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Biomedical subjects

U Hedner

Publications and source records attributed to U Hedner.

At least 109 records · Page 6Linked to original sources
PubMed1988

Amino acid sequence and posttranslational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells.

Blood coagulation factor VII is a vitamin K dependent glycoprotein which in its activated form, factor VIIa, participates in the coagulation process by activating factor X and/or factor IX in the presence of Ca2+ and tissue factor. Three types of potential posttranslational modifications exist in the human factor VIIa molecule, namely, 10 gamma-carboxylated, N-terminally located glutamic acid residues, 1 beta-hydroxylated aspartic acid residue, and 2 N-glycosylated asparagine residues. In the present study, the amino acid sequence and posttranslational modifications of recombinant factor VIIa as purified from the culture medium of a transfected baby hamster kidney cell line have been compared to human plasma factor VIIa. By use of HPLC, amino acid analysis, peptide mapping, and automated Edman degradations, the protein backbone of recombinant factor VIIa was found to be identical with human factor VIIa. Neither recombinant factor VIIa nor human plasma factor VIIa was found to contain beta-hydroxyaspartic acid. In human plasma factor VIIa, the 10 N-terminally located glutamic acid residues were found to be fully gamma-carboxylated whereas 9 full and 1 partial gamma-carboxylated residues were found in the corresponding positions of the recombinant factor VIIa molecule. Asparagine residues 145 and 322 were found to be fully N-glycosylated in human plasma factor VIIa. In the recombinant factor VIIa, asparagine residue 322 was fully glycosylated whereas asparagine residue 145 was only partially (approximately 66%) glycosylated. Besides minor differences in the sialic acid and fucose contents, the overall carbohydrate compositions were nearly identical in recombinant factor VIIa and human plasma factor VIIa.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1988

Characterizing hereditary and acquired defects of plasminogen.

Since plasminogen is the proenzyme of plasmin most acquired defects of plasminogen are associated with situations with an increased fibrinolytic activity. Congenital defects also have been described both such associated with thrombotic disease and such that are not. An increased fibrinolytic activity leading to an acquired plasminogen defect is seen 1) in situations complicated with a free proteolytic activity most often involving both the fibrinolytic and the coagulation systems, 2) as a result of locally increased fibrinolytic activity (angiomas), 3) during thrombolytic therapy using plasminogen activators (SK, UK, tPA). A congenital plasminogen defect characterized by 1) a low protein level as well as one with 2) a normal plasminogen protein level in plasma but a defect activation pattern has been reported. Plasminogen can be determined immunochemically, a method which does not differentiate between functionally active plasminogen/plasmin and complexes between these proteins and inhibitors. Plasminogen activity is measured in a chromogenic method using the chromogenic substrate S2251 (Kabi Diagnostica, Stockholm). In this latter method SK is used as a plasminogen activator and the total plasmin formed is measured amidolytically. Using both the immunochemical and the amidolytical methods it has been possible to identify congenital plasminogen defects characterized by a defective activation of plasminogen into plasmin, a defect that has been associated with thromboembolic disease. Another congenital plasminogen defect seems to be caused by a decreased synthesis of a normal plasminogen molecule. Such a defect may not be associated with thrombotic disease. In situations complicated with an increased fibrinolytic activity, decreased plasminogen levels (in both types of assay) are of diagnostic help. Values down to below 50% or even lower may be seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation Disorders↗
PubMed1988

Arachidonic acid cascade metabolites in porcine E. coli shock. Coagulation, fibrinolytic and hemodynamic response.

Cardiopulmonary hemodynamics and changes in various hemostatic factors (alpha 2M, alpha 2AP, AT III, prothrombin-proconvertin activity, fibrinogen concentration, ethanol gelation test and fibrinolytic activity on fibrin plates) were investigated in pigs during shock induced with live Escherichia coli. Anesthetized pigs were treated with indomethacin or with the combined cyclooxygenase/lipoxygenase inhibitor BW755C before the E. coli infusion or were left untreated as septic controls. Septic shock developed in all of these animals. Pretreatment attenuated the early deterioration of pulmonary circulation but did not modify the coagulation/fibrinolytic activation or the disturbed cardiopulmonary hemodynamics seen in the delayed phase of shock. The arachidonic acid cascade metabolites thus seems to mediate the early, but not the delayed cardiopulmonary reaction and to have minor importance for activation of coagulation and fibrinolysis in E. coli-shocked pigs.

Animals↗
PubMed1988

Safety and efficacy of a low molecular weight heparin (Logiparin) versus dextran as prophylaxis against thrombosis after total hip replacement.

In order to study the plasma levels of factor XaI and IIaI activity an enzymatically depolymerized low molecular weight heparin (LMW-heparin; Logiparin) was given s.c. in a dose of 35 XaI mu/kg b.w. once daily for 7 days to 10 patients undergoing total hip replacement (THR) in a pilot study. The XaI activity was less than or equal to 0.24 XaI units/ml and the IIaI activity less than or equal to 0.043 IIaI mu/ml. No accumulation of the activities were seen. No phlebographically verified thrombi or any bleeding complications were registered. From this study it was concluded that the given dose of Logiparin was safe with regard to bleeding complications. Based on these data, an open, randomized controlled trial was started. In this main study the thromboprophylactic effect of the LMW-heparin (Logiparin) in a dose of 35 XaI mu/kg b.w. once daily was compared with that of dextran 70 in patients undergoing THR. 100 patients were randomized. The over-all thrombosis rate was 28% in patients treated with LMW-heparin and 39% in those given dextran, a non-significant difference. No bleeding complications, deaths or pulmonary embolism were recorded in either group. Peroperative blood loss and transfusion requirements were similar in the two groups. In conclusion, the investigated LMW-heparin (Logiparin) is safe and effective in preventing postoperative thromboembolism in patients undergoing total hip replacement, but the dosage can probably be optimized.

Adult↗
PubMed1987

The effect of low molecular weight heparin on experimental thrombosis and haemostasis--the influence of production method.

Three low molecular weight heparins prepared by enzymatic depolymerization, chemical degradation, and fractionation, respectively were studied in experimental thrombosis and haemostasis models in vivo and in biological assays in vitro. The three low molecular weight heparins, which had comparable molecular weight distributions, showed very similar activities both in vitro and in vivo. All three showed dose dependent thromboprophylactic effect. The antithrombotic effects of the low molecular weight heparins and conventional heparin administered in the same dose (30 XaI u/kg b.w.) did not differ. Neither LMW heparin nor conventional heparin (60 or 90 XaI u/kg b.w.) showed significant effects on the haemostatic plug formation time in the rabbit mesenteric microcirculation. These experiments confirm that low molecular weight heparins are potential antithrombotic drugs, which by intravenous administration have effects similar to those of standard heparin. The method of preparation seems to be of no or minor importance, at least if the molecular weight distributions of the products are similar.

Animals↗
PubMed1987

Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.

A low molecular weight heparin (LMW-heparin) with a mean molecular weight of 4900 dalton was prepared by controlled enzymatic depolymerization of conventional porcine mucosal heparin. The effects of 2,500, 5,000 and 10,000 U (XaI; 29, 58 and 116 mg) on factor Xa inhibition (XaI), factor IIa inhibition (IIaI), APTT, AT III and platelet count were compared to those of 5,000 U (XaI; 26 mg) of conventional heparin given s.c. to 6 healthy volunteers. 5,000 U (XaI; 58 mg) of LMW-heparin was given i.v. A dose related response with regard to the XaI and the IIa-inhibitory activities with peak values at 4 hours after the s.c. injections was obtained. An increase of the XaI/IIaI ratio over the time after injection was seen only after i.v. administration of the LMW-heparin. The APTT was only slightly prolonged and remained within normal range after s.c. injection. AT III and platelet counts were unaffected. The biological half life of the LMW-heparin was 111 minutes if assayed by Xa inhibition, 76 minutes if assayed by IIa inhibition and 40 minutes if assayed by APTT. A strong correlation between the XaI activities obtained and body weight was seen, indicating that LMW-heparin should be administered individually according to body weight.

Adult↗
PubMed1987

On the unreliability of one-stage factor VIII:C clotting assays after infusion of factor VIII concentrates.

A multicentre study was undertaken in order to determine the reliability of the methods of assay of F VIII:C and the position of the peak value obtained after infusion of F VIII:C concentrates. Blood samples were drawn before and 10, 30 and 60 min after injection of F VIII concentrates in six haemophiliacs in one of the centres. Coded, frozen plasma samples were dispatched to the laboratories of the other four centres. F VIII:C was determined by different one-stage methods using the same international standard but with different activators. The results of the different laboratories differed widely and no agreement was reached on the existence of a lag period. To reach a valid conclusion not only the same sample has to be analysed, as in this study, but also the same laboratory technique has to be used by all participating investigators. To reach agreement on in vivo recovery and on elimination curves for different F VIII concentrates multicentre studies must be based on reliable methods of assay.

Adult↗
PubMed1987

Coagulation and fibrinolytic reactions in experimental porcine septic shock: pretreatment with different antiplatelet factors.

The aim of this study was to investigate the influence on various hemostatic factors (alpha 2-macroglobulin, antiplasmin, antithrombin III, prothrombin-proconvertin activity, fibrinogen concentration, ethanol gelation test, and fibrinolytic activity on fibrin plates) of bacteremic shock in swine and the influence on these factors of drugs interfering with platelet function. Anesthetized pigs were given live Escherichia coli intravenously (n = 49) or Ringer's solution (n = 7) and were monitored for 3 hours. Pretreatment was given with indomethacin (n = 6), the TxA2 inhibitor UK 38 485 (n = 7), the prostacyclin analogue ZK 36 374 (n = 7), the 5HT antagonist ketanserin (n = 6), or ketanserin combined with UK 38 485 (n = 9) or dipyridamole (n = 8). Septic shock developed in all E. coli animals. There were decreased levels of platelets and leukocytes and activation of the coagulation/fibrinolytic systems by E. coli. Except for a slight attenuating effect on the antithrombin III (ketanserin and dipyridamole) and alpha 2-macroglobulin (ketanserin) decreases, there were no significant effects of the drugs. It is concluded that live E. coli induced several changes within the coagulation and fibrinolytic systems. Only minor effects were seen when different drugs influencing platelet function were given.

Animals↗
PubMed1986

Heparin-induced osteoporosis in rats.

In order to study the effect of heparin in inducing osteoporosis, 30 female rats were divided in two groups and treated with daily injections of 2 IU heparin/g body weight for 33 and 65 days and compared with the same number of rats acting as controls. The mineral bone mass in the femora of the animals was measured quantitatively. A significant (p less than 0.001) reduction in bone mineral mass was found in the heparin-treated animals. This effect was present to the same degree after 33 days as after 65 days of treatment. It is concluded that heparin in this dose causes osteoporosis in rats after 33 days and that the described method can be used as an experimental model for further studies on this topic.

Animals↗
PubMed1986

The influence of ketanserin on hemostasis in vitro.

Ketanserin is a new selective 5-HT2 receptor blocker. It has been used to indirectly study the influence of serotonin on hemostatic function in vitro. Coagulation and fibrinolysis in vitro were not affected. In high doses adrenalin induced platelet aggregation was inhibited but no influence was seen on collagen or ADP induced aggregation. It can be concluded that it is not very likely that serotonin plays an important role in initial hemostasis. However, the findings ought to be confirmed in vivo.

Adenosine Diphosphate↗
PubMed1986

Return to normal of 99mTc-plasmin test after deep venous thrombosis and its relationship to vessel wall fibrinolysis.

Fourteen patients with deep venous thrombosis (DVT) and a positive 99mTc-plasmin test were followed up to determine how soon a negative test was obtained. Localization and extension of the thrombi were determined by phlebography. Plasminogen activator activity in vein walls and local fibrinolytic activity after venous occlusion were measured in order to find out what the prerequisites for impaired thrombolysis are. The time required to obtain a negative 99mTc-plasmin test showed considerable variation, ranging from less than 1 week to more than 6 months. The 99mTc-plasmin test had returned to normal in 64% of the patients after 6 months. No relationship was found between vessel wall fibrinolysis and time to normalization. Instead, we found an association between the time to normalization of the 99mTc-plasmin test and the size of the thrombus, according to phlebography, as well as between the time to normalization of the 99mTc-plasmin test and the extension of leg points with a positive 99mTc-plasmin test at admission. The finding of abnormal 99mTc-plasmin test results more than 6 months after acute DVT is of practical importance and warrants caution when evaluating patients with symptoms and signs suggestive of acute recurrent DVT.

Adult↗
PubMed1986

Relationship between factor XII, von Willebrand factor and postoperative deep vein thrombosis.

The development of postoperative deep vein thrombosis (DVT) was studied in 45 patients subjected to major abdominal surgery, 17 of whom showed signs of DVT as defined by 125I-fibrinogen test. The preoperative levels of von Willebrand factor (F VIII RAg) and platelets were higher in these 17 patients than in those remaining free from DVT. A contributing factor in DVT development thus may be more active primary haemostasis. Preoperative F XII levels were similar in the two groups, but the post-operative drop in F XII was more pronounced in the DVT group. An inhibitor of plasminogen activation behaved similarly in both groups. C1-inhibitor, the main inhibitor of the F XII-dependent clotting and fibrinolytic pathways, showed a typical acute-phase response postoperatively, without intergroup difference. The study suggested that F XII-dependent pathways play a role in the genesis of venous thrombi, at least in the postoperative period, though whether the postoperative F XII drop was due to a role in clotting or to fibrinolysis activation remains unclear.

Complement C1↗
PubMed1986

The Mallory-Weiss syndrome. An analysis of haemostatic function in a bleeding-free period.

The bleeding source in the Mallory-Weiss syndrome is mucosal tears at the gastro-oesophageal junction. It has been suggested that haemostatic defects play an active role in the syndrome's development. This study was made to analyze whether or not such defects are present during a bleeding-free period following the Mallory-Weiss syndrome. Fourteen patients were examined 4 weeks to 5.8 years after the bleeding episode. In most cases the coagulation mechanism was then found to be normal. Mild haemostatic defects were found in four patients, but were not of consistent type.

Adult↗
PubMed1985

Management of haemophilia A with antibodies--the effect of combined treatment with factor VIII, hydrocortisone and cyclophosphamide.

Immune tolerance has by several methods been induced in haemophiliacs with antibodies. A conversion of "high responders" into "low responders" was previously reported after repeated moderate factor IX doses over periods of 7-10 days in combination with cyclophosphamide and steroids in two patients with haemophilia B and inhibitors. This paper reports similar results in a haemophilia A patient by giving factor VIII, cyclophosphamide, and steroids during relatively short periods of time (7-8 days). The anamnestic response markedly decreased already following the first treatment and never exceeded a level of 1 u/ml (approximately 3 BU/ml) even when boosted with ordinary factor VIII doses for only 3 days. It is concluded that the markedly decreased secondary antibody response is most probably the result of factor VIII given at short intervals (twice a day) for periods of up to about one week when given in combination with cyclophosphamide and steroids. The same effect may be achieved by other methods. The treatment schedule suggested in the present paper is, however, simple and avoids long periods of high antibody levels. Furthermore, the total factor VIII dose used is lower than suggested in most other treatment schedules, which makes the treatment substantially less expensive.

Antibody Formation↗
PubMed1985

The effect of heparin fragments of different molecular weights on experimental thrombosis and haemostasis.

The effect of heparin fragments of different molecular weights has been compared with that of conventional sodium heparin on experimental thrombosis in vivo and ex vivo and experimental haemostasis in vivo. In the first part of the study fragments of different molecular weights were given (4,900, 6,500, 9,500 and 22,200 dalton). All preparations including the control gave a significant prolongation of the haemostatic plug formation time in the rabbit mesenteric microcirculation, and all except the fragment with the lowest molecular weight reduced the frequency of jugular vein thrombosis (induced by a combination of endothelial denudation and stasis). There was a correlation between the XaI activity of the different heparin fragments and frequency of thrombosis. Using an ex vivo method (modification of Chandler's model) a dose dependent lag phase until start of thrombus formation was found. In the second part of the study a dose response investigation was made comparing different doses of a fragment (6,500 dalton) with conventional heparin in the same XaI doses (10, 30 and 60 units/kg). Sodium heparin in the highest dose prolonged the haemostatic plug formation time whereas none of the fragment doses did. The lowest dose both of the fragment and conventional heparin did not reduce the frequency of thrombosis, whereas the two higher doses did. Thus it may be possible to obtain preventive effect on thrombus formation with a heparin fragment.

Animals↗
PubMed1985

Polymorphism of normal factor IX detected by mouse monoclonal antibodies.

Hemophilia B is an X-chromosomal recessive disease due to deficiency of coagulation factor IX. Three monoclonal antibodies against factor IX were prepared and used to develop immunoradiometric assays (IRMAs) of factor IX antigen (IX-Ag). IX-Ag was measured in 65 normal individuals with one IRMA based on polyclonal anti-IX antibodies and two IRMAs based on three monoclonal anti-IX antibodies. One of the monoclonal antibodies differed in specificity since it neutralized less than 50% of the clotting activity of factor IX (IX-C), whereas the other two monoclonal antibodies neutralized 80-95%. When the former antibody was used as the solid phase in IRMA, two groups of normal individuals were distinguished: group A with measurable IX-Ag, and group B without demonstrable IX-Ag. There were no differences between the groups either in IX-C or in IX-Ag measured with polyclonal antibodies. A subgroup comprising only women could be distinguished in group A, in whom intermediate IX-Ag concentrations were found. Family studies showed the group B variant of normal factor IX to be transmitted according to the pattern of X-linked recessive inheritance. The allelic frequency of group A was 0.66, and that of group B was 0.34.

Adolescent↗
PubMed1985

Episodes of increased fibronectin level observed in a patient suffering from recurrent thrombosis related to congenital hypodysfibrinogenaemia (fibrinogen Malmoe).

A study has been conducted in a Swedish patient with severe thrombotic disease and repeated miscarriages related to a hypodysfibrinogenaemia with defective thrombin binding to the abnormal fibrin. The hypodysfibrinogenaemia was found in several members of the family. The patient also had an increased concentration of fibronectin in her plasma at two different occasions. This would appear to be unrelated to the abnormal fibrinogen since a normal concentration of fibronectin has been found in her relatives presenting the same fibrinogen anomaly, and in the patient at two other times. In conclusion, the thrombotic disorder in this patient presenting a congenital hypodysfibrinogenaemia may be explained by the defective thrombin binding to fibrin.

Adult↗