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Biomedical subjects

U Hedner

Publications and source records attributed to U Hedner.

At least 19 recordsLinked to original sources
PubMed1992

Generation of Gla-domainless FVIIa by cathepsin G-mediated cleavage.

Coagulation factor VII contains ten gamma-carboxyglutamic acid residues in the N-terminal region (Gla-domain) which are essential for the hemostatic function of FVII. The present study shows that granulocyte cathepsin G degrades the Gla-domain of FVIIa in vitro. Characterization of the truncated FVIIa by SDS-PAGE and N-terminal amino acid sequence analysis revealed that cleavage had occurred between Tyr-44 and Ser-45 and that further cleavage was only obtained on extensive cathepsin G exposure. Cleavage of vitamin K-dependent coagulation factors by cathepsin G may play a role in vivo, and it offers a convenient way of obtaining proteins deprived of their Gla-domain for functional and structural studies.

1-Carboxyglutamic Acid↗
PubMed1992

Recombinant human factor VIIa (rFVIIa) in a rabbit stasis model.

The thrombogenicity of recombinant human FVIIa (rFVIIa) and FEIBA was studied in a rabbit stasis model. Only minor thrombus formation in isolated vein segments during 10 min. of stasis was seen following the administration of rFVIIa 100-1000 micrograms/kg or FEIBA 50-100 U/kg whereas both compounds caused clear thrombus formation during 30 min. of stasis. RFVIIa caused no change in platelet counts or plasma fibrinogen 3 hours after administration, whereas a small decrease of APTT was seen due to the direct effect of rFVIIa in this assay. In contrast, FEIBA caused a significant and dose-dependent decrease of platelet counts as well as of fibrinogen, and an increase of APTT which demonstrate a general consumption of coagulation factors. In conclusion the study demonstrated a local pharmacological effect of rFVIIa in the absence of a general activation of the coagulation cascade.

Animals↗
PubMed1992

Measurement of basal levels of factor VIIa in hemophilia A and B patients.

Previous results, presented in abstract form, indicate that replacement of thromboplastin with a mixture of phospholipid and truncated soluble tissue factor apoprotein results in a coagulation assay that can directly measure plasma factor VIIa levels without interference from zymogen factor VII (Atherosclerosis Thromb 11:1544a, 1991 [abstr]). We have exploited the specificity and sensitivity of such a factor VIIa specific coagulation assay to directly assess the in vivo relationship of factor VIII and factor IX on the production of factor VIIa levels under nonthrombotic and nonstimulatory conditions. Normal individuals (n = 20) were found to possess an average circulating factor VIIa level corresponding to 4.34 +/- 1.57 ng/mL, or approximately 1% of their total factor VII antigen. Severe factor VIII deficient patients (n = 13) possessed a slightly lower but statistically significant (P less than .01) decrease in their basal factor VIIa levels (2.69 +/- 1.52 ng/mL), corresponding to approximately 60% of that observed in normal individuals. On the other hand, severe factor IX deficient patients (n = 7) were found to possess even lower levels of factor VIIa corresponding to 0.33 +/- 0.15 ng/mL, or less than 10% of that observed in normal individuals. Measurement of total factor VII antigen levels shows that the variation in basal factor VIIa levels stems from differences in the degree of factor VII activation as opposed to differences in factor VII antigen levels. Our present data are consistent with the hypothesis that factor IXa is the principal in vivo activator of factor VII under basal conditions.

Factor VIIa↗
PubMed1992

Management of hemophilia patients with inhibitors.

rFVIIa seems to offer an alternative in the treatment of hemophiliacs as well as nonhemophiliacs with antibodies against FVIII/FIX. The treatment can be given regardless of the inhibitor titer in those patients and is also hemostatically active in hemophilia B patients. It is easy to administer but seems to need a repeated dosing at 2- to 3-hour intervals, at least initially in severe bleedings. A dose of 70 to 100 micrograms/kg body weight seems to induce hemostasis. Depending on the severity of the bleeding, the dose intervals may then be prolonged to 3 hours for 1 to 2 days or until clinical improvement is observed. Thereafter, the dosage interval can be increased to 4 hours if continued therapy is indicated.

Factor IX↗
PubMed1979

Effect of dextran on factor VIII (antihemophilic factor) and platelet function.

Three different properties of factor VIII (antihemophilic globulin) were studied after infusion of 500 ml of six per cent Dextran 70 to healthy volunteers. This dose caused no change in the factor VIII coagulant activity while there was a significant but temporary decrease of factor VIII related antigen. The Ristocetin induced platelet aggregation analysed with native as well as with formalin-fixed platelets, also decreased significantly. The maximal decrease was found a few hours after the infusion. The decrease was seen only if Dextran was infused in vivo and not if Dextran was added to blood in vitro. The dysfunction of factor VIII caused by Dextran resembles that found in one variant of von Willebrand's disease. This finding probably explains the platelet function inhibiting properties of Dextran, and may be of significance for its antithrombotic effects.

Adolescent↗
PubMed1979

Umbilical artery catheterization in newborns. III. Thrombosis--a study of some predisposing factors.

Thrombosis following umbilical artery catheterization is a relatively frequent complication. Low fibrinolytic activity in the vessel walls, high factor VIII and low antithrombin III (AT III, Heparin cofactor activity) in blood are factors known to favour the formation of thrombosis. In 30 newborns who died and in 2 foetuses the fibrinolytic activity determined in the aorta and the femoral vessels was in the normal 'adult' range except for a few very immature infants and the foetuses. The five cases with arterial thrombosis were not associated with low fibrinolytic activity. The various factor VIII activities (VIII:C, VIIIR:Ag, and VIIIR:RCF) ant AT III were studied in 30 sick newborns and in 20 healthy newborns. The sick exhibited increased levels of various factor VIII activities (VIIIR:Ag and VIIIR:RCF mainly) and markedly reduced levels of AT III. The high factor VIII activities and the low AT III found will add to the existing risk of thrombosis due to the presence of a foreign material. AT III substitution is suggested as a possible prophylactic.

Antithrombin III↗
PubMed1978

Familial antithrombin III deficiency as pathogenesis of deep venous thrombosis.

A family including 18 members with decreased antithrombin III (AT III), measured with both a biological and an immunochemical method, is described. The pattern found on crossed immunoelectrophoresis, using heparin in the agarose in the first run, was normal, though the peaks were low. This suggests decreased synthesis of a normal protein in the affected members. AT III deficiency occurred in both the paternal and the maternal branch, of the above 18 persons had had at least one thromboembolic episode. Some of the episodes had been precipitated by the presence or occurrence of some predisposing event or circumstance. This suggests the possible occurrence of a gene making some of the maternal family members more susceptible to certain trigger factors, such as surgery, infection, pregnancy, and the puerperium. The mode of inheritance filled all the criteria for autosomal dominant transmission. Prophylactic treatment, preferably oral anticoagulants and/or dextran, is recommended for all persons with a low AT III concentration in any situation known to increase the predisposition to thrombosis. The effect of heparin in these patients is impaired since the heparin co-factor, which is identical with AT III, is lowered.

Adolescent↗
PubMed1978

A family with thromboembolic disease associated with deficient fibrinolytic activity in vessel wall.

Defective fibrinolytic activity is often a contributory factor in deep venous thrombosis. A family with a high incidence of venous thrombosis in association with such a defect is presented. Of 13 family members who had had thrombosis, 12 showed a defective capacity to release fibrinolytic activity from vessel wall after venous occlusion and/or infusion of DDAVP, a vasopressin derivative. The fibrinolytic activator activity of the vessel wall was normal in all cases. This seems to be the first family in which there is evidence of an inherited abnormal fibrinolytic activity.

Adolescent↗
PubMed1978

[Non-enzymatic fibrinolytic agents].

Non-enzyme fibrinolytic agents include pharmacological agents which are active in vivo but inactive in vitro and synthetic chemical compounds which when added to blood or plasma in vitro directly induce fibrinolysis. There are a number of drugs with a short duration of action such as adrenalin, nicotinic acid, vasopressin and histamine. Vasoactive drugs probably act by stimulating the liberation of vascular activator. The effect of nicotinic acid is rapidly exhausted when injections are repeated. By contrast, the biguanides and certain anabolic steroids are capable of exerting a long term stimulation of endogenous fibrinolysis. Amongst these substances, phenformin, metformin, ethyloestrenol, stanozolol and a new substance, moroxydine chloride, have been studied. The biguanides appear to be capable of exerting an effect upon the synthesis and liberation of plasminogen vascular activator. The combination of an anabolic steroid and a biguanide would appear to be the most powerful. These various drugs have been used with success in cases of recurrent venous thrombosis in patients with an abnormally low level of plasminogen activator in the venous walls and/or low fibrinolytic activity after venous stasis. Chemical fibrinolytic agents were studied only in vitro, since the use of these substances in human therapeutics would seem to be still difficult in view of the fact that they are active only in a narrow range of concentrations.

Anabolic Agents↗