is a thrombotic process in at least 80% of cases. The acute phase of stroke is characterized by brisk thrombin activity and relatively depressed fibrinolytic activity. The presence of inhibitors of plasminogen activation may play a role in this impairment of fibrinolytic activity. Fibrinolytic activity rises slowly in the subacute phase after a stroke, but the contribution of specific activators and inhibitors during this time has not been delineated. These findings have important implications for the treatment of acute stroke. An important question remains as to whether all these changes are secondary to the stroke, or whether preexisting abnormalities of fibrinolysis contribute to the occurrence of a stroke. Large prospective epidemiologic studies using current techniques are necessary to determine whether fibrinolytic abnormalities are risk factors for stroke. [68] If this is so it would provide an important means of identifying patients at high risk for stroke. Further, it might eventually lead to new strategies of stroke prevention via augmentation of the fibrinolytic system.

Acute cigarette smoke exposure alters lung eicosanoid and inflammatory cell concentrations in rabbits

We studied lung clearance of technetium-labeled diethylenetriamine pentaacetic acid [( 99mTc]DTPA), plasma and bronchoalveolar lavage fluid (BALF) concentrations of 6-keto-PGF1 alpha (stable metabolite of prostacyclin, prostaglandin I2, PGI2), TxB2 (stable metabolite of thromboxane A2, TxA2), and leukotriene B4 (LTB4), and inflammatory cells as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Thirty-one rabbits were randomly assigned to four groups: control sham exposure (SS, n = 6), sham smoke ibuprofen-pretreated (SS-I, n = 7), CSE (n = 6), and CSE ibuprofen-pretreated (CSE-I, n = 12). Ibuprofen, a cyclooxygenase eicosanoid inhibitor, was administered as a single daily intramuscular injection (25 mg/kg) for 7 d before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine [99mTc]DTPA biological half-life (T1/2). The CSE-I group was retrospectively divided into rabbits who survived the 30-breath subset (CSE-IL, n = 6) and those who died during the 30-breath CSE (CSE-ID, n = 6). In the CSE, CSE-IL, and CSE-ID groups, [99mTc]DTPA T1/2 as well as BALF LTB4 levels were significantly decreased. Plasma and BALF 6-keto-PGF1 alpha increased in CSE rabbits compared to the other groups. Alveolar macrophages were lower in the CSE-ID rabbits than in the CSE-IL group. CSE and CSE-IL BALF lymphocyte levels were decreased compared to SS values. Our data indicate that acute CSE is associated with significant increases in 6-keto-PGF1 alpha and decreases in LTB4 as well as a significant reduction in lymphocytes. Furthermore, pretreatment with ibuprofen before CSE was associated with severe lung injury in half of the rabbits. The severity of lung injury may be related to a combination of a lower number of alveolar macrophages and blockade of lung PGI2.

Acute cigarette smoke exposure causes lung injury in rabbits treated with ibuprofen.

We studied lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA), plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2, and pulmonary edema as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Forty-six rabbits were randomly assigned to 4 groups: control sham smoke exposure (SS, N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), and CSE ibuprofen-pretreated (CSE-I, N = 19). Ibuprofen (cyclooxygenase eicosanoid inhibitor) was administered as a single daily intramuscular injection (25 mg/kg) for 7 days before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine 99mTcDTPA biological half-life (T1/2). In the ibuprofen pretreated group, CSE caused significant decreases in 99mTcDTPA T1/2 and dynamic lung compliance. Furthermore, these changes in lung function were accompanied by severe injury to type I alveolar cell epithelium, pulmonary edema, and frequently death of the rabbits. These findings suggest that inhibition of the cyclooxygenase pathway before CSE exacerbates lung injury in rabbits.

Time Course of Platelet Activation Following Acute Ischemic Stroke

To assess the time course of platelet activation after acute ischemic stroke we measured the platelet protein ß-thromboglobulin (BTG) in 66 patients. Serial samples were obtained over a 3-month period. Mean values of BTG in patients with lacunar infarction were not significantly elevated at any time. In nonlacunar strokes, the mean BTG level during the first week after stroke was not significantly elevated. The mean BTG level rose in the second week and became statistically different from control (mean ± SEM; 33.1 ± 3.6 vs. 21.3 ± 2.0 IU/ml, p = 0.01). Mean values then declined to normal. Significant differences were noted among stroke subtypes. During the first week, mean values of BTG were higher in cardioembolic stroke (36.9 ± 6.2 IU/ml, p = 0.007 vs. controls) than in atherothrombotic stroke (22.1 ± 2.8 IU/ml, p = 0.82). By the second week, mean BTG values were significantly elevated for both cardioembolic (44.4 ± 8.3 IU/ml, p < 0.001) and atherothrombotic (33.8 ± 5.0 IU/ml, p = 0.01) strokes. The rise of this marker following stroke suggests that at least some of the platelet activation associated with stroke is a secondary phenomenon. Cardioembolic stroke is associated with as much platelet activation as atherothrombotic stroke and may have greater platelet activation during the first week after stroke.