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Biomedical subjects

F Brosstad

Publications and source records attributed to F Brosstad.

At least 55 records · Page 3Linked to original sources
PubMed1998

Improved blood preservation with 0.5CPD erythro-sol. Coagulation factor VIII activity and erythrocyte quality after delayed separation of blood.

BACKGROUND AND OBJECTIVES: Delay between blood collection and the separation of its components may result in lowered yield of factor VIII (FVIII) and loss of 2,3-biphosphoglycerate (2,3-BPG). This study was to see whether the use of 0.5 CPD resulted in better preservation of FVIII and maintenance of 2,3-BPG. MATERIALS AND METHODS: 55 units of blood were collected in 0.5CPD and 48 in CPD SAG-M. Ten of the collections were paired, so that the same donors were bled in a single session partly in an 0.5CPD system and partly in CPD SAG-M. After collection, the blood was promptly cooled to 20 degrees C and stored at that temperature for up to 24 h. RESULTS: Preservation of FVIII activity was significantly better in 0.5CPD compared with CPD. The content of von Willebrand factor was stable in the anticoagulant solutions for 24 h at that temperature. Plasma separated from both media had how levels of prothrombin fragment 1 + 2 and complement activation. Paired collections substantiated previous reports that red cell storage is significantly improved in 0.5CPD compared with CPD SAG-M with respect to 2,3-BPG and haemolysis. CONCLUSIONS: Red cell metabolism and oxygen-releasing capacity are kept at acceptable levels in 0.5CPD blood for 24 h at 20 degrees C before component separation. The concentration of red cell 2,3-BPG remained at normal or slightly subnormal levels during further storage in 0.5CPD at 4 degrees C for 2-4 weeks before gradual decay to an average of 39% at 48 days.

2,3-Diphosphoglycerate↗
PubMed1998

Increased potency and decreased elimination of lamifiban, a GPIIb-IIIa antagonist, in patients with severe renal dysfunction.

Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (i.v.). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the antiplatelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.

Acetates↗
PubMed1997

[Hepatic vein thrombosis. Diagnostic and therapeutic difficulties].

Budd Chiari syndrome (liver vein thrombosis) may be a diagnostic and therapeutic problem. On the basis of four different cases we review the major diagnostic and therapeutic principles involved. Imaging techniques are necessary in order to establish the diagnosis. Ultrasound examination with Duplex doppler is usually sufficient, but MR angiography is also useful. Treatment options are thrombolysis, surgery or liver transplantation. What treatment is selected will depend on the clinical situation and the prognosis.

Adult↗
PubMed1996

D-dimer specific monoclonal antibodies react with fibrinogen aggregates.

Human fibrinogen exposed to 46.5 degrees C was subjected to gel permeation chromatography. The protein eluted in two distinct peaks. The first peak appeared in the void volume containing soluble fibrinogen aggregates, while the other peak represented monomeric fibrinogen. In contrast to the monomeric peak material, the aggregate fraction reacted with a panel of monoclonal antibodies specific for fragment D-dimer using an ELISA system. Edman degradation showed that both the aggregate and the monomeric fractions were devoid of soluble fibrin, and immunoblots of SDS-PAG electrophoretic profiles disclosed no sign of stabilized high molecular weight derivatives. We have previously shown that the aggregate fraction of similarly treated fibrinogen, in contrast to the monomeric fraction, stimulates the t-PA catalyzed conversion of plasminogen to plasmin and concomitantly exposes the sequences Aalpha-(148-160) and gamma-(312-324) involved in t-PA stimulation. Our present and previous findings suggest that soluble fibrinogen aggregates possess a fibrin-like structure, and that fibrin or fibrinogen polymer formation is a prerequisite for the enhancing effect on t-PA-mediated plasminogen to plasmin conversion which is seen even with the polymers in the soluble state.

Antibodies, Monoclonal↗
PubMed1996

Complete heparin-coated (CBAS) cardiopulmonary bypass and reduced systemic heparin dose; effects on coagulation and fibrinolysis.

OBJECTIVE: Heparin-coated extracorporeal circuits allow reduced amounts of systemic heparin and protamine. However, the effects on the coagulation and fibrinolytic systems when reducing systemic anticoagulation, have partly remained unknown. METHODS: Thirty-three patients undergoing elective first time myocardial revascularization were prospectively randomized either to have a cardiopulmonary bypass (CPB) circuit completely coated with covalently bound heparin, in combination with reduced systemic heparinization (activated clotting time (ACT) > 250 s (n = 17), or to a control group perfused with identical but uncoated circuits and full heparin dose (ACT > 480 s) (n = 16). Tests indicative of thrombin generation, platelet activation, and fibrinolytic activity were performed intraoperatively and postoperatively. RESULTS: During CPB, the plasma level of prothrombin fragment 1.2 (PF 1.2) increased from median 1.5 (1.1-1.9) nmol/l to 5.4 (3.3-6.6) nmol/l in the heparin-coated group, and was significantly higher (P = 0.01) than the increase from 1.4 (1.2-1.9) nmol/l to 3.2 (2.2-4.3) nmol/l seen in the control group. However, the increase on CPB was modest compared to the major elevation observed after completed surgery and reversal of the anticoagulation. The concentrations reached median 9.7 (6.8-19.5) nmol/l in the heparin-coated group and 13.2 (4.2-18.4) nmol/l in the control group (no significant intergroup difference). A similar pattern was observed for the thrombin-antithrombin (TAT) complex. Regression analysis revealed significant correlation between the levels of the thrombin markers and duration of CPB in both groups (P < 0.05). There was no correlation between ACT or plasma heparin levels on bypass and the PF 1.2 and TAT complex. The platelet release of beta-thromboglobulin increased in both groups during CPB and significantly more in the control group at the end of bypass (P < 0.01), indicating less platelet activation in the heparin-coated group. There were no significant intergroup differences with regard to fibrinolytic activity. Plasma fibrinogen as well as platelet counts were unchanged after the operation, compared to baseline. Except for one patient in the control group sustaining perioperative myocardial infarction, the postoperative course was uneventful in all cases. CONCLUSIONS: Completely heparin-coated CPB can safely be performed in combination with reduced systemic heparinization. The heparin and protamine amounts could be lowered to 35% of normal doses. Indications of more thrombin generation on CPB compared to the uncoated controls were seen, but the levels remained within low ranges in both groups. There was no evidence of thromboembolic episodes or clot formation in the extracorporeal circuits.

Adult↗
PubMed1996

Immunologic quantification of fibrin deposition in thrombi formed in flowing native human blood.

We describe a new method for quantification of fibrin in thrombi formed in native human blood at venous and arterial shear conditions in a parallel-plate perfusion chamber device. Thrombi consisting of various proportions of fibrin and platelets were digested by plasmin. Fibrin deposition (micrograms/cm2) was calculated from the measured D-dimer levels. Fibrin deposition in thrombi formed on a tissue factor (TF)-rich surface increased with increasing shear rate from 37 micrograms/cm2 at 100/s to 77 micrograms/cm2 at 2600/s (significant at 95%, ANOVA). The plasma levels of thrombin-antithrombin III complexes (TAT) increased in concert. In contrast, fibrin deposition in thrombi formed on collagen fibrils and the corresponding TAT plasma levels were independent of the shear rate and much lower than those elicited by the TF-rich surface (significant at 95%, ANOVA). The intra-individual variation in fibrin deposition was on average 10%, whereas the inter-individual differences were > 500%. Such a large inter-individual difference has not been detected by morphometry which usually is employed in similar studies. The present method is more accurate and less time-consuming than the morphometric approach. The novel method measures fibrin on the surface and in and around the thrombi, thus total deposited fibrin. In contrast, the morphometry approach quantifies surface coverage with fibrin only, thus being semiquantitative at best.

Collagen↗
PubMed1996

Aggregated, conformationally changed fibrinogen exposes the stimulating sites for t-PA-catalysed plasminogen activation.

The present paper shows that conformationally changed fibrinogen can expose the sites A alpha-(148-160) and gamma-(312-324) involved in stimulation of the tissue-type plasminogen activator (t-PA)-catalysed plasminogen activation. The exposure of the stimulating sites was determined by ELISA using mABs directed to these sites, and was shown to coincide with stimulation of t-PA-catalysed plasminogen activation as assessed in an assay using a chromogenic substrate for plasmin. Gel permeation chromatography of fibrinogen conformationally changed by heat (46.5 degrees C for 25 min) demonstrated the presence of both aggregated and monomeric fibrinogen. The aggregated fibrinogen, but not the monomeric fibrinogen, has exposed the epitopes A alpha-(148-160) and gamma-(312-324) involved in t-PA-stimulation. Fibrinogen subjected to heat in the presence of 3 mM of the tetrapeptide GPRP neither aggregates nor exposes the rate-enhancing sites. Thus, aggregation and exposure of t-PA-stimulating sites in fibrinogen seem to be related phenomena, and it is tempting to believe that the exposure of stimulating sites is a consequence of the conformational changes that occur during aggregation, or self-association. Fibrin monomers kept in a monomeric state by a final GPRP concentration of 3 mM do not expose the epitopes A alpha-(148-160) and gamma-(312-324) involved in t-PA-stimulation, whereas dilution of GPRP to a concentration that is not longer anti-polymerizing, results in exposure of these sites. Consequently, the exposure of t-PA-stimulating sites in fibrin as well is due to the conformational changes that occur during self-association.

Amino Acid Sequence↗
PubMed1995

Effects on coagulation and fibrinolysis with reduced versus full systemic heparinization and heparin-coated cardiopulmonary bypass.

BACKGROUND: Extracorporeal circulation with circuits coated with surface-bound heparin has allowed reduced levels of systemic heparinization. Clinical benefits have included reduced postoperative bleeding and less homologous blood usage. However, the effects on the hemostatic and fibrinolytic systems have remained in part unknown. METHODS AND RESULTS: Indications of thrombin generation, platelet activation, and fibrinolytic activity were investigated in patients undergoing coronary artery bypass surgery. Two groups were perfused with cardiopulmonary bypass (CPB) circuits completely coated with surface-bound heparin: one group with low systemic heparin dose (activated clotting time [ACT] > 250 seconds; n = 17) and a second group having a full heparin dose (ACT > 480 seconds; n = 18). A third control group was perfused with ordinary uncoated circuits and full heparin dose (n = 17). The plasma level of thrombin-antithrombin complex and prothrombin fragment 1.2 increased in all groups during bypass, and somewhat more in both the heparin-coated groups toward the end of CPB, compared with the control group (P < .01). However, the increase during CPB was minimal compared with the major elevation observed 2 hours after surgery in all groups. Platelet release of beta-thromboglobulin increased in all groups (P < .01) during CPB and significantly more in the high-dose group compared with the other two groups (P = .03). Fibrinolytic activities were similar in all groups, and there were no indications of major consumption of coagulation factors. CONCLUSIONS: Reduced systemic heparinization (ACT > 250 seconds) in patients having extracorporeal circulation with completely heparin-coated circuits did not lead to increased thrombogenicity. Thrombin formation remained within low ranges during CPB compared with patients receiving a full heparin dose and with the major elevations observed after surgery.

Adult↗
PubMed1995

Stimulating effect on tissue-type plasminogen activator--a new and sensitive indicator of denatured fibrinogen.

A high clottability and a short thrombin clotting time have routinely been considered as evidence of genuineness of the fibrinogen molecule. Since denatured fibrinogen stimulates the t-PA-catalysed conversion of plasminogen to plasmin, it was of interest to study the sensitivity of t-PA-stimulation as evidence of fibrinogen denaturation. Therefore, fibrinogen was intentionally exposed to various denaturating conditions (freeze-drying, heating, EDTA, alkali), and the clottability, the thrombin clotting time and the t-PA-stimulating effect were recorded. We found that the clottability was a poor indicator of fibrinogen denaturation, whereas the t-PA-stimulating effect could detect even mild fibrinogen denaturation. The thrombin clotting time was shortened after freeze-drying or heating at 47 degrees C, in spite of what might have been expected. Thus, denaturation is not necessarily accompanied by a prolonged clotting time. In some instances therefore, the t-PA-stimulation is an even more sensitive and reliable indicator of fibrinogen denaturation than is the thrombin clotting time. Consequently, this parameter should be combined with the thrombin clotting time to characterise preparations of fibrinogen.

Blood Coagulation↗
PubMed1995

Completely heparinized cardiopulmonary bypass and reduced systemic heparin: clinical and hemostatic effects.

BACKGROUND: When heparinized circuits are used for cardiopulmonary bypass, the amounts of heparin and protamine administered systemically can be reduced. However, it is not entirely known what effects this reduction in systemic anticoagulation has on clinical performance and on the coagulation and fibrinolytic systems. METHODS: Two hundred three patients undergoing first-time elective myocardial revascularization were prospectively randomized either to a group in which a completely heparin-coated circuit was used for perfusion (group H; n = 101 patients) and in which a reduced heparin dose was given (activated clotting time, > 250 seconds) or to a control group (group C; n = 102 patients) in which an uncoated, but otherwise identical, circuit was used and in which full systemic heparinization was induced (activated clotting time, > 480 seconds). Indicators of thrombin generation, platelet activation, and fibrinolytic activity were studied in a subset of 34 patients. RESULTS: The total amount of postoperative mediastinal drainage was significantly reduced in group H (median, 575 mL) compared with that in group C (median, 635 mL; p = 0.002). Two patients in group C but none in group H received homologous red blood cell transfusions (p = not significant). The loss of hemoglobin in group H was a median of 21 g/L, and this was significantly lower than the 25 g/L noted in the control group (p = 0.006). During cardiopulmonary bypass, the plasma levels of thrombin-antithrombin complex and prothrombin fragment 1.2 increased in both groups. At the end of cardiopulmonary bypass the plasma levels of these markers of thrombin formation were significantly higher in group H, although the increase was modest compared with the major increase observed 2 hours after operation in both groups. There were no significant intergroup differences in the platelet counts, the concentration of beta-thromboglobulin, or the plasma levels of fibrinogen and D-dimer. No differences in perioperative morbidity, the postoperative kidney function, or the intubation time were observed, and there were no hospital deaths. CONCLUSIONS: The combination of complete heparin-coated cardiopulmonary bypass circuits and low systemic heparinization is safe for patients undergoing elective coronary artery bypass procedures and reduces the perioperative blood loss. There was no evidence of increased thrombogenicity, fibrinolytic activity, or consumption of coagulation factors. No clinical or technical side effects were observed.

Adult↗
PubMed1995

Platelet-derived microvesicles and activated platelets express factor Xa activity.

Activated platelets and platelet-derived microvesicles demonstrate procoagulant properties. It is known that following stimulation, negatively charged phospholipids and factor Va become located on their surfaces. The aim of this study was to see whether activated platelets and platelet-derived microvesicles also expressed some factor Xa activity on their surfaces in a system where factor Xa did not come from external sources. In order to study this question, flow cytometry, as well as the use of a chromogenic substrate to factor Xa and a clotting assay in a factor X depleted plasma, were applied. A prothrombinase assay was also applied using prothrombin, CaCl2 and a chromogenic substrate to thrombin. The platelets were gel-filtered or washed, suspended in Tris-buffered saline, and activated by calcium ionophore A23187 or the thrombin receptor agonist peptide SFLLRN. Microvesicles and activated platelets were separated by centrifugation. Flow cytometry using a monoclonal antibody against factor Xa demonstrated the presence of factor Xa on the surface of the activated platelets. In addition, platelet-derived microvesicles and activated platelets demonstrated factor Xa activity on their surfaces detected directly by splitting of the chromogenic substrate to factor Xa, or by the prothrombinase assay. The thrombin generation in the last assay could be inhibited by a selective factor Xa inhibitor (recombinant tick anticoagulant peptide (rTAP)), soybean trypsin inhibitor, and antithrombin III plus LMW-heparin, all inhibiting at the factor Xa level, as well as by leupeptin which also inhibited the thrombin-chromogenic substrate interaction as such.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1995

Autotransfusion after open heart surgery: quality of shed mediastinal blood compared to banked blood.

The need to conserve a patient's own blood and avoid homologous transfusion is now well recognized. Therefore, techniques designed to reduce requirements for homologous blood transfusions have been developed. One of the methods is autotransfusion of shed mediastinal blood after open-heart surgery. The objectives of the present study were to investigate osmotic fragility and oxygen transport capacity of shed mediastinal blood compared to patient blood and stored packed red blood cells (SAGM). Shed mediastinal blood from ten consecutive patients undergoing elective cardiac surgery (coronary bypass grafting) was studied and compared to patient blood, 10 units of 3 weeks old and 10 units of 5 weeks old stored packed red blood cells (SAGM). Oxygen transport capacity was investigated by calculation of p50 for oxygen by use of the oxygen status algorithm (OSA 2.0) programme and measurement of 2,3-diphosphoglycerate (2,3-DPG) concentrations. The osmotic fragility was determined using increasing concentrations of saline. 2,3-DPG concentrations in shed mediastinal blood (5.3 mikromol/ml erythrocyte) were within the range measured in patient blood, but significantly higher than SAGM blood (P < 0.001). P50 for oxygen (3.5 kPa) in shed mediastinal blood was not significantly different compared to patient blood, but significantly higher (P < 0.01) compared with stored SAGM blood. The osmotic fragility in shed mediastinal blood was not significantly different compared to patient blood, but significantly lower (P < 0.001) than the osmotic fragility in stored SAGM blood. This suggests that red cells saved from shed mediastinal blood have better oxygen transport capacity and may have longer survival compared to stored blood.

Aged↗