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Biomedical subjects

U Marzec

Publications and source records attributed to U Marzec.

12 recordsLinked to original sources
PubMed2006

Limited generation of activated protein C during infusion of the protein C activator thrombin analog W215A/E217A in primates.

Anticoagulation with activated protein C (APC) reduces the mortality of severe sepsis. We investigated whether the circulating protein C (PC) pool could be utilized for sustained anticoagulation by endogenous APC. To generate APC without procoagulant effects, we administered the anticoagulant thrombin mutant W215A;E217A (WE) to baboons. In preliminary studies, administration of high dose WE (110 microg kg(-1) i.v. bolus every 120 min; n = 2) depleted PC levels by 50% and elicited transient APC bursts and anticoagulation. The response to WE became smaller with each successive injection. Low dose WE infusion (5 microg kg(-1) loading + 5 microg kg(-1) h(-1) infusion; n = 5) decreased plasma PC activity by 15%, from 105% to 90%, to a new equilibrium within 60 min. APC levels increased from 7.5 ng mL(-1) to 86 ng mL(-1) by 40 min, then declined, but remained elevated at 34 ng mL(-1) at 240 min. A 22-fold higher dose WE (n = 5) decreased PC levels to 60% by 60 min without significant further depletion in 5 h. The APC level was 201 ng mL(-1) at 40 min and decreased to 20 ng mL(-1) within 120 min despite continued activator infusion. Co-infusion of WE and equimolar soluble thrombomodulin (n = 5) rapidly consumed about 80% of the PC pool with significant temporal increase in APC generation. In conclusion, low-grade PC activation by WE produced sustained, clinically relevant levels of circulating APC. Limited PC consumption in WE excess was consistent with the rapid depletion of cofactor activity before depletion of the PC zymogen. Reduced utilization of circulating PC might have similar mechanism in some patients.

Amino Acid Substitution↗
PubMed1996

Exaggerated platelet reactivity in major depression.

OBJECTIVE: This study investigated whether depressed patients exhibit exaggerated platelet reactivity. METHOD: In vivo platelet activation, secretion, and dose-response aggregation were measured in 12 depressed patients and eight normal comparison subjects after overnight bed rest and following orthostatic challenge. RESULTS: The depressed patients exhibited increased platelet activation at baseline, demonstrated by increased binding of monoclonal antibody (moAb) annexin V protein reacting with prothrombinase complex binding sites. Following orthostatic challenge, the depressed patients exhibited increases in binding of moAbs PAC1 and anti-LIBS1 against activated glycoprotein IIb/IIIa and GE12 against P-selectin expressed upon secretion. The normal comparison subjects exhibited increases in platelet activation only with GE12. CONCLUSIONS: Depressed patients exhibit enhanced baseline platelet activation and responsiveness in comparison with normal subjects. Heightened susceptibility to platelet activation may be a mechanism by which depression is a significant risk factor for ischemic heart and cerebrovascular disease and/or mortality after myocardial infarction.

Adult↗
PubMed1984

Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells.

The effect of thrombin on the release of tissue plasminogen activator from endothelial cells was studied in primary cultures of human umbilical vein endothelial cells. Tissue plasminogen activator concentration in conditioned medium was measured by a two-site radioimmunometric assay. The addition of increasing concentrations (0.01 to 10 U/ml) of thrombin to confluent cultures produced a saturable, dose-dependent increase in the rate of release of tissue plasminogen activator. A sixfold increase in tissue plasminogen activator concentration (from 2 to 12 ng/ml) occurred after the addition of 1 U/ml thrombin (8 X 10(-9) M) to cultures containing 5 X 10(4) cells/cm2. Enhanced release was not observed until 6 h after thrombin addition, reached a maximum rate of 1.3 ng/ml per h between 8 and 16 h, and then declined to 0.52 ng/ml per h after 16 h. The 6-h lag period before increased tPA release was reproducible and independent of thrombin concentration. Thrombin inactivated with diisopropylfluorophosphate or hirudin did not induce an increase in tissue plasminogen activator levels. A 50-fold excess of diisopropylfluorophosphate-treated thrombin, which inhibits binding of active thrombin to endothelial cell high affinity binding sites, did not inhibit the thrombin-induced increase. It is concluded that proteolitically active thrombin causes an increase in the rate of release of tissue plasminogen activator from cultured human endothelial cells. The 6-h interval between thrombin treatment and enhanced tissue plasminogen activator release may reflect a delaying mechanism that transiently protects hemostatic plugs from the sudden increase in the local concentration of this fibrinolytic enzyme.

Blood↗
PubMed1978

The specificity of the reaction of collagen with platelets.

1. Human platelets will react with a number of different collagens from guinea-pig to ostrich. 2. Human skin collagen when treated with pepsin does not react with human platelets. 3. Calf platelets display a different pattern of reactivity than that of human platelets.

Animals↗
PubMed1977

Structural correlates of platelet functional damage by physical forces.

Human platelets, which were selectively damaged either in a device designed to impose surface injury or one in which damage is primarily limited to shear forces in the fluid bulk, were examined with the electron microscope in an effort to correlate functional and ultrastructural evidence of injury. Surface injury results in more severe inhibition of platelet adhesion and aggregation, as well as PF-3 and PF-4 activity. These functional effects are accompanied by profound and widespread ultrastructural changes, including membrane defects, enlargement of the open cannicular system, alterations in dense bodies and alpha granules, and the development of globular shapes. Very little serotonin is lost, but there is an increase in the number of abnormal dense bodies. In contrast, the shear injured cells demonstrate few functional defects, despite a lesser but still substantial number of structural changes, at forces up to 10(5) dynes/cm2. At higher shears, both functional and structural evidence of severe injury is present, along with apparently normal platelet aggregation.

Blood Platelets↗
PubMed1976

Prolonged pulseless perfusion in unanesthetized calves.

Nonpulsatile left ventricular (LV) bypass was achieved in nine alert, active calves for periods of up to two weeks using a centrifugal blood pump. Data were compared to prebypass control values and to results obtained from seven calves that underwent nonthoracotomy, retrograde LV cannulation, and pulsatile bypass for up to 35 days. Nonpulsatile flow produced an increase in heart rate of 20% (P less than .05) and an increase in aortic pressure of 10% (P less than .05). Cardiac output and systemic vascular resistance were similar in both groups for three days; thereafter, vascular resistance decreased as cardiac output progressively increased. Serum renin, lactate, and pyruvate values remained normal; creatinine clearances were not significantly different than control values, and there were no significant changes in body weight. These data indicate no untoward effects as a result of prolonged pulseless perfusion.

Anesthesia↗
PubMed1975

Platelet function in calves: a study of adhesion, aggregation, release, clotting factor activity and life span.

Normal calf platelets were found to significantly differ human platelets in a number of important respects. The average calf platelet count is more than twice the average human value. Calf platelets demonstrated no adhesion to glass, in a test in which over 50% of human platelets adhered. Responsiveness to several aggregating, agents, including ADP, thrombin and collagen, was markedly diminished in the calf platelet, requiring much higher concentrations of the stimulating agent to produce comparable responses. In addition, calf platelet clot-promoting activity was far less effective than with human platelets following stimulation with Celite or Russell's viper venom, although the total platelet factor 3 content exceeded that found in human paltelets, following complete disruption. In addition, the calf platelet has a significantly shorter life span and higher turnover rate than the human. These species differences in normal platelet function must be considered in evaluating the results of experiments with artificial organs in the calf model.

Animals↗