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Biomedical subjects

N Egberg

Publications and source records attributed to N Egberg.

At least 37 records · Page 2Linked to original sources
PubMed1996

Altered properties of the fibrin gel structure in patients with IDDM.

High plasma fibrinogen levels are associated with vascular complications in the general population. Fibrin, the structural element in a clot, is derived from fibrinogen by activation of thrombin. An abnormal fibrin gel structure has been demonstrated in patients with myocardial infarction and in diabetic patients during poor metabolic control. In the present study the properties of fibrin gel structure were investigated in 20 patients with insulin-dependent diabetes mellitus (IDDM): 10 patients without (age: 30 +/- 8; diabetes duration: 7 +/- 6 years), and 10 patients (age: 44 +/- 7; diabetes duration: 27 +/- 9 years) with microangiopathy. Fifteen healthy subjects served as controls (age: 40 +/- 8 years). The glycosylated haemoglobin level (HbA1c) was elevated (p < 0.001) in the patients: 6.5 +/- 1.5% in diabetic patients without, and 7.1 +/- 1.0% in diabetic patients with microangiopathy. C-reactive protein and plasma fibrinogen were similar as compared to healthy control subjects. The properties of the fibrin gel structure; i.e. the permeability coefficient (Ks) and the fibre mass length ratio (mu) formed in recalcified plasma on addition of thrombin were investigated. Ks was decreased in the diabetic patients, with (6.5 +/- 2.0 cm2; p < 0.01) and without microangiopathy (6.5 +/- 2.7 cm2; p < 0.05), as compared to healthy subjects (10.0 +/- 3.4 cm2), while mu was not significantly (p = 0.14) altered. The results indicate a lower fibrin gel porosity in patients with IDDM, despite normal plasma fibrinogen and irrespective of microangiopathy. The abnormal fibrin gel structure may be due to an increased glycosylation of the fibrin (-ogen) molecule caused by long-term hyperglycaemia and may be of importance for the development of angiopathy in diabetic patients.

Adult↗
PubMed1996

Low molecular mass heparin instead of unfractionated heparin during infrainguinal bypass surgery.

OBJECTIVES: To test whether low molecular mass heparin (LMMH) is comparable to unfractionated heparin (UFH) as an anticoagulant during infrainguinal bypass surgery and to investigate laboratory evidence of hypercoagulation in patients undergoing infrainguinal bypass surgery. MATERIALS AND METHODS: Eighteen patients were randomised to receive either UFH or LMMH (70 anti-Xa units/kg b.w.). Soluble fibrin, measured as fibrin monomers (FM) and fibrinopeptide A (FPA), were measured in blood from the femoral vein before, during and after release of the occluding clamps during surgery. In addition, fibrinogen prothrombin complex, thrombin-antithrombin complex, platelets and antithrombin were measured before surgery. Heparin levels (Anti Xa) were measured during surgery. RESULTS: Increased levels of fibrinogen, FPA, thrombin antithrombin complex and FM were recorded prior to surgery. During surgery no further increase was noted. The anti Xa levels were slightly higher in patients with LMMH than in patients receiving UFH. Levels of FM were significantly lower in patients receiving LMMH. No difference in FPA was noted. A positive correlation between fibrinogen and FPA and FM respectively was recorded. Four patients, two in each group, were reoperated for graft occlusion. One patient in the UFH group required reoperation because of bleeding. CONCLUSIONS: LMMH is comparable to UFH as an anticoagulant during infrainguinal bypass surgery. Variables reflecting hypercoagulability are elevated in this group of patients and are positively correlated to the fibrinogen level. High fibrinogen levels could thus be a risk for perioperative thrombosis.

Aged↗
PubMed1996

Activated platelets and impaired platelet function in intensive care patients analyzed by flow cytometry.

Intensive care patients often have disturbances in their coagulation and fibrinolysis systems, which may result in haemorrhage or disseminated intravascular coagulation (DIC). DIC is a dreaded complication that may develop rapidly and has a high mortality rate. Platelets play a central role in haemostasis and it is thus important to have assays that rapidly can monitor platelet activation and platelet function. We have used flow cytometry to measure platelet activation and function in intensive care patients. Fluorescein labelled chicken antibodies were used to detect platelet bound fibrinogen as these antibodies have advantages over mammalian antibodies in flow cytometry. We found increased levels of circulating activated platelets and microparticles in vivo and impaired platelet function after stimulation in vitro. The two patients with the highest percentage of microparticles died shortly after blood sampling.

Disseminated Intravascular Coagulation↗
PubMed1995

Effects of hemodialysis and long-term erythropoietin treatment on protein C, and on free and total protein S.

We studied 37 hemodialysis patients during hemodialysis in order to assess the effects of dialysis on endogenous plasma coagulation inhibitors (antithrombin III, protein C, free and total protein S). The patients were examined prior to erythropoietin (EPO) treatment, upon reaching target hemoglobin (Hb) and after 3 months at steady state Hb levels. The levels of protein C increased significantly during dialysis. However, EPO treatment did not affect the levels of any of the endogenous coagulation inhibitors, either upon reaching target Hb or after 3 months of steady state Hb. The sequence of change during dialysis of protein C, free and total protein S was constant when comparing respective patterns prior to EPO treatment to those at target Hb and steady state Hb respectively. In conclusion, hemodialysis seems to activate synthesis of endogenous coagulation while partial correction of anaemia with EPO does not affect the levels of these inhibitors.

Adult↗
PubMed1995

Treatment with recombinant human erythropoietin induces a moderate rise in hematocrit and thrombin antithrombin in healthy subjects.

Recombinant human erythropoietin (EPO) therapy in uremic patients raises the hematocrit (Hct) and increases physical exercise capacity (1,2) and quality of life (1). In general, partial correction of anemia to subnormal levels in uremic patients has proven to be safe with few serious adverse effects apart from hypertension (3). Ever since the advent of EPO the prospect of abuse of the hormone by sportsmen has been subject to scrutiny. Both maximal oxygen uptake and endurance capacity are increased after EPO treatment in healthy subjects (4). Moreover, EPO treatment in healthy subjects has been found to induce an accentuated blood pressure reaction after submaximal exercise (5). Previous studies have shown that extreme physical exertion can predispose to an increased intravascular coagulation (6). Moreover there is a significantly increased risk of thrombosis in patients with myeloproliferative disorders, particularly in polycythemia vera (7). An enhanced risk of cardiovascular events may therefore arise should sportsmen abuse EPO as a blood doping agent. The aim of this study was to examine the effects of an EPO-induced increase in Hct on the coagulation system in healthy subjects.

Adult↗
PubMed1995

Studies on phospholipid antibodies, APC-resistance and associated mutation in the coagulation factor V gene.

The influence of antibodies against phospholipids (PLa) on APC response was investigated in 155 women with a history of thromboembolism and/or repeated foetal losses. PLa were determined as antibodies against cardiolipin (CLa) and phosphatidyl serine (PSa) and as lupus anticoagulant (LA) tested by dilute Russell's Viper Venom time and by the Textarin/Ecarin ratio. APC-response was studied by a clotting (aPTT-based) and by an amidolytic (factor IXa-X-based) assay. A reduced response to APC (APC-resistance) was found in 49% of 65 PLa-positive and in 13% of 90 PLa-negative samples (chi 2 = 23.9; p < 0.5 x 10(-4)). It was more common in the samples with LA, as compared to CLa+PSa positive (58% vs. 30%, not significant). The presence of the mutation causing Arg506-Gln substitution in coagulation factor V was investigated in 84 samples. The occurrence of the mutation in APC-resistant patients with CLa+PSa or with LA in one of the two assays was similar to those without PLa (84% and 100%, respectively). In the absence of APC resistance, the occurrence of the mutation was similar in the samples with and without PLa (14% vs. 11%). Samples with LA, determined by both tests used, comprised a special group where the frequency of the mutation in the APC resistant samples was significantly reduced (p < 0.01). In the latter samples, the pathogenic mechanism of APC resistance may be connected with the influence on phospholipid membranes.

Abortion, Habitual↗
PubMed1995

Pathologic fibrin formation and cold-induced clotting of membrane oxygenators during cardiopulmonary bypass.

In 1,800 patients undergoing cardiac surgery over a 2-year period, 11 incidents of abnormal inlet pressure elevations occurred before the membrane oxygenators. In 3 patients, the oxygenators had to be changed during cardiopulmonary bypass. This complication was found to be caused by fibrin formation possibly secondary to precipitation of fibrinogen with other coagulation factors in the heat exchangers of the oxygenators during the cooling phase. Large amounts of fibrin were demonstrated in the heat exchanger of the oxygenators. After careful washing of the apparatus, plasmin was added and fibrin was detected by measuring D-dimer levels. In heat exchangers from uneventful operations, only trace amounts of fibrin were found. Because there were no cold agglutinins demonstrated in the patients before surgery, cryoprecipitation studies were performed soon after surgery. When the patients' plasma samples were studied at different temperatures, from 37 degrees C down to 3 degrees C, cryoprecipitates or a gel (in 1 patient only) were formed. This indicated that there might be something abnormal with regard to fibrinogen-fibrin formation. The study patients were therefore investigated after the acute phase of the operation had ended for various coagulation factors, as well as for fibrin gel network characteristics. The results were compared with those of a control group (n = 10) with uneventful operations. There were no differences between the groups with regard to levels of coagulation factors VII and VIII and von Willebrand factor, although they were increased in both groups. The mean levels of coagulation inhibitors, antithrombin and Protein S, were slightly lower in the study patients. All of these patients had a highly pathologic, ie, tight fibrin gel network, except for the patient in whose sample a gel formed, despite being treated with aspirin or oral anticoagulants. The network was also tighter in some of the controls (v middle-aged reference individuals), although it was significantly tighter in the patients. It is concluded that some individuals who have an increased tendency to form tighter fibrin gel networks might be at increased risk for a severe complication during cardiac surgery performed under hypothermia.

Aged↗
PubMed1995

Long-term effects of erythropoietin treatment on the coagulation system during standardized hemodialysis.

We studied 37 hemodialysis patients, treated with erythropoietin (EPO), prior to and upon reaching target Hb and after 3 months at steady state Hb levels. Our aim was to analyze the effects of EPO on markers of all stages of coagulation and anticoagulation during a standardized hemodialysis procedure upon reaching target Hb as well as long term effects of a stable Hb. The Hb rose from 82 +/- 9 to 111 +/- 12 g/L at target Hb (p < 0.0001) and was 108 +/- 15 g/L after 3 months of steady state. The heparin dose was individually titrated, using a whole blood activated coagulation time method (WBACT) and kept constant during the first phase of the study. The titrated heparin dose increased significantly at target Hb and this increase persisted after 3 months at steady state. Accordingly the increase in WBACT decreased significantly. There was a significant increase in platelets at target Hb and this increase persisted at steady state. beta-thromboglobulin increased significantly at target Hb and this increase persisted after 3 months at steady state. Platelet factor 4 was unchanged throughout the study period. Inhibitors of plasma coagulation: AT III, protein C and total and free protein S were unchanged throughout the study period. There was no changes in indicators of intravascular coagulation: TAT, fibrin monomers or FPA throughout the study period. There was no FPA generation during dialysis. The residual blood volume in the dialyzer was unaffected throughout the study period. There was a significant decrease in D-dimers at target Hb and after 3 months at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Thrombotic risk factors and oral contraception.

Eighty-one women with a history of thrombosis were classified into three groups: group I (n = 29), women in whom thrombosis developed during oral contraception; group II (n = 33), those who used oral contraceptives (OC) without complications but experienced vascular occlusion in other risk situations; group III (n = 19), women who never used OC. The level of antibodies to anionic phospholipids (PLa), a response to activated protein C (APC), and the presence for the mutation in the coagulation factor V gene causing APC resistance were studied. In the studied groups, APC resistance was present in 14% to 42% of patients. PLa were elevated in about half of APC-resistant patients. The incidence of APC resistance correlated with the recurrency of the thrombotic events within the groups. In most cases it was tightly connected to the mutation in the factor V gene. Women in whom thrombosis developed while they were taking OC (group I) differed from the others, having a remarkable disagreement between the lowest incidence of APC resistance and a relatively increased number of the mutation (14% vs 38%, p < 0.025). This finding suggested that the APC response is flexible. An influence of OC that predisposes a reduction in APC response is discussed.

Adolescent↗
PubMed1995

Stimulated Glanzmann's thrombasthenia platelets produced microvesicles. Microvesiculation correlates better to exposure of procoagulant surface than to activation of GPIIb-IIIa.

The mechanism of formation of platelet-derived microvesicles remains controversial. The aim of the present work was to study the formation of microvesicles in view of a possible involvement of the GPIIb-IIIa complex, and of exposure of negatively charged phospholipids as procoagulant material on the platelet surface. This was studied in blood from three Glanzmann's thrombasthenia patients lacking GPIIb-IIIa and healthy blood donors. MAb FN52 against CD9 which activates the complement system and produces microvesicles due to a membrane permeabilization, ADP (9.37 microM), and the thrombin receptor agonist peptide SFLLRN (100 microM) that activates platelets via G-proteins were used as inducers. In a series of experiments platelets were also preincubated with PGE1 (20 microM). The number of liberated microvesicles, as per cent of the total number of particles (including platelets), was measured using flow cytometry with FITC conjugated antibodies against GPIIIa or GPIb. Activation of GPIIb-IIIa was detected as binding of PAC-1, and exposure of aminophospholipids as binding of annexin V. With normal donors, activation of the complement system induced a reversible PAC-1 binding during shape change. A massive binding of annexin V was seen during shape change as an irreversible process, as well as formation of large numbers of microvesicles (60.6 +/- 2.7%) which continued after reversal of the PAC-1 binding. Preincubation with PGE1 did not prevent binding of annexin V, nor formation of microvesicles (49.5 +/- 2.7%), but abolished shape change and PAC-1 binding after complement activation. Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation). Stimulation of normal platelets with 100 microM SFLLRN gave 16.3 +/- 1.2% microvesicles, and strong PAC-1 and annexin V binding. After preincubation with PGE1 neither PAC-1 nor annexin V binding, nor any significant amount of microvesicles could be detected. SFLLRN activation of the thrombasthenic platelets produced a small but significant number of microvesicles (6.4 +/- 0.8%). Incubation of thrombasthenic platelets with SFLLRN after preincubation with PGE1, gave results identical to those of normal platelets. ADP activation of normal platelets gave PAC-1 binding, but no significant annexin V labelling, nor production of microvesicles. Thus, different inducers of the shedding of microvesicles seem to act by different mechanisms. For all inducers there was a strong correlation between the exposure of procoagulant surface and formation of microvesicles, suggesting that the mechanism of microvesicle formation is linked to the exposure of aminophospholipids. The results also show that the GPIIb-IIIa complex is not required for formation of microvesicles after activation of the complement system, but seems to be of importance, but not absolutely required, after stimulation with SFLLRN.

Adult↗
PubMed1994

Partial expression of GP Ib measured by flow cytometry in two patients with Bernard-Soulier syndrome.

Bernard-Soulier syndrome is a rare, congenital bleeding disorder caused by absent or defective GP Ib platelet membrane receptor for the von Willebrand factor (vWF). We studied two brothers with moderate bleeding symptoms. Bleeding time was prolonged and ristocetin-induced platelet aggregation was absent. Flow cytometric analysis showed that both boys had a subnormal expression of GP Ib. One antibody used (AN51) was bound only to 30% of the platelets and at a subnormal density. A second antibody (SZ2) also bound at a subnormal density but a normal fraction of the platelets were immunoreactive. Ristocetin stimulation of the patients' platelets in the presence of plasma resulted in a low binding of vWF, about 30% of healthy controls. On the other hand the expression of GP IIb/IIIa on the platelet membrane appeared to be supernormal even when the increased platelet size was taken into account as shown by the ratio between the density of GP IIIa and CD 9 structures. We conclude that these brothers have a variant of the Bernard-Soulier syndrome with a low expression of a GP Ib receptor.

Bernard-Soulier Syndrome↗
PubMed1994

Coagulation inhibition capacities of low-molecular mass and unfractionated heparin, as determined by thrombin generation.

The common unfractionated heparin preparations (UFH) accelerate inhibition of most of the enzymes in the coagulation cascade, while low-molecular mass heparin (LMMH) mainly accelerates inhibition of activated coagulation factor X (FXa). The present study addresses the question of whether LMMH may be a weaker anticoagulant than UFH when the two preparations are added to plasma with equal FXa inhibitory activities. Normal and coagulation factor VIII (FVIII)-deficient plasma was used. Thrombin generation was determined by assaying the formation of the thrombin-antithrombin complexes (TAT) and of fibrinopeptide A (FPA), two parameters that showed a strong positive correlation. At a heparin concentration of 0.5 or 1.0 FXa-inhibiting IU/ml, the formation of TAT and FPA was substantial and always much more increased with LMMH than with UFH. At 4.0 FXa-inhibiting IU/ml, no FPA was generated, but traces of thrombin were. In recalcified FVIII-deficient plasma (one of the batches containing FVIII antibodies), more TAT was formed with 0.1 FXa-inhibiting IU/ml LMMH than with UFH with the same FXa-inhibiting activity. It is concluded that LMMH is a weaker anticoagulant than UFH, partly because of a poor thrombin inhibition capacity which facilitates acceleration of coagulation by FVIII activation and partly because of a poor inhibition of enzymes preceding the prothrombinase stage, both mechanisms leading to increased enzymatic activity above the prothrombin stage. As judged from the higher degree of thrombin generation with LMMH than with UFH, there is no support for the assumption that LMMH is as good an antithrombotic agent as UFH is, without reducing the haemostatic capacity as much as UFH does.

Antithrombin III↗
PubMed1994

Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin.

Twenty-four patients with von Willebrand disease type III were screened for mutations in the von Willebrand factor (VWF) gene using the PCR technique, followed by direct sequencing. More than 250 kb of genomic DNA were sequenced, including the promoter and coding regions (52 exons) of the VWF gene from 24 patients. In addition to the previously reported mutations of a single cytosine deletion in exon 18 and the nonsense mutations in exons 28, 32, and 45, nine new mutations were detected: two nonsense mutations in exons 15 and 16, one allele with a thymidine insertion in exon 14, one allele with a cytosine insertion in exon 28, one 20-bp deletion in exon 15, one mutation in the donor splice site of exon 43, and three missense mutations in exons 28, 49, and 51. Forty-two mutant chromosomes were identified (42/48); 11 probands are homozygous for the mutations, and 8 are compound heterozygous. In addition, a new subfamily of the Alu sequence in the promoter region and 10 new polymorphisms were identified.

Alleles↗
PubMed1994

A new variant of interaction between phospholipid antibodies and the protein C system.

The influence of 38 IgG fractions with either cardiolipin antibodies only (CLa) or both CLa and lupus anticoagulant activity (LA) on the response to activated protein C (APC) and on the snake venom activation of protein C were investigated. Five of eight IgG fractions with LA activity showed a tendency to reduce the effect of APC in the aPTT method and to simulate the APC-resistance phenomenon. This effect was not observed in IgG fractions without LA activity. The addition of IgG fractions did not decrease enzymatic activation of protein C in normal plasma. No correlation was found between sample protein C activity and CLa level or the extent of clotting time prolongation. These observations suggested that acquired resistance to APC in the presence of some types of phospholipid antibodies may be a cause of thrombophilia in such patients.

Adult↗
PubMed1993

SIN-1 partially and RGDS totally counteracts platelet aggregation as assessed in vitro by two independent whole blood methods.

The cyclic GMP stimulant SIN-1 and the GP IIB/IIIA receptor antagonist RGDS were compared with regard to platelet antiaggregatory effects as measured in vitro by filtragometry and by whole blood aggregometry. In filtragometry platelet aggregation is measured as the time to partial occlusion of a filter in the test unit. Beta-thromboglobulin concentrations increased over the filter (p < 0.002) indicating that in filtragometry part of the mechanism of aggregation could be platelet activation across the filter. In whole blood aggregometry platelet aggregation is induced by a chemical stimulant. As tested in blood from healthy volunteers, linear dose-effect relations were found with both methods, for SIN-1 in the 10(-7)-10(-6) M range (p < 0.02, filtragometry and p < 0.05, whole blood aggregometry) and for RGDS in the 10(-5)-10(-4) M range (p < 0.0001, filtragometry and p < 0.02, whole blood aggregometry). At the highest dose RGDS totally counteracted platelet aggregation in both test systems. Maximal SIN-1 platelet antiaggregatory effects were less (p < 0.04, filtragometry and p < 0.01, whole blood aggregometry) than for RGDS. SIN-1 concentrations in the 10(-4) M range had no further antiaggregatory effects. In conclusion, with two principally different methods for the assessment of whole blood platelet aggregation, SIN-1 was found to be a partial antagonist while RGDS a total antagonist.

Amino Acid Sequence↗
PubMed1993

Hemophilia B in a 46,XX female probably caused by non-random X inactivation.

A female whose father had severe hemophilia B was found to have a factor IX activity of about 1%. No chromosomal abnormality could be detected and DNA analysis gave no indications of deletions or mutations of Taq I cleavage sites in the factor IX gene. Analysis of the methylation pattern of locus DXS255 indicates that the expression of hemophilia B in this patient is caused by non-random X inactivation.

Blotting, Southern↗
PubMed1993

Effect of surface-immobilized heparin on the activation of adsorbed factor XII.

Two different heparin surfaces, structurally closely related and of similar negative charge characteristics, were compared with regard to adsorption and activation of coagulation Factor XII (FXII). One surface was prepared by immobilization of unfractioned heparin, which yielded a surface containing both heparin molecules with high and with low affinity for antithrombin (unfractioned [UF] heparin surface). The other surface consisted of a fraction of heparin molecules with low affinity for antithrombin (LA heparin surface) and essentially devoid of antithrombin-binding as well as anticoagulant activity. Both surfaces adsorbed FXII from plasma to a similar extent, and essentially the same quantities of bound factor could be recovered from the surfaces. The two heparin surfaces, however, differed markedly with regard to activation of the adsorbed FXII. On the LA heparin surface, a major portion of the surface-bound FXII was recovered in its enzymatically active form (FXIIa), but only trace amounts of the FXII taken up by the UF heparin surface had undergone activation. When FXII-deficient plasma was used instead of normal plasma, no surface-associated enzyme activity could be recovered on either surface. The presence of free standard heparin or low molecular weight heparin in the plasma exposed to the LA heparin surface did not prevent conversion of FXII to FXIIa.

Adsorption↗