Development of an ischemic stroke survival score. (1/41)

BACKGROUND AND PURPOSE: There has been substantial interest in identifying predictors of survival for stroke patients. Current instruments used for measuring stroke severity are confined to either neurological, functional, or disability measures. The purpose of this study was to develop a stroke survival score that combines instruments from different domains to better predict long-term survival. METHODS: We took advantage of a particularly broad array of clinical and physiological variables collected during the Stroke Treatment with Ancrod Trial. Four hundred fifty-three patients completed a battery of instruments at day 7 after stroke and then were followed for 1 year. RESULTS: Of the 453 patients, 53% were male, 77% were aged 65 years or older, and 89% were white. One hundred nine patients (24%) died during the study period. Age was a highly significant predictor of mortality (P<0.001), but there were no statistically significant differences in 12-month survival with respect to sex, race, or educational level. The best model for predicting survival was the Ischemic Stroke Survival Score. This model included the Scandinavian Stroke Scale, Rapid Disability Rating Scale, age, and prior stroke. This model had substantially greater predictive power (R(2)=0.30, c statistic=0.86) than the Scandinavian Stroke Scale alone (R(2)=0.20, c statistic=0.78). CONCLUSIONS: This study demonstrates that combining day 7 poststroke information from multiple domains substantially improves the ability to predict 12-month survival of ischemic stroke patients compared with data from a single domain. The high mortality rate emphasizes the importance of preventive measures for a disease that has identifiable and modifiable risk factors.  (+info)

Analysis of fibrin formation and proteolysis during intravenous administration of ancrod. (2/41)

Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of acute ischemic stroke. Treatment with ancrod leads to fibrinogen depletion. The present study investigated the mechanisms leading to the reduction of plasma fibrinogen concentration. Twelve healthy volunteers received an intravenous infusion of 0.17 U/kg body weight of ancrod for 6 hours. Blood samples were drawn and analyzed before and at various time points until 72 hours after start of infusion. Ancrod releases fibrinopeptide A from fibrinogen, leading to the formation of desAA-fibrin monomer. In addition, a considerable proportion of desA-profibrin is formed. Production of desA-profibrin is highest at low concentrations of ancrod, whereas desA-profibrin is rapidly converted to desAA-fibrin at higher concentrations of ancrod. Both desA-profibrin and desAA-fibrin monomers form fibrin complexes. A certain proportion of complexes carries exposed fibrin polymerization sites E(A), indicating that the terminal component of the protofibril is a desAA-fibrin monomer unit. Soluble fibrin complexes potentiate tissue-type plasminogen activator-induced plasminogen activation. Significant amounts of plasmin are formed when soluble fibrin in plasma reaches a threshold concentration, leading to the proteolytic degradation of fibrinogen and fibrin. In the present setting, high concentrations of soluble fibrin are detected after 1 hour of ancrod infusion, whereas a rise in fibrinogen and fibrin degradation products, and plasmin-alpha(2)-plasmin inhibitor complex levels is first detected after 2 hours of ancrod infusion. Ancrod treatment also results in the appearance of cross-inked fibrin degradation product D-dimer in plasma. (Blood. 2000;96:2793-2802)  (+info)

The effect of angrod on the delayed hypersensitivity response in rats. (3/41)

Delayed hypersensitivity was induced in rats by means of sheep erythrocytes and bovine serum albumin-lipid conjugate. Administration of heparin to rats sensitized to either antigen resulted in diminution of the delayed hypersensitivity reaction. Administration of ancrod, however, failed to inhibit the delayed cellular reaction to either antigen. Granuloma formation remained unaffected when rats were injected with either heparin or ancrod. The lack of ancrod effect, in contrast to heparin effect, on delayed hypersensitivity is discussed.  (+info)

A quantitative evaluation of anticoagulants in experimental nephrotoxic nephritis. (4/41)

The protective effects of anticoagulants in nephrotoxic nephritis in rabbits have been studied, using various doses of heparin and defibrination with ancrod. Massive doses of heparin (2000 units/kg/day) were required before significant reduction in glomerular fibrin deposition, extracepillary cell proliferation and urea retention occurred. Doses of 300 and 1000 units/kg/day were insufficient to modify fibrin deposition and cell proliferation. Defibrination with ancrod provided protection, judged by histological and functional criteria, comparable to 2000 units of heparin/kg/day; but fibrin could still be demonstrated in the glomeruli of animals treated with 2000 units of heparin/kg/day, contrasting with the virtual absence of fibrin in animals given ancrod.  (+info)

The effects of defibrination with ancrod in experimental allergic glomerular injury. (5/41)

Quantitative studies of the effects of defibrination (with ancrod) have been undertaken in two forms of allergic glomerular damage, nephrotoxic serum nephritis and acute serum sickness in rabbits. No differences in intrarenal fixation of nephrotoxic antibody, complement activation or host antibody response were detected between defibrinated and untreated rabbits with nephrotoxic serum nephritis. Defibrination prevented intraglomerular fibrin deposition in this disease; but some glomerular damage as shown by a rise in blood urea and endothelial proliferation still occurred in defibrinated animals. No differences in immune elimination of BSA, circulating immune complex formation or intrarenal localization of immune complexes were noted in defibrinated animals with acute serum sickness. No intraglomerular fibrin deposition was detected in treated or untreated animals in this disease model. It is concluded that the protective effects of ancrod are directly related to defibrination, and not to any other modification of allergic events.  (+info)

Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene up-regulation. (6/41)

Staphylococcus aureus undergoes a density-dependent conversion in phenotype from tissue-adhering to tissue-damaging and phagocyte-evading that is mediated in part by the quorum-sensing operon, agr, and its effector, RNAIII. Contributions of host factors to this mechanism for regulating virulence have not been studied. We hypothesized that fibrinogen, as a component of the inflammatory response, could create spatially constrained microenvironments around bacteria that increase density independently of bacterial numbers and thus potentiate quorum-sensing-dependent virulence gene expression. Here we show that transient fibrinogen depletion significantly reduces the bacterial burden and the consequential morbidity and mortality during experimental infection with wild-type S. aureus, but not with bacteria that lack expression of the quorum-sensing operon, agr. In addition, it inhibits in vivo activation of the promoter for the agr effector, RNAIII, and downstream targets of RNAIII, including alpha hemolysin and capsule production. Moreover, both in vitro and in vivo, the mechanism for promoting this phenotypic switch in virulence involves clumping of the bacteria, demonstrating that S. aureus responds to fibrinogen-mediated bacterial clumping by enhancing density-dependent virulence gene expression. These data demonstrate that down-modulation of specific inflammatory components of the host that augment bacterial quorum sensing can be a strategy for enhancing host defense against infection.  (+info)

Embolization itself stimulates thrombus propagation in pulmonary embolism. (7/41)

The role of active thrombosis in the pathophysiology of pulmonary embolism is unclear. We tested the hypothesis that venous thrombi significantly increase their thrombotic activity once they embolize into the high-flow circulation of the pulmonary arteries. Thrombotic activity was measured using an immunoassay that measures both fibrinopeptide B (FPB) as well as its most abundant metabolite des-arginine FPB. Thrombi were formed in the femoral veins of adult dogs. In one group, the thrombi were embolized without anticoagulation. In the second group, heparin (300 U/kg bolus, then 90 U x kg(-1) x h(-1) infusion) was administered before embolization to prevent subsequent thrombotic activity. Plasma FPB concentrations were significantly suppressed in the heparinized group relative to the nonheparinized group for 1 h postembolization (P = 0.038). We conclude that pulmonary embolization itself causes preexisting venous thrombi to greatly intensify their thrombotic activity and that embolization-associated thrombus propagation can be prevented by heparin.  (+info)

Soluble fibrin is the main mediator of Staphylococcus aureus adhesion to platelets. (8/41)

BACKGROUND: Infective endocarditis (IE) caused by Staphylococcus aureus is associated with significant morbidity and mortality rates. Platelets play a dual role as adhesive cells forming associates with bacteria as well as specialized inflammatory cells. The specific role of the various factors involved in bacteria-platelet association has not yet been fully elucidated. METHODS AND RESULTS: We observed a dramatic increase in the capability to bind S aureus when platelets were activated with thrombin (from 5% to 30%, P<0.001). To pinpoint platelet-binding sites involved in the interaction, platelets from knockout mice and from patients with selective inherited deficiency of membrane proteins or of granules were used. CD36, GPIIb/IIIa, and P-selectin were excluded as receptors for S aureus. Platelets from patients with alpha-delta-storage pool disease and Gray platelet syndrome indicate the requirement of alpha-granule contents. Platelet activation by ADP did not promote platelet-S aureus associate formation, although these platelets were covered with bound fibrinogen. Only small numbers of associates between fibrinogen-covered bacteria and ADP-activated platelets were observed. Formation of fibrin alone was also not sufficient to induce association. Only when fibrin formation and platelet activation occurred together were large numbers of associates formed (P<0.001). A potential receptor for fibrin on S aureus is clumping factor A. Addition of thrombospondin-1 to control platelets increased the number of associates (P=0.02). CONCLUSIONS: Soluble fibrin but not fibrinogen is the main mediator of platelet-S aureus association. In addition, platelet activation and the release of alpha-granule contents, particularly thrombospondin-1, is a requirement for platelet-S aureus association.  (+info)

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