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Biomedical subjects

B Astedt

Publications and source records attributed to B Astedt.

At least 19 recordsLinked to original sources
PubMed1997

Preeclampsia is associated with a reduced response to activated protein C.

OBJECTIVE: Resistance to activated protein C is an inherited mutation of the coagulation factor V gene, a major factor predisposing to thromboembolic events. The purpose of this study was to investigate the occurrence of heterozygote and homozygote activated protein C resistance in women with preeclampsia. STUDY DESIGN: Activated protein C resistance and protein C and antithrombin III levels were determined in women (n = 50) with a history of preeclampsia and in controls (50 women with a previous normal pregnancy). The mutation of the factor V gene was analyzed. RESULTS: Activated protein C resistance was found in 22% of women with previous preeclampsia compared with 10% among controls. Two women in the previous preeclampsia group had a homozygote mutation of factor V; the others were heterozygous. There was a significant difference in the activated protein C ratio between women with previous preeclampsia and the control group, 2.6 +/- 0.4 versus 3.1 +/- 0.5 (p = 0.04). None of the women had protein C or antithrombin III deficiency. CONCLUSION: The results indicate that activated protein C resistance may be a contributory factor in the pathogenesis of preeclampsia.

Antithrombin III↗
PubMed1997

Plasminogen activators and plasminogen activator inhibitors in plasma of premature and term newborns.

OBJECTIVE: To compare the plasminogen activators (tPA, uPA) and their inhibitors (PAI-1, PAI-2) at different gestational ages, related to levels in women at term and non-pregnant women. METHODS: Blood samples were obtained by puncture of the umbilical cord vein, in gestational weeks 39-40 (n = 21), 30-32 (n = 15), and 27-29 (n = 9). Analyses of PA and PAI antigen concentrations and of PAI-1 activity were performed. RESULTS: The mean tPA antigen level in term newborn infants was 14.5 micrograms/l compared to the premature newborns (7.0 micrograms/l), women at term (7.5 micrograms/l) and non-pregnant women (2.3 micrograms/l). PAI-1 activity and PAI-2 antigen concentrations were also higher in term newborn than in premature infants. CONCLUSIONS: The plasma levels of the plasminogen activators and inhibitors are higher in term newborn compared with premature newborn infants, reflecting maturation of protein synthesis.

Female↗
PubMed1996

Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease.

OBJECTIVES: To assess the effect of estrogen replacement therapy on hemostatic risk factors for cardiovascular disease (CVD) in postmenopausal women during 2 years of treatment. METHODS: In an open prospective study, patients (n = 42) were investigated before and during 2 years of treatment, and compared to an untreated postmenopausal control group (n = 18) followed during the same period, healthy premenopausal women (n = 20) being included as a reference group for premenopausal values. The patients underwent treatment with transdermal 17 beta-estradiol (E2) (50 micrograms/24 h), oral medroxyprogesterone acetate (5 mg/day) being added for 12 days every second month. RESULTS: After 2 years of treatment there was a significant increase in t-PA antigen (P = 0.01) and a significant decrease in F VII antigen (P = 0.01). PAI-1 antigen concentrations decreased slightly. Fibrinogen concentrations were already significantly decreased at 3-month follow-up (P = 0.01), and were still low after 2 years. By contrast, at 2-year follow-up the postmenopausal control group manifested significant increases in F VII and PAI-1 antigen and slight increases in fibrinogen, which resulted in significant differences between patients and controls. Regression analysis showed the increase in the serum estradiol concentrations to be inversely correlated to the decreases in the plasma concentrations of F VII antigen (r = -0.34, P = 0.001) and fibrinogen (r = -0.35, P = 0.001). There were no changes in AT III or protein C in any group. CONCLUSIONS: The increase in serum estradiol concentrations due to replacement therapy did not adversely affect the studied components of the fibrinolytic and protein C defense system against thrombosis, and resulted in beneficial decreases in F VII antigen and fibrinogen. These findings may help to explain the beneficial effects of estrogen replacement therapy in terms of protection from cardiovascular disease.

Administration, Cutaneous↗
PubMed1996

Aggravation of gingival inflammatory symptoms during pregnancy associated with the concentration of plasminogen activator inhibitor type 2 (PAI-2) in gingival fluid.

Gingival inflammatory symptoms are aggravated during pregnancy. In vitro studies suggest a hormonal influence on the plasminogen activator inhibitor type 2 (PAI-2), and a disturbed balance of the fibrinolytic system could help to explain pregnancy gingivitis. Gingival crevicular fluid (GCF) was sampled in 14 women in pregnant and post-pregnant states. The gingival condition was assessed by the gingival index of Løe & Silness (GI) and the amount of bacterial plaque by the plaque index of Silness & Løe (PI). The ratio of sites with gingivitis to sites with bacterial plaque was calculated (G/P-ratio). Antigen levels of tissue plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitors type 1 (PAI-1) and PAI-2 in GCF were determined with ELISAs and 17 beta-oestradiol and progesterone in serum with radioimmunoassays. For each individual the differences (delta) in hormone levels and PAs and PAIs between pregnancy and post-pregnancy were calculated. Based on differences in G/P-ratio between pregnancy and post-pregnancy, subgrouping was done into a high-reacting and a low-reacting group. For the total group, the mean G/P-ratio was 2.0 during and 1.2 after pregnancy (p = 0.064). A statistically significant correlation between delta progesterone and delta PAI-2 was noted: the higher delta progesterone, the lower delta PAI-2. No other significant correlations between hormone levels and components of the fibrinolytic system were found. For the total group of women, the concentrations of PAI-2, PAI-1 and t-PA were significantly higher during than after pregnancy. The individuals in the high-reacting group, however, showed a lower or unchanged production of PAI-2 during pregnancy, while those in the low-reacting group showed a greatly increased production. The lower inhibitory capacity in terms of a low production of PAI-2 during pregnancy in women with a higher inflammatory reaction indicates that the components of the fibrinolytic system may be involved in the development of pregnancy gingivitis and implies that PAI-2 serves as an inhibitor of importance for tissue proteolysis. The present finding contributes to the explanation of pregnancy gingivitis.

Adult↗
PubMed1996

Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients.

BACKGROUND AND PURPOSE: Abnormal endogenous fibrinolytic activity may be a risk factor for stroke. Since the possible variation of tissue-type plasminogen activator (TPA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen concentrations over time after stroke has been rarely studied, it was examined in plasma from stroke patients in the acute and convalescent phases of the disease and in a control group. METHODS: Plasma concentrations of TPA and PAI-1 were determined in 135 stroke patients and in 77 control subjects. All but 4 patients were examined within 7 days after stroke onset, and 32 patients and 18 control subjects were reexamined 2 to 4 years later. RESULTS: In the acute phase, stroke patients had significantly higher TPA (median, 10 micrograms/L) and PAI-1 (median, 14 micrograms/L) antigen concentrations, compared with control subjects (median values, 6 micrograms/L [P = .0001] and 8 micrograms/L [P < .01], respectively); TPA levels were higher in both the cerebral infarction (n = 122) and cerebral hemorrhage (n = 12) subgroups, whereas PAI-1 levels were higher in the cerebral infarction subgroup only. Stepwise logistic regression analysis (with correction for age, sex, history of hypertension, diabetes mellitus, and heart disease) showed TPA antigen level to be an independent discriminator between the cerebral infarction subgroup and control subjects (P = .0001), whereas the corresponding difference for PAI-1 antigen levels just failed to reach significance (P = .05). TPA antigen levels were correlated with concentrations of serum cholesterol (Spearman's rho = 0.15; P < .05), serum triglyceride (rho = 0.33; P = .0001), and plasma homocysteine (rho = 0.19; P < .01). PAI-1 antigen levels were correlated with serum triglyceride levels only (rho = 0.41; P = .0001). At reexamination after 2 to 4 years, neither TPA nor PAI-1 levels had changed significantly from the baseline values. CONCLUSIONS: In stroke patients, high TPA antigen concentrations may indicate an activation of the fibrinolytic system or may be due to a delayed clearance of TPA complexed with inhibitors. High PAI-1 antigen concentrations in patients with cerebral infarction represent increased fibrinolytic inhibition. The findings in this longitudinal study suggest that TPA and PAI-1 antigen concentrations both differ little between the acute and convalescent phases after stroke.

Acute Disease↗
PubMed1996

On the affinity between the plasminogen activator inhibitor type 2 and apolipoprotein A1.

The plasminogen activator inhibitor type 2 (PAI-2) is present in its high molecular weight, glycosylated form in pregnancy plasma. When the protein was purified from retroplacental blood by immunoaffinity chromatography on a PAI-2 antibody column and the retained material was further fractionated by gel filtration chromatography, it was always contaminated by apolipoprotein A1, the latter protein being identified by its N-terminal sequence, molecular weight in SDS-PAGE and immunological properties. The co-purification of the two proteins seemed to indicate a strong affinity between them, suggesting apolipoprotein A1 to be a carrier protein for this PAI-2 form. Further investigation to check this hypothesis showed that the binding of apolipoprotein A1 to the immunoaffinity support was PAI-2-independent and caused by a general surface affinity. This finding was corroborated by a study of the microtitre plate binding properties of the proteins. Pure, high molecular weight PAI 2 did not bind to apolipoprotein A1-coated wells, but the latter protein bound to coated as well as to uncoated wells. Thus, there is no evidence for a specific binding between the two proteins.

Apolipoprotein A-I↗
PubMed1995

The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice.

Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role. An increased expression of urokinase type plasminogen activator (uPA) is of significance for degradation of the extracellular tumor matrix, facilitating invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We report here experiments on a uPA-producing human prostate xenograft (DU 145) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity. DU 145 cells were inoculated s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the non-treated mice, resulting in 64% lower final tumor weight. In addition, uPA-antigen levels in the membrane fractions of DU 145 tumors from p-aminobenzamidine-treated mice were found to be decreased by 59%. We also show that p-aminobenzamidine has an anti-proliferative effect in cell culture at low cell number, correlating with a dose-dependent decrease in uPA production. In conclusion, we show that a low-molecular-weight uPA-inhibitor, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-producing tumor.

Adenocarcinoma↗
PubMed1995

Reduction of menstrual blood loss in women suffering from idiopathic menorrhagia with a novel antifibrinolytic drug (Kabi 2161).

OBJECTIVE: To compare the effect of Kabi 2161 (a prodrug of tranexamic acid) and placebo on the reduction of menstrual blood loss in women suffering from idiopathic menorrhagia and to evaluate tolerance and effectiveness in a two-dose regimen. DESIGN: A randomised, double blind parallel group study using double dummy technique. SETTING: The departments of gynaecology at three medical centres in Sweden. SUBJECTS: Ninety-one outpatients visiting the gynaecological clinics from March 1991 to May 1992 were randomised into the study; 68 women fulfilled the study. INTERVENTIONS: Two run-in cycles, followed by administrations of Kabi 2161 (600 mg) tablets (1 four times daily or 2 twice daily) or placebo for the first five days of three menstrual cycles. MAIN OUTCOME MEASURES: Objective measurement of the change in menstrual blood loss during the treatment periods compared with menstrual blood loss during the run-in periods. RESULTS: A statistically significant reduction of menstrual blood loss was found for each treatment group, compared with the placebo group (P < 0.001). The mean reduction with 95% confidence interval (CI) was 33% (24-40) in the group treated with 1 four times daily and 41% (33-49) in the group treated 2 twice daily. The difference between the treated groups in reduction of menstrual blood loss is not significant. No significant differences were found in the frequencies of reported unwanted events during run-in and during treatment between the different treatment groups. There were also no significant differences between the treatment groups and the placebo group. CONCLUSION: Kabi 2161 in a dosage of 2.4 g per day gave a statistically significant reduction in objectively measured menstrual blood loss in a two (41%) as well as in a four (33%) dosage regimen compared with placebo. Frequency of unwanted events did not differ from those during run-in or from those in the placebo group. The optimal daily dosage needs to be further evaluated in a dose titration study.

Adult↗
PubMed1995

Antenatal drugs affecting vitamin K status of the fetus and the newborn.

Coumarin derivatives and anticonvulsants administered during pregnancy enter the fetal circulation, interfering with the action of vitamin K. Vitamin K plays a crucial part in the gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors prothrombin, FVII, FIX, and FX. Other vitamin K-dependent proteins in the coagulation cascade are protein C and protein S. Vitamin K-dependent bone proteins are osteocalcin and gamma-carboxyglutamate matrix protein. Administration of coumarol derivatives results in under carboxylation of the vitamin K-dependent proteins. Anticoagulation therapy with warfarin is followed by an increased risk of embryopathy, which has been shown to be greatest between gestational weeks 6 and 12. Administration of warfarin is also followed by an increased risk both of fetal intraventricular hemorrhage, and of cerebral microbleedings, which may result in microencephaly and mental retardation. Treatment with coumarol derivatives should therefore be avoided during pregnancy, even in pregnant women with artificial heart valves, and replaced by heparin. Hemorrhage in the newborn related to the use of anticonvulsant drugs during pregnancy occurs very early within the first 24 hours, probably due to increased degradation of vitamin K. Transplacental administration of vitamin K has been shown to prevent neonatal hemorrhage induced by maternal anticonvulsant therapy. Prophylactic administration of vitamin K, especially by intramuscular injection, has been reported to be associated with an increased risk of childhood cancer. However, subsequent extensive studies have yielded no evidence of any relationship between prophylactic vitamin K administration and the occurrence of childhood cancer.

Abnormalities, Drug-Induced↗
PubMed1994

Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer.

We quantitated urokinase and tissue plasminogen activator (u-PA, t-PA), plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2), and fibrinolytic activity in peripheral blood (PB), tumour blood (TB), peritoneal/ascitic fluid (PAF) and cystic fluid (CF) from 104 patients with benign and 36 patients with malignant ovarian tumours, and in peripheral blood from 62 healthy controls. PB levels of u-PA were higher in patients with benign and malignant tumours than in controls. High concentrations of u-PA were found in CF, but not in TB, suggesting that u-PA is released by the tumour tissue, but not by the tumour vasculature. PB levels of t-PA were higher in both tumour groups than in controls. Increased levels of t-PA were found in TB, but not in CF, indicating that t-PA is released by the tumour vasculature, but not by the tumour tissue. PB levels of PAI-1 were higher in patients with both benign and malignant tumours than in controls. High levels of PAI-1 were present in both TB and CF from malignant tumours, suggesting that PAI-1 is released from the tumour vasculature as well as the tumour tissue. Elevated concentrations of PAI-2 were found in CF, but not in TB, indicating release from the tumour tissue, but not from the vasculature. High levels of t-PA, PAI-1 and PAI-2 were found in PAF of malignant tumours, and resorption from this compartment may explain elevated PB levels in patients with ascites. None of the PAs/PAIs proved useful as a PB marker for detection of early stage ovarian cancer. However, an index based on PAF levels of t-PA and PAI-1 discriminated between malignant and benign ovarian cysts in the absence of ascites. In addition, our study stresses the importance of including patients with benign tumours as well as healthy controls when markers for malignant tumours are evaluated.

Ascitic Fluid↗
PubMed1994

Plasminogen activator of urokinase type and its inhibitor of placental type in hypertensive pregnancies and in intrauterine growth retardation: possible markers of placental function.

OBJECTIVE: Our purpose was to study the plasma concentrations of the plasminogen activator of urokinase type and its specific inhibitor of placental type in pregnancies complicated by hypertension or fetal growth retardation. STUDY DESIGN: Consecutive patients with pregnancy-induced hypertension (n = 17), mild preeclampsia (n = 17), severe preeclampsia (n = 19), and intrauterine growth retardation (n = 19) were studied. Blood samples were obtained just before delivery (mean 2 days). Women with normal pregnancies (n = 40), longitudinally followed between the tenth and fortieth gestational weeks, served as a control group. RESULTS: The plasma concentrations of the urokinase type antigen were significantly lower in women with severe preeclampsia or intrauterine growth retardation than those in women with normal pregnancies (p < 0.001). In all four groups with complicated pregnancies the antigen concentrations of the urokinase type and its inhibitor were significantly correlated with both placental weight and birth weight. CONCLUSIONS: The plasma concentration of the urokinase type antigen would appear to reflect placental function, and both the antigen and its inhibitor concentrations are correlated with placental and fetal growth.

Birth Weight↗
PubMed1994

Renal function and urinary urokinase in hypertensive and diabetic pregnancies.

Urokinase (u-PA) dissolves and removes fibrin deposits in the renal secretory pathways in various renal diseases. During pregnancy nephropathy creates a problem in preeclampsia and diabetes, but the underlying mechanism of glomerular damage is different. Preeclamptic nephropathy is characterized as 'glomerular endotheliosis' with hypertrophy of the intracapillary cells, and diabetic nephropathy as 'glomerulosclerosis' with hyaline deposits. The role of fibrin deposition for the etiology of renal damage in preeclampsia is controversial. Changes of the urinary secretion of u-PA may reflect the type of glomerular damage. Our hypotheses were that renal insufficiency is associated with a low u-PA activity in both conditions, and that severe disease is parallel to declining concentrations of u-PA. We compared the glomerular filtration rate, S-Creatinine and S-Urate with urinary u-PA excretion in 24 hypertensive and 20 diabetic pregnant women. In diabetic patients, a low u-PA concentrations was associated with an impaired renal function. In hypertensive pregnancy, the u-PA excretion did not reflect the severity of the hypertensive disease or renal function. No association was found between u-PA excretion and renal function post partum in any group. We conclude that renal urokinase activity plays a role for renal function in diabetic but not in hypertensive pregnancy.

Female↗
PubMed1993

Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications.

Tranexamic acid (AMCA) is an inhibitor of fibrinolysis used to treat fibrinolytic bleeding (e.g., menorrhagia and gastro-intestinal haemorrhage), and to prevent bleeding at surgery, in cases of abruptio placentae and general haemorrhage. As AMCA stabilises preformed clots and prolongs their dissolution, it has been debated whether treatment with AMCA might predispose to thrombosis by depressing the fibrinolytic system. Pregnant women constitute a group with low fibrinolytic capacity and an increased frequency of thrombosis further increased after Caesarean section, and are thus more likely to be susceptible to antifibrinolytic therapy. We therefore carried out a retrospective analysis of the case records of 2,102 patients with various bleeding disorders during pregnancy. Of the 256 patients treated with AMCA (mean duration of treatment, 46 days), 169 were delivered by Caesarean section. Of the remaining 1,846 patients (i.e., controls), 443 were delivered by Caesarean section. The relationship between the use of AMCA and the occurrence of thrombo-embolism was calculated with 95% confidence limits. Of the AMCA treated group (n = 256), two patients--one of whom belonged to the Caesarean section subgroup (n = 168)--had pulmonary embolism. Of the controls (n = 1,846), three patients had deep vein thrombosis and one had pulmonary embolism, all four cases belonging to the Caesarean section subgroup (n = 443). Thus, the findings in this high risk group of women with complicated pregnancies, frequently entailing delivery by Caesarean section, provided no evidence of any thrombogenic effect of AMCA.

Abruptio Placentae↗
PubMed1993

Can the birth of a large infant predict risk for atherosclerotic vascular disease in the mother?

We have previously demonstrated that women who had given birth to large infants had a six-fold increased risk of developing Type 2 (non-insulin-dependent) diabetes mellitus compared with a control group matched for age and parity. However, the patients were extremely obese which explained, in part, the increased risk. In the present investigation we studied whether the delivery of large infants correlated with risk factors for atherosclerotic vascular disease other than obesity and diabetes, and therefore could serve as early markers for syndrome X. The study consisted of 73 women who 20-27 years earlier had given birth to large infants weighing 4,500 g or more. Another group of 73 women matched for age, parity and BMI who had delivered infants weighing less than 4,500 g within a 3-month period served as a control group. Of these 73 patient/control pairs, 48 (66%) were able to participate in the investigation. Mean age was 52.2 years (range 40-66 years). No differences were noted for family history of diabetes and medication prescribed for vascular disease between the groups. An oral glucose tolerance test was performed and glucose, insulin and C-peptide at 0 and 2 h were estimated. Triglycerides, cholesterol, LDL and HDL cholesterol were analysed at baseline. We found no tendency towards hyperinsulinaemia and hyperglycaemia in the patients and both groups had the same relative increase in levels of insulin and C-peptide. No difference between the groups regarding manifest symptoms of vascular disease, either in blood pressure or in proteinuria were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Passage of the menopause is followed by haemostatic changes.

The passage of the menopause has been reported to be followed by a steadily increasing risk of cardiovascular disease (CVD). Changes in the concentrations of certain coagulation factors and fibrinolytic components are considered risk factors for CVD. We evaluated the differences in some of these variables between a premenopausal group (A) (n = 28) and two postmenopausal groups, one of women less than 18 months past the menopause (B) (n = 28), the other of women more than 18 months past the menopause (C) (n = 21). The variables measured were serum oestradiol content, plasma antithrombin III (AT III) activity, protein C activity and the plasma concentrations of tissue type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI-1) antigen, and fibrinogen. As compared with the premenopausal women (group A), group C showed significantly higher values for AT III and protein C activity and for t-PA and PAI-1 antigen; and group B and C both showed significantly higher fibrinogen concentrations. This probably means that haemostatic balance was maintained in the postmenopausal women, although the increased concentrations of fibrinogen and PAI-1 might constitute risk factors for the development of cardiovascular disease.

Adult↗
PubMed1993

Rebound increase of PAI-1 following local intra-arterial rt-PA infusion, a possible cause of reocclusion.

We studied systemic changes in the plasminogen activating system induced by local intra-arterial infusion of recombinant t-PA (rt-PA) in ten patients with arterial occlusion. The arterial infusion of rt-PA resulted in an immediate increase of t-PA activity and antigen in venous plasma. Concomitantly the plasma was depleted of PAI-1 activity with a moderate decrease of PAI-1 antigen, presumably due to immediate complexing of rt-PA by PAI-1 and gradual elimination of the rt-PA/PAI-1 complex from the circulation. Activation of plasminogen in the circulation was reflected by the occurrence of fibrinogen/fibrin degradation products. This rapid systemic activation of the fibrinolytic system at local intra-arterial administration of rt-PA might be due to the opening of small collaterals or backward flow through open arteries, allowing rt-PA to enter the general circulation. The disappearance of detectable PAI-1 activity during rt-PA infusion was followed by a rebound effect with a significant increase of PAI-1 antigen. As this increase may have contributed to the reocclusion which occurred in four patients, it might be advisable to replace heparin by rt-PA at a lower dosage in the immediate phase following rt-PA infusion.

Aged↗