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Biomedical subjects

U Hedner

Publications and source records attributed to U Hedner.

At least 91 records · Page 5Linked to original sources
PubMed1991

No transplacental passage of standard heparin or an enzymatically depolymerized low molecular weight heparin.

In 21 women who had an abortion by hysterotomy between the 15th and 23rd week of pregnancy, the possibility that unfragmented heparin or low molecular weight heparin (LMWH) passed the placental barrier to the foetus was studied. Laboratory analyses included amidolytic assays of factor Xa inhibitory activity (XaI), antithrombin III (ATIII) and a direct measurement of heparin-like substances in plasma with a competitive binding assay. The ATIII concentration in foetal plasma was about 20% of that in normal human plasma and varied considerably between individuals (2-27%). The XaI activity did not differ between the two treated groups, but the mean XaI activity of the combined groups differed from zero (P less than 0.05). If the XaI activity was corrected for the ATIII concentration, the heparin activities no longer differed significantly from zero. As the concentration of heparin-like substances were above the detection limit (0.35 microgram/ml) in 6/16 analysable samples of foetal plasma, a further 15 women who had not received any heparin were included as controls. In 12/14 analysable foetal plasmas heparin-like substances in concentrations above 0.35 micrograms/ml could be detected. Determination of heparin activity in foetal plasma is thus difficult due to the influence of endogenous ATIII on heparin assays. In conclusion, this study did not demonstrate any evidence for the passage of heparin or LMWH across the placental barrier. No differences were detected whether unfragmented heparin or LMWH had been given to the mothers. Our results also indicate the presence of an endogenous glycosaminoglycan in foetal plasma.

Adolescent↗
PubMed1990

Recombinant human extrinsic pathway inhibitor. Production, isolation, and characterization of its inhibitory activity on tissue factor-initiated coagulation reactions.

Previous studies have shown that extrinsic pathway inhibitor (EPI) is an effective inhibitor of factor Xa alone or factor VIIa-tissue factor complex in the presence of factor Xa. Since tissue factor exposure is implicated in thrombogenesis, we hypothesized that EPI may be valuable in the treatment of some thromboembolic episodes. Furthermore, EPI may be an important factor in bleeding complications in hemophiliacs. In the present study, human EPI was expressed in baby hamster kidney cells using a mammalian expression vector. Transfected cells expressed 1-2 micrograms/ml of recombinant EPI (rEPI) which was purified to homogeneity by heparin-Sepharose chromatography, ion-exchange chromatography, and reverse phase high performance liquid chromatography. Purified rEPI exhibited a specific activity of 30,000 units/mg and migrated as a single band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent molecular weight of 42,000. In addition, the NH2-terminal sequence of rEPI was identical to that of HepG2 EPI and HeLa EPI. The ability of rEPI to inhibit factor X activation by a complex of factor VIIa-tissue factor was then examined in the presence and absence of plasma concentrations of human factors VIII and IX. Using relipidated human brain tissue factor apoprotein, rEPI inhibited the factor VIIa-mediated activation of factor X half-maximally at 2.5 and 1 nM in the presence and absence of factors VIII and IX, respectively. Using monolayers of a human bladder carcinoma cell line (J82) as the source of tissue factor, the activation of factor X by cell-bound factor VIIa was inhibited half-maximally by 5 nM rEPI in the presence of factors VIII and IX. The proteolytic activity of J82 cell-bound factor Xa toward prothrombin was inhibited half-maximally at approximately 5 nM rEPI, while the amidolytic activity of factor Xa in solution was inhibited by rEPI with a Ki of 130 pM. Recombinant EPI also inhibited the amidolytic activity of factor VIIa half-maximally at 10 nM rEPI in the presence of relipidated tissue factor apoprotein and calcium. These results indicate that, in the presence of plasma concentrations of factors VIII and IX, at least 10 times the plasma concentration of EPI is required to reduce factor VIIa-dependent factor X activation one order of magnitude in vitro. In the absence of functional factor VIII and IX, rEPI at plasma levels was a potent inhibitor of factor VIIa-mediated factor X activation, and this activity presumably accounts for the inability of hemophiliacs to initiate hemostasis via the extrinsic pathway.

Amino Acid Sequence↗
PubMed1990

Effect of recombinant human FVIIA on warfarin-induced bleeding in rats.

Recombinant human factor VIIa (rFVIIa) was given to warfarin-treated rats. One and two warfarin treatments reduced endogenous factor X levels to about 10% and less than 5%, respectively. The reduction of plasma levels of vitamin K-dependent coagulation factors was accompanied by a treatment-dependent prolongation of activated partial thromboplastin time (APTT) and prothrombin time (PT) as well as by increased bleeding time and blood loss in the rat tail bleeding test. rFVIIa 50 micrograms/kg and 250 micrograms/kg normalized PT and shortened APTT in rats given warfarin once. Bleeding was completely normalized by rFVIIa 250 micrograms/kg. In rats given warfarin twice rFVIIa 250 micrograms/kg shortened PT but had no effect on APTT, whereas the effect on bleeding was variable. The elimination half life of rFVIIa in rats was found to be 30-40 minutes. The study indicates that rFVIIa may be useful in patients with bleeding due to decreased levels of vitamin K-dependent coagulation factors.

Animals↗
PubMed1990

Effects of low molecular weight heparin and unfragmented heparin on induction of osteoporosis in rats.

A comparison between the effect of low molecular weight heparin (LMWH) and unfragmented heparin (UH) on induction of osteoporosis was made in 60 rats treated with either UH (2 IU/g bw), LMWH in 2 doses (2 XaI U/g or 0.4 XaI U/g) or placebo (saline) for 34 days. Studied variables were: bone mineral mass in femora; fragility of humera; zinc and calcium levels in serum and bone ash and albumin in plasma. A significant reduction in bone mineral mass was found in all heparin-treated rats. There was no difference between UH and LMWH in this respect. The effect was dose-dependent in LMWH-treated animals. The zinc contents in bone ash were decreased in all heparin-treated rats as compared with controls. No recognizable pattern was seen in alterations of zinc or calcium in serum. The fragility of the humera, tested as breaking strength did not differ between treatment groups and controls. In conclusion, if dosed according to similar factor Xa inhibitory activities, LMWH induces osteoporosis to the same extent as UH and in a dose-dependent manner. The zinc content in bone ash was decreased after heparin treatment, irrespective of type of heparin given.

Animals↗
PubMed1990

Factor VIIa in the treatment of haemophilia.

Recombinant FVIIa is being developed for treatment of haemophiliacs with antibodies against FVIII/FIX. rFVIIa was shown to be haemostatically active in haemophilia A and B dogs as well as in 20 haemophilia patients (one haemophilia B and 19 haemophilia A patients). Thirteen patients were treated for life-threatening bleedings and nine at surgery (dose: 60-90 micrograms/kg q 3-4 h). One patient underwent synovectomy in a knee joint under the cover of rFVIIa as the sole coagulation factor without any problems. One patient with FXI deficiency was successfully treated at an orchidectomy. The haemophilia B patient was treated in association with a compartment syndrome (surgical fasciotomy) with a complete haemostasis. He later uneventfully underwent skin grafting. Two CNS bleeds, a severe mouth bleed were treated as well as an extensive nasopharyngeal bleed in a patient with an acquired inhibitor against FVIII. Shortening of the prothrombin time as well as of the APTT was seen. No side-effects were observed. It is speculated whether FVIIa in complex with not only tissue factor but also phospholipids exposed at the site of injured cells directly activates FXa and thereby the final common pathway of the coagulation cascade.

Animals↗
PubMed1990

Comparison of the effect of plasma-derived and recombinant human FVIIa in vitro and in a rabbit model.

Both purified plasma-derived FVIIa (pFVIIa) and recombinant FVIIa (rFVIIa) were shown to shorten the in vitro APTT in haemophilic plasma significantly. After addition of 3.8 micrograms/ml of pFVIIa or rFVIIa, corresponding to 110-140 FVII U/ml, the APTT was normalized in both haemophilia A and haemophilia B plasma. Furthermore, the prolonged APTT in plasma from a patient with acquired inhibitors against FVIII:C was normalized by addition of pFVIIa or rFVIIa in vitro. These results indicate an alternative pathway to the FVII or FVIIa-TF complex formation involving phospholipids (present in the APTT reagent). No signs of systemic activation of the coagulation system in rabbits following infusion of 500, 1000, 5000 U pFVIIa or rFVIIa/kg body weight, corresponding to about 150 micrograms/kg body weight, were seen. This corresponded to 2-3 times the clinical dose of FVIIa.

Animals↗
PubMed1989

Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo.

Treatment of deep venous thrombosis with low molecular weight heparin (LMWH-Novo, Logiparin) was carried out with two different doses of Logiparin, 75 XaI U/kg b.w. twice daily and 150 XaI U/kg b.w. once daily subcutaneously for 5 days. Simultaneously warfarin was given from the first day of heparin treatment. Mean age of the twenty patients was 65 years and one third was females. No serious side effects, hematomas, pulmonary emboli or signs of recurrent thrombosis occurred during treatment with either dose regime. Venografic assessment with Marder scoring one week after initiation of Logiparin treatment showed a slight not significant improvement apparent in 40% of the patients. The activities of F-IIaI and F-XaI in the blood plasma were found to increase after injection of Logiparin. These two parameters seem to be the most suitable for monitoring the effect during treatment. For future studies on the therapeutic effect of Logiparin in deep venous thrombosis a single dose of 150 to 200 F-XaI activity per 24 hours seems to be most suitable.

Aged↗
PubMed1989

Potentiated thrombolysis in a Chandler system using rtPA and lys-plasminogen.

The effect of glu/lys-plasminogen on rtPA induced thrombolysis was studied in a Chandler model using rabbit blood. Glu/lys-plasminogen in various concentrations was added to the Chandler loop before or after thrombi were formed from 2 ml of rabbit blood containing 125I-labelled rabbit fibrinogen. The thrombolysis was estimated as radioactivity in the supernatant/total radioactivity. Thrombi formed in the presence of extra lys-plasminogen (conc greater than or equal to 0.025 mg/ml blood) lysed spontaneously to a significantly higher extent than thrombi formed in the presence of glu-plasminogen or saline. If the glu/lys-plasminogen was added to a preformed thrombus no thrombolysis occurred. When added together with single-chain rtPA (s.c. rtPA) or two-chain rtPA (t.c.rtPA) the thrombolysis was similar to the one obtained by s.c./t.c.rtPA alone. If on the other hand s.c./t.c.rtPA was added to lys-plasminogen enriched thrombi (greater than 0.01 mg/ml blood) a significantly enhanced thrombolysis as compared to the one achieved by s.c./t.c.rtPA alone was obtained. Based on the observation that lys-plasminogen potentiates the lysis of thrombi in a Chandler model a bolus dose administered preoperatively may enhance spontaneous lysis of thrombi formed during surgery.

Animals↗
PubMed1989

Thromboxane A2-receptor blockade and prostacyclin in porcine Escherichia coli shock.

Septic shock was induced by intravenous infusion of live Escherichia coli in pigs to investigate the influences on central hemodynamic, coagulation, and fibrinolytic reactions by a thromboxane A2 (TxA2)-receptor blocker (BM 13.177; n = 6) and a prostacyclin analogue (iloprost or ZK 36,374; n = 7). The early pulmonary vasoconstriction following E coli infusion was attenuated, but not abolished, by BM 13.177. Only minor effects were seen after pretreatment with iloprost. Neither drug had any major effect on the coagulation and fibrinolytic activation. These results confirm that TxA2 is an important, but not the only, mediator of early pulmonary vascular response in porcine septicemia and that neither TxA2 nor prostacyclin is of major importance for the hemostatic reactions in this shock model.

Animals↗
PubMed1989

Recurrent thromboembolism in pregnancy and puerperium. Is there a need for thromboprophylaxis?

By sending a questionnaire (response rate 93%) to 321 women with a history of venous thromboembolism and previous coagulation tests, 72 patients were identified who had a total of 87 pregnancies after the thromboembolic episode. The main aim of the study was to analyze the influence of prophylaxis during pregnancy and delivery on the development of further thromboembolic complications. During pregnancy there was no difference in frequency of thromboses between the group given prophylaxis (n = 20) and the group not receiving it (n = 67). At delivery the frequency of thrombosis was 5.3% among the 57 women given prophylaxis and 11.1% among the 30 without prophylaxis, a difference that is not significant. The implication of these findings is discussed both concerning the indications for giving prophylaxis and concerning the problem of designing relevant prophylactic trials.

Female↗
PubMed1989

Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease.

Recombinant factor VIIa (rF.VIIa) is a two-chain procoagulant enzyme (Mr, approximately 50,000) active only when complexed with tissue factor in the extrinsic clotting system. We administered human rF.VIIa to hemophilic and von Willebrand disease (vWD) dogs to determine its hemostatic effectiveness and survival in the circulation. Hemophilia A dogs lacking factor VIII demonstrated an immediate increase in plasma rF. VIIa and prompt stoppage of hemorrhage at bleeding time (BT) sites. In seven studies in two dogs, the range of dose of rF. VIIa was 50-220 micrograms/kg, with an apparent 7- to 11-fold increase in plasma factor VII and a mean recovery in plasma of 34%. The t1/2 was 2.8 +/- 0.5 hr. The BT was normalized except in an animal given the minimum dose. In four studies in two hemophilia B dogs lacking factor IX, BT was normalized. The elevation in plasma factor VII was by a factor of 8-30, with a mean recovery of rF.VIIa in plasma of 44%. In two studies in a homozygous vWD dog lacking von Willebrand factor, which is needed for platelet function, BT was not corrected even though large doses of rF. VIIa were given. The human rF. VIIa protein was immunogenic for dogs. These studies indicate that factor VIIa corrects the hemostatic defect in dogs with hemophilia A and B, diseases primarily of the intrinsic clotting system, but does not correct the hemostatic defect in vWD.

Animals↗
PubMed1989

Clinical experience with human plasma-derived factor VIIa in patients with hemophilia A and high titer inhibitors.

FVIIa purified from human plasma and spontaneously activated during the purification procedure was given to 4 patients with hemophilia A and inhibitors against FVIII:C in association with joint bleeds. A dose of 9-20 micrograms/kg b.w. (700-1,000 U/kg b.w.) seemed to be hemostatically active in moderate to severe joint bleeds. Plasma levels of FVII of 5-7 U/ml were achieved and recoveries varied between 17 and 66%. The lower recovery rates of 17-39% were all found in 1 of the patients. No immediate side effects were seen. Neither were any signs of a systemic activation of the coagulation system observed. It is concluded that highly purified FVIIa may be useful in the treatment of hemophilia A patients with inhibitors against FVIII:C.

Adult↗
PubMed1989

Coagulation and fibrinolysis during the normal menstrual cycle.

Thirteen healthy women (age 24-44 yrs) were studied during their menstrual cycle. Samples were taken 2-3 times weekly for six consecutive weeks. Plasma concentrations of oestradiol and progesterone were determined in each blood sample and only women found to be ovulatory were included. From the hormone data the cycles were divided in five phases (early follicular phase, late follicular phase, early luteal phase, late luteal phase and menstrual period). The samples for the coagulation and fibrinolysis assays as well as the venous occlusion (20 min) tests were drawn or performed between 8-9 a m after fasting for 8 hrs. The fibrinogen F VIII:C and AT III were assayed and did not show any variations through the study period. Neither were any differences found in platelet counts, platelet mean volumes or platelet function measured as platelet adhesion and plasma beta-thromboglobulin. The fibrinolytic activity after venous occlusion decreased slightly during the late luteal phase (phase 4) as compared with the other phases. Large individual differences were, however, seen and no statistically significant differences between the five different phases were found. The plasminogen activator inhibitor (PAI-1) varied during the cycle but in most individuals within the normal range. In 7/13 women substantial fluctuations of the fibrinolytic activities during the cycle were seen. Four women had a significant fall of the fibrinolytic activity after venous occlusion during the late luteal phase (phase 4) and 3 others during the menstrual phase (phase 5). No co-variation between the fibrinolytic activities and PAI-1 was found. Multiple regression analysis showed a co-variation between fibrinolytic activities and progesterone.

Adult↗
PubMed1989

Influence of aprotinin, a protease inhibitor, on porcine E. coli shock. Studies on coagulation, fibrinolytic and hemodynamic response.

The effect of a protease inhibitor, aprotinin, on hemostasis (a2M, a2AP, AT III, prothrombin-convertin activity, fibrinogen, fibrinogen monomers and fibrinolytic activity on fibrin plates) was investigated in pigs with septic shock. Anesthetized pigs were given live Escherichia coli i.v. (n = 7), or aprotinin (1,000,000 KIE i.v.) 15 min before live E. coli (n = 6), or Ringer's solution only (sham controls, n = 8). Septic shock developed in all E. coli-infused pigs. Pulmonary vascular resistance increased, platelet and leukocyte counts fell and signs of systemic activation of the coagulation and fibrinolytic systems appeared in the E. coli groups, but aprotinin attenuated the effects on these systems and also on the pulmonary circulation. Five of the six aprotinin-pretreated pigs survived, but none of the seven with septic shock and no pretreatment. Thus the shock induced by infusion of live E. coli and the resultant changes in the coagulation and fibrinolytic systems and in cardiopulmonary hemodynamics were diminished by aprotinin pretreatment.

Animals↗