A family history can display a synergistic effect of atherogenic and prothrombotic risk in pregnancy.
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Adult↗
Biomedical subjects
K Bremme
Publications and source records attributed to K Bremme.
Toxic and essential elements in placentas of Swedish women.
OBJECTIVES: To evaluate interactions between toxic and essential elements in the mother-fetus relationship and possible predictors of trace element concentrations in placenta and cord blood. DESIGN AND METHODS: A group of 106 Swedish women was investigated for concentrations of cadmium, lead, and several essential elements in placenta as well as cadmium, lead, zinc, and selenium in venous blood collected at gestational week (gw) 36 and umbilical cord blood. Relations between these elements and maternal and child's characteristics were examined. RESULTS: The concentrations of cadmium in placenta ranged from 10 to 170 nmol/kg, with the median value (Md) being 46 nmol/kg. Cord blood cadmium (Md of 0.19 nmol/L) was only about 10% of that in maternal blood. Smokers had significantly higher cadmium concentrations in blood (p < 0.001) and placenta (p = 0.001) than non-smokers. The median placental concentration of lead was 26 nmol/kg (range 0-630 nmol/kg). The lead levels in cord blood (Md of 54 nmol/L) were almost the same as in maternal blood. Statistically significant negative associations were found between cord blood lead, on one hand, and child's weight, length, and head circumference, on the other. The placental levels (medians and ranges) of the essential elements (micromol/kg) were 160 (120-280) for zinc, 2.4 (2.0-3.3) for selenium, 15 (10-20) for copper, 0.084 (0.02-0.32) for cobalt, 0.055 (0.03-0.12) for molybdenum, and 1.2 (0. 65-5.1) for manganese, respectively. Several of the essential elements in placenta correlated significantly with each other. Multiparous mothers had significantly lower concentrations of zinc (p = 0.002) and selenium (p = 0.049) in serum as well as zinc (p = 0. 001) and calcium (p = 0.004) in placenta than nulliparous ones. Also, cord blood zinc decreased with parity. CONCLUSIONS: The results showed that lead, but not cadmium crossed easily the placental barrier. There were no negative effects of cadmium on the zinc status. Cord blood lead, on the other hand, was a negative predictor of child's birth weight, length and head circumference, indicating that lead might have negative influence on growth in children even at very low exposure levels. There was a depletion of maternal stores of essential elements with increasing parity.
Cadmium↗
Primary habitual abortions are associated with high frequency of factor V Leiden mutation.
OBJECTIVE: To analyze the prevalence of the mutation G1691A in factor V gene (Leiden mutation), of mutation C677T in the methylenetetrahydrofolate reductase (MTHFR) gene, and of polymorphism in G20210A in the prothrombin gene in women with recurrent abortions; further, to identify a subgroup at higher risk of being carriers of these mutations. DESIGN: Prospective case control evaluation. SETTING: University clinic. PATIENT(S): Eighty-four women with 3 or more consecutive miscarriages were compared with 69 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Polymerase chain reactions were performed to identify the mutations G1691A in factor V and C677T in MTHFR genes and the polymorphism G20210A in the prothrombin gene. RESULT(S): In women with primary habitual abortions, 27.8% carried the Leiden mutation. No difference was observed in the prevalence of mutation C677T in the MTHFR gene or in polymorphism G20210A in the prothrombin gene. CONCLUSION(S): The Leiden mutation may play a considerable role for women having primary recurrent abortions.
Abortion, Habitual↗
Decrease in protein C inhibitor activity and acquired APC resistance during normal pregnancy.
BACKGROUND: Since protein C inhibitor (PCI) inhibits activated protein C (APC) and a number of proteases, one would expect lower concentrations of PCI in a hypercoagulable state due to increased consumption of the inhibitor. Normal pregnancy is associated with a state of activated hemostasis, where response to APC is depressed. We aimed to study whether PCI function varies during normal pregnancy, and assess the relationship between this inhibitor and acquired APC resistance. METHODS: PCI activity in plasma was tested during pregnancy and postpartum in 28 healthy pregnant women without factor V Leiden Arg(506) - Gln mutation and in 14 non-pregnant female controls. The PCI levels determined in the present study was compared to the APC ratio (APC-r), we investigated previously, in the same samples. RESULTS: The levels of PCI in the pregnant group, as compared to that in the control group (4.74 +/- 0.48), gradually decreased from the first to the third trimester, i.e., 3.30 +/- 1.31 microg/mL in week 12 (p < 0.001), 2.66 +/- 1.44 microg/mL in week 20 (p < 0.001), 1.92 +/- 1.18 microg/mL in week 28 (p < 0.001), 1.30 +/- 0.94 microg/mL in week 32 (p < 0.001) and 1.49 +/- 1.12 microg/mL in week 37 (p < 0.001). After delivery, they rose to 5.02 +/- 1.93 microg/mL, similar to that in the controls (p > 0.05). The values of APC-r showed the same tendency during gestation and postpartum. CONCLUSION: With advance of normal pregnancy, decreasing PCI function corresponds to increasing APC resistance, probably due to that activated hemostasis acts as a link connecting the two variables.
Activated Protein C Resistance↗
A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results.
The aim of this study was to design a simple laboratory method that can screen the overall haemostatic potential in plasma (OHPP) when a hyper- or hypocoagulable state is present. A fibrin time curve was made via spectrophotometric registration of fibrin generation and lysis in plasma, to which exogenous thrombin and tissue type plasminogen activator was added. The area under the curve, calculated by the sum of absorbance (ABS-sum), varied in correlation to the concentrations of platelets or purified pro-/anticoagulants: tissue factor, von Willebrand factor, fibrinogen, antithrombin, plasminogen, or plasminogen activator inhibitor type 1. The ABS-sums also changed in positive relation to the haemostatic function investigated in 16 menopausal women and 14 young healthy nonpregnant women (controls). The findings imply that the ABS-sums not only offer a general information about fibrin generation and lysis in vitro, but also reflect the OHPP (i.e., final combined effects of platelet activity, coagulation, and fibrinolysis in vivo). Preliminary results were satisfactory; the levels of OHPP, expressed as the ABS-sums, were higher in normal pregnant women than in the controls, and even higher in preeclamptic patients than in pregnant women with no complications, which corresponds to the different grades of hypercoagulability in the three groups. Moreover, the level of OHPP was considerably lower in an untreated infant with von Willebrand's disease type 3 and in factor VIII- or factor IX-deficient plasma samples.
Adult↗
Clinical evaluation of a solid-phase test for red cell antibody screening of pregnant women.
BACKGROUND: The aims of this study were to evaluate the results of a new solid-phase screening test for detecting atypical red cell (RBC) antibodies in a large number of pregnant women and to compare these results to the clinical outcome of the newborn. STUDY DESIGN AND METHODS: A total of 38,700 infants born in Stockholm were studied retrospectively. Of these infants, 18,500 were born to pregnant women screened with the solid-phase test. Data were collected on all newborns with a positive direct antiglobulin test (DAT) and on infants requiring an exchange transfusion or a blood transfusion. These data were correlated to the screening results for the mothers. RESULTS: Of 409 DAT-positive newborns, a serologic explanation for the positive DAT was found in 349. Three hundred four cases were due to ABO incompatibility between mother and child; 19 of these infants needed an exchange transfusion. Forty-two cases were due to unexpected maternal RBC antibodies; 11 of these infants were given an exchange transfusion. All 11 were identified before birth. Three other infants had DAT-positive tests due to ABO incompatibility and to unexpected maternal RBC antibodies. CONCLUSION: ABO incompatibility is a major indication for exchange transfusion in DAT-positive newborns. There was no evidence that the solid-phase screening test had failed to detect any clinically significant RBC antibodies. Finally, the results of this study do not indicate a need for routine screening of D+ women more than once during each pregnancy.
ABO Blood-Group System↗
Can the laboratory assay of protein C activity assist in monitoring the hemostatic function in pre-eclampsia?
Published reports do not agree about whether protein C activity is non-significantly changed or decreased in a hypercoagulable state induced by pre-eclampsia without hemolysis-elevated liver enzyme/low platelet (HELLP) syndrome. In order to assess the relationship between this anticoagulant and enhanced hemostasis, levels of protein C activity, thrombin-antithrombin complexes, soluble fibrin, fibrin D-dimers and antithrombin were determined in 30 pre-eclampsia patients without the HELLP syndrome, in 22 normal pregnant women in gestational weeks 30-35, and in 13 non-pregnant controls. Levels of thrombin-antithrombin complexes, soluble fibrin and D-dimers increased (P < 0.05) whereas antithrombin decreased (P < 0.05) in patients with pre-eclampsia, compared with normal pregnant women. Levels of protein C did not differ significantly between patients with pre-eclampsia, normal pregnant women and controls (P > 0.05). The 5th and 95th percentiles of protein C levels in normal pregnant women were 0.53 and 1.30 U/ml, respectively; levels between these two values could be considered physiological. When the pre-eclampsia patients were subdivided according to these percentiles, none belonged to the subgroup with protein C < or = 5th percentile; 23% (seven of 30) fell into the subgroup with protein C > or = 95th percentile. Elevated levels of hypercoagulation markers were shown in the groups whose protein C fell within 5th-95th or > or = 95th percentiles (P < 0.05), compared with normal pregnant women. Concentrations of protein C and thrombin-antithrombin complex were significantly correlated (r = 0.69, P > 0.05) in patients with pre-eclampsia. In summary, in subjects with pre-eclampsia without the HELLP syndrome, protein C activity may be similar to that in normal pregnant women. However, such a 'physiological' anticoagulant level in association with the enhanced thrombin generation and fibrin formation does not necessarily reflect a physiological capability of coagulation. Thus, assays of protein C activity might not always assist in monitoring the hemostatic function during pre-eclamptic pregnancy.
Adult↗
Haemostatic, endothelial and lipoprotein parameters and blood pressure levels in women with a history of preeclampsia.
To determine whether perturbations of haemostatic function and lipoprotein metabolism prevail long after preeclampsia and increase the risk of future coronary heart disease (CHD), we conducted a follow-up study in women with (cases, n = 25) or without (controls, n = 24) a history of preeclampsia. Blood samples were taken in the follicular and in the luteal phases of a menstrual cycle. Levels of blood pressure (BP) and proteinuria measured during the index pregnancy were included in the evaluation. Compared to control women who had undergone a normal pregnancy, the formerly preeclamptic patients had higher systolic (p <0.01) and diastolic (p <0.05) BPs and increased plasma levels of von Willebrand factor (vWF), fibrinogen, cholesterol, triglycerides and very low density lipoprotein (VLDL) (all p <0.05). The lipid, vWF, and fibrinogen levels were positively related to the degree of BP elevation but not to the degree of proteinuria during the index pregnancy. Except for the increase in vWF level, all biochemical perturbations were only present in the luteal but not in the follicular phase samples. In conclusion, persistent endothelial dysfunction with ensuing dysregulation of blood pressure, haemostatic perturbation and dyslipoproteinemia after preeclampsia may indicate a proneness to future CHD.
Adult↗
Serum transferrin receptor: a specific marker of iron deficiency in pregnancy.
BACKGROUND: Current markers of iron deficiency tend to be less reliable in pregnancy. OBJECTIVE: Our aim was to study the usefulness of soluble serum transferrin receptor (sTfR) as a marker for iron deficiency during early and late gestation and to define iron status in 254 pregnant Swedish women. DESIGN: We performed a cross-sectional and longitudinal evaluation of sTfR in comparison with concentrations of serum ferritin and hemoglobin in blood collected around gestational weeks 11 and 36. RESULTS: The specificity of sTfR was 100%. The sensitivity in relation to both anemia and depleted iron stores was approximately 70%, but this figure is less reliable because of few samples. sTfR in early pregnancy was low: 11% of women had a value below the reference interval. sTfR increased significantly from early to late pregnancy even in the group of women with persisting iron stores. In late pregnancy, 14% of women developed tissue iron deficiency and 5% had iron deficiency according to a combination of all 3 markers. CONCLUSIONS: sTfR seems to be a specific and sensitive marker of iron deficiency in pregnancy and may have advantages over serum ferritin and hemoglobin. The low sTfR concentration in early gestation seems to be caused by reduced erythropoiesis, whereas the increase from early to late pregnancy reflects increased erythropoiesis, and in case of iron deficiency, also tissue iron deficiency. Further studies are needed to verify whether decreased erythropoiesis reduces the possibility of detecting iron deficiency during early gestation by sTfR.
Anemia↗
Reactivity against phospholipids during pregnancy.
Antibodies against phospholipids (PLa) are often thought to be associated with the development of activated protein C (APC) resistance. In the present study, PLa were followed throughout 29 healthy pregnancies and compared to APC resistance. The level of PLa did not change during pregnancy [6.9 +/- 3.7 GPL week 12 versus 6.3 +/- 2.8 GPL week 37; 3.3 +/- 1.8 MPL versus 3.2 +/- 1.5 MPL; and lupus anticoagulant (LA) coefficient 0.99 +/- 0.11 versus 0.94 +/- 0.09], in contrast to the APC resistance, which was suppressed (0.96 +/- 0.22 versus 0.78 +/- 0.13, P < 0.05), but both parameters elevated after delivery (up to 8.7 +/- 4.2 GPL; 1.13 +/- 0.1 LA coefficient; 1.11 +/- 0.22 nAPC ratio; P < 0.05). Three women possessed PLa (1 CLa IgG +/- IgM; 1 IgG CLa +/- PSa +/- PEa; 1 PSa), no LA activity was registered. In the PLa-positive women, dynamics of the nAPC ratio during pregnancy was not related to PLa.
Activated Protein C Resistance↗
A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy.
Seventeen women with previously verified thromboembolism were included in a pharmacokinetic evaluation of dalteparin during the third trimester of pregnancy. The bioavailability of morning subcutaneous administration of dalteparin (crossover study) was also compared with that in the evening. Fifteen women injected themselves subcutaneously with 5000 IU and two with 2500 IU dalteparin once daily. An anti-FXa activity of 0.20-0.40 IU/ml 3 h after injection was obtained. The means +/- SD, when comparing morning and evening doses for 5000 IU, were: Cmax 0.21 +/- 0.05 and 0.20 +/- 0.05 IU anti-FXa/ml, AUC 0-24 h 1.97 +/- 0.46 and 1.93 +/- 0.55 IU x h/ml and tmax 3.71 +/- 0.89 and 4.32 +/- 1.60 h, respectively (NS). The two regimens were equivalent. A measurable anticoagulant effect was still observed 16 h after injection of 5000 IU dalteparin. The half-lives after a morning and an evening dose of 5000 IU dalteparin were 4.92 +/- 2.80 and 3.87 +/- 1.15 h, respectively (NS). There were no changes in thrombin marker levels during the two pharmacokinetic measurements.
Adult↗
Production of phospholipid antibodies in selected thrombophilic women differing in genotype at the 506 site of factor V.
The composition of antibodies against phospholipids (PLa) was analysed in 54 PLa-positive thrombophilic women, different in the factor V genotype (Arg506-Gln mutation carriers, n=23; and noncarriers, n=31). The presence of antibodies against prothrombin was also studied. The incidence of cardiolipin antibodies (CLa) and lupus anticoagulant (LA) activity was similar among the carriers and noncarriers, while phosphatidylserine antibodies (PSa) were often the only PLa detected in the carriers of the mutation (7/23 vs. 2/31; chi2=5.47, p<0.05). Antibodies against prothrombin were found in 11 of 54 patients. They segregated with PSa (8/19 vs. 3/35; chi2=8.54, p<0.025), but were equally distributed between carriers and noncarriers. The analysis of nAPC-ratio in patients with different PLa showed that it was consistently lower in the mutation carriers in whom none of the PLa caused further suppression. The noncarrier group positive for LA in several assays was associated with a reduction of nAPC-ratio (0.82+/-0.25 vs. 1.12+/-0.22, p<0.05). Our findings indicate that PLa contributing to the development of APC resistance are restricted to those possessing LA activity.
Adult↗
Soluble fibrin in plasma as a sign of activated coagulation in patients with pregnancy complications.
BACKGROUND: Disseminated intravascular coagulation (DIC) is a frequently observed complication in pregnant women. The laboratory diagnosis of DIC is difficult but the development in the detection of circulating soluble fibrin has improved the possibility. METHODS: A number of pregnant women (n= 175) with obstetric complications e.g. preeclampsia, hypertension, intrauterine growth retardation (IUGR) and intrahepatic cholestasis was examined for plasma soluble fibrin and subjected to some routine hemostatic tests, mainly during the third trimester of pregnancy. RESULTS: Of these patients, 57 of 175 (33%) had an elevated concentration of soluble fibrin (above 23 nmol/L) as compared with a healthy group of women sampled in the third trimester. Eighteen patients (10%) had highly increased levels, above 100 nmol/L. In comparison, none of the 23 healthy, pregnant women investigated had a value above 40 nmol/L. CONCLUSIONS: Hemostatic abnormalities, including increased concentrations of soluble fibrin, are quite frequently observed in women with obstetric complications, most likely as a sign of a systemic activation of coagulation. Although a higher concentration of plasma soluble fibrin was observed in many of the women, no clear correlation to the outcome of the pregnancy was obtained. Whether or not plasma soluble fibrin is of any value, either diagnostically or the treatment of patients with pregnancy complications, remains to be shown.
Blood Coagulation Tests↗
Thromboprophylaxis with low molecular mass heparin, 'Fragmin' (dalteparin), during pregnancy--a longitudinal safety study.
Twenty-five women with previous verified thromboembolic complications were treated with delteparin (Fragmin) during pregnancy and puerperium. Women with known hereditary thrombophilia (antithrombin, protein C and protein S deficiencies) or with phospholipid antibodies were excluded. The dose at entry was calculated according to body weight and thereafter monitored by anti-FXa activity aiming at 0.20-0.40 IU/ml plasma 3 h post injection. Dalteparin or dextran was used during delivery. Twenty-two women completed the study and 14 of these could be given the same dose throughout pregnancy. There was an increased dose response postpartum. There were no thromboembolic recurrences or severe bleeding complications. The level of antithrombin activity remained normal. Our thrombosis-prone pregnant women had initially increased levels of thrombin markers but no further increase was observed during the dalteparin thromboprophylaxis. Retrospectively, three heterozygous and three homozygous individuals for the FV Leiden mutation leading to activated protein C resistance were identified. In conclusion, dalteparin could safely be used as thromboprophylaxis during pregnancy in these thrombosis-prone women. Women weighing 50-79 kg at entry could be treated with 5000 IU of dalteparin once daily during pregnancy, without monitoring. Postpartum, many of the women were given a reduced dose.
Adult↗
Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance.
A total of 74 non-pregnant women with a previous episode of thrombosis were investigated for activated protein C (APC) resistance in the aPTT-based and factor IXa-X-based assays and for the presence of mutations in all APC-cleavage sites in the heavy chains of factor V and factor VIII. DNA fragments were amplified with the polymerase chain reaction (PCR) and those encoding for the Arg-306 and Arg-506 (factor V) and for Arg-740 (factor VIII) cleavage sites were subjected to restriction enzyme analysis. DNA fragments of 29 selected patients corresponding to the Arg-306 and Arg-679 cleavage sites in factor V, and to the Arg-336 and Arg-562 cleavage sites in factor VIII were sequenced. APC resistance was found in 40 cases, using the aPTT-based assay and in 35, using the factor IXa-X-based assay (23 patients were APC resistant in both assays), whereas 22 individuals had a normal response to APC. Forty-three patients carried Arg-506 to Gln mutation in factor V. No other polymorphism or mutation was found in the genes for factors V or VIII in the vicinity of the APC cleavage sites. It was concluded that the difference in response to APC in the two assays may not be explained by the presence of mutations in the APC cleavage sites of factor V and factor VIII in this group of patients. The data do not exclude the presence of mutations elsewhere in the factor V or factor VIII genes.
Adult↗
Acquired deficiency of antithrombin in association with a hypercoagulable state and impaired function of liver and/or kidney in preeclampsia.
To determine whether decreases in plasma antithrombin (AT) level, as seen in non-gestational acquired AT deficiency, result from a hypercoagulable state and/or liver/kidney damage, AT activity was measured in 24 uncomplicated and 30 preeclamptic women. The fifth percentile of AT levels in the normal pregnancies was used as a cut-off value to subdivide the preeclamptic patients into two groups. Markers of activated coagulation, i.e, levels of thrombin-antithrombin complex (TAT), fibrin D-dimer, soluble fibrin, von Willebrand factor (vWF) and platelet counts, were determined. Indicators of hepatic or renal function, i.e. concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urinary albumin (U-albumin) and serum albumin (S-albumin), were assayed. AT levels were lower in those with preeclampsia than in the normal pregnancy group (P < 0.01). In the group with AT levels less than the cut-off point, levels of fibrin D-dimer (P < 0.05), soluble fibrin (P < 0.05), vWF (P < 0.05), ALT (P < 0.05), AST (P < 0.05), creatinine (P < 0.01) and U-albumin (P < 0.01) were increased, whereas platelet counts (P < 0.05) and S-albumin (P < 0.05) were decreased. All patients with ALT levels > 0.46 mu kat/1, AST > 0.58 mu kat/1, S-albumin < 23 g/1 and/or U-albumin > 4.9 g/24 h had AT levels < or = cut off. AT levels correlated with vWF (rs = - 0.73, P < 0.01) and creatinine (Rs = -0.70, P < 0.01). It is suggested that in preeclampsia, acquired AT deficiency is secondary to a hypercoagulable state, and/or associated with impaired hepatic and/or renal function.
Alanine Transaminase↗
Variability of the response to activated protein C during normal pregnancy.
The response to activated protein C (APC) was investigated in 28 healthy women, non-carriers of the Arg506-Gln mutation in factor V, throughout pregnancy (gestation weeks 12, 20, 28, 32 and 37) and after the delivery. A suppression of APC response was observed which reached lowest values by week 28 (nAPC-ratio 0.78 +/- 0.13), sustained low up to the end of pregnancy and rose after delivery (1.11 +/- 0.22; P < 0.05). APC resistance (nAPC ratio < 0.75) was registered in 16 of the 28 women (57%). A reduction of APC ratio was directly related to its value in the non-pregnant state, being most pronounced in the women with the highest APC ratio. Factor VIII increased during pregnancy and correlated inversely to APC ratio (Z coefficient = -0.645, P < 0.0001). The correlation became weaker in the course of pregnancy, losing significance by week 32. This was explained by the differences in profiles of the two variables: the lowest measured APC ratio preceded the peak of factor VIII in most cases. The most pronounced rise of factor VIII was found in the women with minimal levels of APC ratio between 0.8 and 0.7. These results allowed us to speculate that APC response is closely regulated during pregnancy, aiming to maintain a certain relevant level. Transitory reduction of APC response is connected to factor VIII and discussed as a prevalent mechanism of functional APC resistance during pregnancy.
Adult↗
Prediction of changes in levels of haemostatic variables during natural menstrual cycle and ovarian hyperstimulation.
To find if there is a relation between levels of haemostatic variables at low and high hormonal levels (oestradiol and progesterone) in an individual, blood samples were drawn from 12 women repeatedly during one menstrual cycle (Study I) and from 14 women undergoing in vitro fertilization, before hormonal stimulation and daily during the periovulatory period (Study II). Regression coefficients were calculated between minimum (independent) and maximum (dependent) values in both studies. In Study II highly significant regression coefficients were found between oestradiol minimum (pretreatment) and maximum (median 105 and 4730 pmol/l, respectively) for coagulation factors FVIII, von Willebrand Factor (antigen), FVII (activity and antigen), fibrinogen, protein C, protein S (free), antithrombin, plasminogen and plasminogen activator inhibitor-1; furthermore, between progesterone-minimum at day -3 or -2 (related to ovum pick up) and maximum (median 4.7 and 98 nmol/l, respectively) for FVIII, von Willebrand Factor, FVII (activity and antigen), protein C, protein S (free), and plasminogen. In Study I, where much lower hormonal levels were obtained at maximum (oestradiol median 297 pmol/l and progesterone 47 nmol/l), the same pattern was observed especially for FVII, FX, fibrinogen, plasminogen and plasmin inhibitor. Thus, the concentration of a haemostatic variable at a low oestradiol or progesterone level can predict the level at a high hormonal level.
Adult↗