PubMed Health⌕ Search

Biomedical subjects

F B Taylor

Publications and source records attributed to F B Taylor.

At least 19 recordsLinked to original sources
PubMed1992

Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C.

This study examines the assumption that both the anticoagulant and fibrinolytic activity that follow the generation of thrombin induced by infusion of factor Xa/PCPS are due to generation of activated protein C. Untreated controls or animals given unrelated antibody were compared with animals pretreated with a specific monoclonal antibody to protein C (HPC4). Compared with untreated controls excess HPC4 substantially reduced the level of protein C activation as observed by protein C immunoblotting and enzyme-linked immunosorbent assay for antitrypsin/activated protein C complexes. Despite this, the anticoagulant activity as reflected by the decline of factors Va and VIIIa levels (as observed by coagulation assays and by factor V immunoblotting) was significantly greater than controls. The fibrinolytic activity (as observed by assays of tissue plasminogen activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater than controls. We conclude that neutralization of the protein C anticoagulant system while resulting in a significantly more intense coagulant response to Xa/PCPS does not preclude inactivation of factors Va and VIIIa and the full expression of the fibrinolytic response. We conclude further that after thrombin generation in vivo, protein C activation is not a prerequisite for the promotion of the fibrinolytic response previously observed, and that the inactivation of factors Va/VIIIa may be mediated by enzymes other than activated protein C. The reduction in alpha 2-antiplasmin levels in association with increased tissue plasminogen activator activity suggests that plasmin is a likely candidate.

Animals↗
PubMed1992

Activation of the contact system in lethal hypotensive bacteremia in a baboon model.

The hypotension in septicemia is believed to be mediated by the combined action of many mediators including cytokines, prostaglandins, and complement components. To evaluate the contribution of the contact/kinin-forming system to hypotension, the authors used an established experimental baboon model of bacteremia in which two concentrations of Escherichia Coli (E. coli) were used to produce lethal and nonlethal hypotension. The lethal group (n = 5) developed irreversible hypotension that significantly correlated with the decline in levels of high molecular weight kininogen (HK) and an increase in alpha 2 macroglobulin-kallikrein complexes (alpha 2M-kal). The nonlethal group (n = 9) experienced reversible hypotension, a less striking decline in HK, and only slight elevation in alpha 2M-kal. No significant changes were found in levels of factor XII, prekallikrein, and factor XI in either group. A significant change in the contact system, which reflects the fatal outcome, is the rise in alpha 2M-kal. This study suggests that irreversible hypotension correlates with prolonged activation of the contact system.

Animals↗
PubMed1992

Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody.

A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.

Animals↗
PubMed1991

DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.

One of the aims of research in the area of thrombosis has been to design an effective anticoagulant that would function in a predictable and direct manner. In evaluating the role of coagulation in sepsis we used factor Xa blocked in the active center with [5-(dimethylamino)1-naphthalenesulfonyl]-glutamylglycylarginyl+ ++ chloromethyl ketone (DEGR-Xa). We infused 1 mg/kg of DEGR-Xa together with LD100 concentrations of Escherichia coli (4 x 10(10) organisms/kg) into five baboons. As controls, we infused E coli alone into five baboons. The inflammatory, coagulant, and cell injury responses to E coli of both the treated and control groups were lethal and were similar in every respect except for the complete inhibition of the consumption of fibrinogen in the DEGR-Xa group. The half life of DEGR-Xa was approximately 10 hours and 2 hours, as determined by isotopic and enzyme-linked immunosorbent assays, respectively. These results for the first time demonstrate that, although coagulation occurs in E coli sepsis, fibrin formation per se did not influence the lethal outcome in this model. These results also show the effectiveness of DEGR-Xa as an anticoagulant and raise the possibility that it could serve as an alternative to anticoagulants currently in use.

Amino Acid Chloromethyl Ketones↗
PubMed1991

Deep venous thrombosis in the baboon: an experimental model.

Experimental models of deep venous thrombosis, heretofore, have not been available for laboratory studies. This investigation establishes a novel model of venous thrombosis by inhibiting the protein C system combined with venous stasis and subtle venous injury. Ten adolescent baboons were studied in pairs, with one animal receiving saline solution (B2, B4, B6, B8, B10) and one being exposed to thrombogenic reagents (B1, B3, B5, B7, B9). These reagents represented a combination of a monoclonal antibody (HPC4) to protein C, 1 to 4 mg/kg administered over 5 minutes, and tumor necrosis factor administered over 3 minutes at a dose of 150 micrograms/kg through a catheter placed into the left superficial femoral vein with distal ligation. To encourage stasis, a pediatric size blood pressure cuff was inflated to 40 mm Hg on the right thigh for 50 minutes of every hour during the first experimental day (day 1) in B5 to B10. The animals were observed for a 6-hour period on day 1 and then for an 11- to 15-day period until sacrifice. Hemodynamic and hematologic parameters were recorded along with duplex imaging of the iliac veins and inferior vena cava on a daily basis. Venography was performed on day 1, day 4, and the day of sacrifice. At sacrifice the entire iliac and vena caval system was carefully dissected, opened, and photographed. Experimental animals given the HPC4 and tumor necrosis factor developed left iliac vein thrombosis extending into the inferior vena cava. Duplex imaging, venography, and autopsy revealed that control animals receiving saline solution never developed comparable thrombus. Experimental subjects exhibited thrombus on duplex imaging by day 4 (B1), day 3 (B3), day 2 (B5), 120 minutes (B7), and 360 minutes (B9) after receiving HPC4 and tumor necrosis factor. Venograms performed on day 1 exhibited thrombus in B5, B7, and B9. The extent of thrombus, the timing of its occurrence, and its effect on the animals' left leg followed a dose-dependent relationship for the animals in which the occlusive blood pressure cuff was used. Significantly greater declines in blood pressure, white blood cell count, and platelet count were found in affected animals given HPC4 and tumor necrosis factor reagents as compared to control subjects. All affected animals demonstrated the appearance of fibrin split products and a markedly prolonged prothrombin time. This investigation, for the first time, establishes a reproducible model of deep venous thrombosis involving inhibition of protein C that will facilitate further laboratory studies on venous thrombosis.

Animals↗
PubMed1991

Sequential renal alterations in septic shock in the primate.

This is a descriptive sequential study of the response of the baboon to LD100 Escherichia coli. The response was found to consist of three stages based on electron microscopic, physiologic, and clinical laboratory data. This study associates the inflammatory, coagulant, and cell injury (stage 1-3) responses with markers of activation of inflammatory cells (tumor necrosis factor) and of the vascular endothelium (tissue plasminogen activator). This work also shows that in contrast to the underlying parenchymal cells of the organ, the vascular endothelium remains intact throughout the response to LD100 E. coli. The possible role of the vascular endothelium in mediation of events at both its luminal (blood) and antiluminal (parenchymal) surfaces is discussed.

Animals↗
PubMed1991

Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody.

Gram-negative bacteremia poses a major health problem, causing one-half of cases of lethal septic shock acquired during hospitalization. Bacterial lipopolysaccharide (LPS) and the inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-1 (IL-1), have been shown to be essential mediators of septic shock. Among the effects of these mediators is a coagulopathy that may be triggered by induced expression of tissue factor (TF) on macrophages and endothelial cells. We now report that 500 micrograms/kg of either immunoglobulin G (IgG) or Fab fragments of a monoclonal antibody against TF administered to baboons as a pretreatment attenuates the coagulopathy and protects against LD100 Escherichia coli. This study provides direct evidence of an essential effector role for TF in septic shock.

Adrenal Glands↗
PubMed1991

Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli.

This descriptive study compares the inflammatory, coagulant, and hemodynamic responses of the baboon to a 2-hr infusion of lethal and sublethal concentrations of Escherichia coli (40 and 4.0 billion organisms per kilogram, respectively). The response to lethal E. coli challenge occurred in three stages: an inflammatory stage marked by a fall in white blood cell count (0-2 hr), a coagulant stage marked by a fall in fibrinogen concentration (2-6 hr), and a hypoxic cell injury stage marked by a rise in SGPT/BUN and by a gradual cardiovascular collapse, and death (6-24 hr). The inflammatory, or first stage coincided with the appearance in plasma of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1 beta), which peaked at 120 and 240-300 min, respectively; a slow but continuous appearance and rise of interleukin-6 (IL-6); and the appearance of endotoxin reaching a maximum at 120 min. This contrasted markedly with the response to sublethal E. coli, in which only one of the three stages was observed (inflammatory) and only minor amounts of the cytokines or endotoxin appeared in the plasma. This study describes the cytokine and endotoxin profiles and the bacteremia in the primate under experimental conditions. It shows for the first time the extreme qualitative differences in their response to lethal and sublethal concentrations of E. coli. It raises the possibility that lethality is associated with an override of the tissue threshold for processing these mediators, as marked by their appearance in plasma in response to lethal E. coli infusion.

Alanine Transaminase↗
PubMed1990

Early myocardial dysfunction induced with endotoxin in rhesus monkeys.

The effects of endotoxemia on basic cardiovascular function were examined in the in situ hearts of five anesthetized rhesus monkeys. Cardiovascular function was assessed by each heart's ability to maintain sufficient oxygen delivery, as measured by the reduction-oxidation state of cytochrome aa3 during periods of increased work and decreased oxygen availability. In addition, the effects of endotoxemia on the baroreflex loop were tested by infusion of the alpha-agonist phenylephrine (5 micrograms/kg). Finally, the oxidative capacity of heart mitochondria, isolated 4 h after the infusion of endotoxin, was determined. Immediately following the 30 min intravenous infusion of endotoxin (10 mg/kg), there was a reduction of cytochrome aa3 evident in the paced heart (200 beats/min) exposed to a brief hypoxic episode. This reduction indicates a loss of the ability of the heart to adjust oxygen delivery to the metabolic needs of the subepicardium. The pressor response to phenylephrine was also affected immediately following infusion, decreasing to 14.5 +/- 9.2% of control at 4 h. The chronotropic response to phenylephrine, mediated by the baroreceptor reflex, was reduced at t = 30 mins and was essentially abolished 3 h after infusion. There was no diminution of the oxidative capacity of the isolated mitochondria. These data indicate that endotoxemia has early depressive effects on the cardiovascular system in nonhuman primates.

Animals↗
PubMed1990

Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha).

The purpose of this study was to determine the efficacy of treatment with anti-TNF monoclonal antibody in preventing the deleterious effects of sepsis in a nonhuman primate. Experiments were carried out on anesthetized baboons intravenously infused with a lethal dose of Escherichia coli (E. coli). Twelve baboons (six control and six experimental) received 2 hr infusions of E. coli. The experimental group was administered a bolus of anti-TNF antibody, 15 mg/kg, 30 min after beginning the E. coli infusion. Control baboons lived an average of 19 hr (12-34 hr). All antibody-treated baboons survived more than 7 days with a significantly improved quality of life compared to the control group. Although some adverse changes occurred during the monitoring period in surviving baboons, they maintained nearly normal arterial pressures, and serum urea nitrogen and creatinine concentrations. The severe histopathologic changes in lungs, liver, adrenals, kidneys, and spleen documented at death in baboons receiving E. coli only were absent after 7 days in baboons given E. coli and early post-treatment with antibody to TNF.

Animals↗
PubMed1989

Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia.

Plasma antithrombin III (ATIII) levels decrease early during gram-negative septicemia, and even a moderate decrease in this major inhibitor of the coagulation system is associated with serious disseminated intravascular coagulation (DIC). Herein the efficacy of high-dose (at least 250 units/kg) ATIII supplementation in animal models of Escherichia coli endotoxemia or bacteremia is reported. An endotoxemic rat model demonstrated that: (1) DIC occurs very early, before the appearance of deleterious cardiovascular abnormalities; (2) ATIII prophylaxis attenuates DIC, metabolic dysfunction, and organ damage; (3) ATIII prophylaxis increases permanent survival; (4) ATIII treatment one hour after endotoxin challenge attenuates DIC, metabolic dysfunction, and organ damage, although not as well as when given prophylactically, and survival is not increased. An endotoxemic sheep pulmonary dysfunction model demonstrated that: (1) ATIII prophylaxis prevents the typical decrease in arterial oxygen partial pressure; (2) ATIII prophylaxis combined with alpha-1-proteinase inhibitor significantly attenuates indices of pulmonary dysfunction. An E. coli bacteremic baboon model demonstrated that ATIII prophylaxis and treatment significantly attenuate indices of DIC and organ damage and prevent death in an otherwise completely lethal dose bacterial challenge. In conclusion, prophylactic treatment with high doses of ATIII may be efficacious in disease states of impending disseminated intravascular coagulation, such as primary or secondary gram-negative septicemia.

Animals↗
PubMed1988

Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons.

Infusion of Escherichia coli (LD100) was followed by coagulopathic and cell injury responses, cardiovascular collapse, and death in 18 to 32 hr in four out of four baboons. Infusion of AT-III in sufficient amounts to achieve AT-III levels of more than 4 units/ml of plasma before and during the infusion of E. coli reduced the intensity of the coagulopathic and cell injury response and prevented vascular collapse and death in four out of four baboons. Failure to achieve AT-III levels of more than six units/ml at T +60 min during the infusion of E. coli resulted in failure to prevent its lethal effects in three out of three baboons even though levels as high as 10 units/ml were achieved later in the course of the experiment. These studies suggest that thrombin and/or its products can contribute to the inflammatory response to E. coli and that AT-III is of potential value as a prophylactic but not as a therapeutic agent in the treatment of patients at high risk of developing gram negative sepsis.

Animals↗
PubMed1988

Staphylococcus aureus-induced shock: a pathophysiologic study.

The purpose of the present study was to determine the effects of lethal intravenous infusions of Staphylococcus aureus (SA) in adult dogs. Animals were maintained under anesthesia for 6 hr and observed until death following the 1-hr infusions of SA organisms. Findings unique to SA administration compared to those with Escherichia coli were the absence of significant necrosis of the mucosal intestinal glands of the small and large intestines; widespread intravascular colonization of bacteria in lung, heart, kidney and adrenal tissues often associated with neutrophil sequestration, microabscess formation, and necrosis; relative constant blood pressure, fibrinogen, fibrin degradation products (FDP), serum glutamic pyruvic transaminase (SGPT), blood (serum) urea nitrogen (BUN), creatinine, pH, and PO2, all of which remained relatively unchanged for 6 hr. Rapid early increases were observed in temperature, respiration rate, lactate, and hematocrit, while PCO2, platelet and white blood cell concentrations decreased. Results suggest unique qualitative differences in responses to Staphylococcal-induced shock compared to those caused by gram-negative bacteria.

Animals↗