Retrospective evaluation of the safety and efficacy of low-molecular-weight heparin as thromboprophylaxis during pregnancy.
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Female↗
Biomedical subjects
L Heilmann
Publications and source records attributed to L Heilmann.
Maternal and cord blood hemostasis at delivery.
Today we known that the coagulation system of the neonate differs in many ways from that of the adult system. We see a general reduction of the coagulation factors II-XIII (except VIII), the fibrinogen and of the coagulation inhibitors ATIII, protein C and heparin cofactor II at the same time. In addition the newborns show different levels of the coagulation factors for premature and full-term infants. This situation necessitates the generation of not one, but several, reference ranges for the various components of the hemostatic system. While the above-mentioned factors of the coagulation and fibrinolytic system of the newborn are well studied, our knowledge of others is still lagging behind that of the adult. That applies to the vWF and PAI and even more to D-Dimer. Our aim was to collect some data for vWF, PAI and D-Dimer to complete the understanding of the physiology of the hemostatic system in the newborn. Therefore we used the blood samples from 59 newborns and their mothers to obtain a number of different components of the coagulation and fibrinolytic system. Besides some rheological parameters (erythrocyte aggregation, plasma viscosity) we measured the aPTT, PT and the plasma levels of ATIII, fibrinogen and protein C (PC). But we paid special attention to the plasma levels of von Willebrand factor (vWF), plasma activator inhibitor (PAI) and D-Dimer. The blood samples were collected from the umbilical cord and the cubital vein of the mother immediately after delivery, anti-coagulated, centrifuged and stored until measurement at -70 degrees C. ATIII, aPTT, PT and fibrinogen were measured by the clotting technique test on the Chromotimer (Behring, Marburg, Germany). D-Dimer, vWF and protein C were determined with a commercially available ELISA obtained from Boehringer Mannheim (Mannheim, Germany). PAI activity was measured by a two-stage amiolytic method (Behring, Marburg). Besides the known differences of the neonatal hemostatic components to their mothers, such as a prolonged aPTT (52.19 s +/- 13.4 newborn, 35.26 s +/- 4.2 mother), reduced PT (64.34 s +/- 20.15 vs. 91.03 s +/- 1.25), ATIII (83.36% +/- 24.42 vs. 92.58% +/- 11.43) and fibrinogen (156.05 mg/dl +/- 91.68 vs. 344 mg/dl +/- 55.25), we found some peculiarities. The newborns show a clear reduction in the vWF (97.79 ng/ml +/- 36.33 vs. 183.43 ng/ml +/- 16.03) as well as the PAI (0.846 U/ml +/- 1.44 vs. 7.652 U/ml +/- 0.764). D-Dimer levels in the umbilical cord samples (1514.02 ng/ml +/- 953.56) are clearly prolonged in contrast to the maternal levels (740.2 ng/ml +/- 139.68). We were also able to find a difference of these factors related to gestational age. Premature infants showed a clearly higher level of PAI (2.2 U/ml +/- 2.86 vs. 0.69 +/- 1.13; p = 0.0136) compared with full-term infants, as well as significantly lower levels of ATIII (48.8% +/- 23.19 vs. 86.62 +/- 22.04; p = 0.0006) and protein C (25.33% +/- 9.37 vs. 35.73 +/- 7.53; p = 0.0027). D-Dimer, vWF, fibrinogen and the rheological parameters are similar. This seems to show an increased tendency for bleeding with the premature infant. Newborns show a balance of the coagulation system solely on a lower level. This is due to the general reduction of the coagulation factors with a reduction of the coagulation inhibitors at the same time. The physiologically low level of the vitamin K dependent and other coagulation factors and ATIII leads to a prolonged aPTT and reduced PT of the newborn. As well as these differences, known from literature, we found the following specialities: lower vWF and PAI and higher D-Dimer levels of the newborn compared with their mothers.
Antithrombin III↗
Blood coagulation and thrombosis in patients with ovarian malignancy.
Ovarian cancer cells appear to be capable of both thrombin formation and induction of fibrin degradation which may be essential prerequisites for the development of deep vein thrombosis (DVT) as well as the spread of malignancy. To study further this coagulation-cancer interaction in 60 patients with untreated ovarian cancer of FIGO stage I-IV the incidence of DVT was recorded pre-operatively, post-operatively on day 1, 3, 5, 7, 10, before each of six cycles of Cisplatinum/ Epirubicin/Cyclophosphamide chemotherapy, during follow-up and in the post-operative period of second look surgery. In addition, blood coagulation tests results were determined prospectively. Two patients were excluded from these calculations due to previous DVT 5 to 6 weeks before the diagnosis of ovarian cancer but all patients were eligible for surgery and randomized to receive either daily low molecular weight heparin (LMWH) (n = 28) or unfractionated heparin (UFH) (n = 32) for perioperative thrombosis prophylaxis until the 7th post-operative day. According to the FIGO stage, patients were equally distributed in the 2 heparin treatment groups. The predictive value of pre-operative coagulation test results, clinical parameters, and type of heparin used were tested in univariate and multivariate analysis for development of post-operative DVT and overall patients survival. Impedance plethysmography for DVT screening was used. The presence of DVT was then confirmed by phlebography. Only D-dimer and fibrinogen levels were correlated significantly with the FIGO stage while antithrombin, protein C, and plasminogen activator inhibitor activity were not. The incidence of DVT was 6.7% (4/60) up to the 7th and 8.3% (5/60) between the 8th and 29th post-operative day. DVT occurred in 10.6% (5/47) during chemotherapy. Pre-operative coagulation test results, the type of heparin used, and clinical parameters were not significant risk factors for post-operative DVT development in univariate analysis. The D-dimer and fibrinogen levels were significant risk factors for reduced overall survival in univariate analysis but only the FIGO stage was an independent predictor (in multivariate analysis). After a median follow up of 26.5 months (min. 8 months, max. 41 months), 21.4% of LMWH treated and 37.5% of UFH-treated patients died of cancer (p = 0.26). Pre-operative test results were neither predictive for DVT nor the outcome of cancer but patients showed an improved though not statistically significant overall survival after LMWH treatment.
Aged↗
Plasmatic plasminogen activator inhibitor activity in patients with primary breast cancer.
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Breast Neoplasms↗
Acute maternal hydration in third-trimester oligohydramnios.
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Female↗
Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer.
PURPOSE: Influences of adjuvant epirubicin/cyclophosphamide (EC) chemotherapy on blood coagulation were investigated in patients with operable breast cancer and the incidence of thromboembolic events was recorded. PATIENTS AND METHODS: In 50 consecutive node-positive breast cancer patients, serial coagulation studies (fibrinogen method of Clauss, antithrombin III, protein C amidolytic methods, D dimer enzyme-linked immunoadsorbent assay [ELISA] techniques, and plasminogen activator inhibitor [PAI] activity u-PA inhibition test) and impedance plethysmography (IPG) for screening of deep vein thrombosis (DVT) were performed preoperatively and postoperatively, before each of six cycles of adjuvant chemotherapy (60 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide) and 3 months thereafter. Seventy-two healthy women served as controls. RESULTS: During chemotherapy, the phlebographically proven DVT incidence was 10% (n = 2 after second cycle; n = 3 after third cycle). Preoperative levels of D-dimer, fibrinogen, and the PAI activity were significantly higher than in healthy women and only mean levels of the D-dimer were significantly higher in patients with DVT compared with patients without DVT. Postoperatively, only D-dimer and fibrinogen levels significantly increased, while in the course of chemotherapy, these levels were significantly decreased. Mean D-dimer levels and PAI increased steadily in patients with DVT. Preoperatively and during chemotherapy, levels of antithrombin III and protein C were within the normal range. Only one patient with DVT had decreased protein C levels throughout chemotherapy. CONCLUSION: Monitoring with sophisticated coagulation tests during adjuvant EC chemotherapy for breast cancer does not identify patients at higher risk for DVT development. Preoperatively, in patients with later DVT, an imbalance of hemostasis is already present; thus, thrombosis might predominantly be initiated by malignancy-induced hypercoagulability and secondarily by the influence of EC chemotherapy. Prospective randomized trials must determine whether prophylactic anticoagulation during EC chemotherapy reduces the incidence of DVT.
Adult↗
[Placental transfer of low-molecular weight heparin].
Prophylaxis of thromboembolism in pregnancy with low molecular weight heparin (LMWH) offers several advantages over conventional heparin (UFH) including the once daily application and the reduction of heparin-related side effects like osteoporosis, thrombocytopenia and allergy. Until now the use of LMWH in obstetrics failed because of a possible placental passage. The aim of our randomised controlled study with a total of 59 pregnant women was to control the placental passage of UFH and LMWH at term. 35 pregnant women received either 5000 I.U. UFH or 1500 aPTT units LMWH (Mono-Embolex) subcutaneously two hours prior to the termination or no injection. Maternal and fetal blood samples were taken after delivery to assay heparin activity by the heptest coagulation assay and the S2222 chromogenic substrate method. After application of LMWH heptest coagulation assay rose significantly from 20.8 +/- 2.0 to 40.3 +/- 9.4 s (p = 0.001), after UFH just from 21.6 +/- 1.5 to 22.9 +/- 3.7 s (p = 0.09). In the fetal blood samples, however, neither UFH nor LMWH could be measured. The data demonstrates that neither UFH nor LMWH used in this study crosses the placenta two hours after application and encourages the use of LMWH for the prophylaxis of thromboembolism during pregnancy.
Adolescent↗
Red cell deformability in gestational hypertension.
Erythrocyte deformability and red cell characteristics (MCV, MCHC, Hct) were studied in 18 patients with gestational hypertension, 24 normotensive primigravidae and 20 nonpregnant nulliparous women. The deformability of red cells was determined by red cell filtration in a filtrometer MF4 after prefiltration through cotton wool. We found a statistically reduced deformability in patients with gestational hypertension compared with normal pregnancy and nonpregnant controls. Our data suggest a strong correlation between red cell filterability and newborn weight (r = 0.59, p < 0.02). The deformability of erythrocyte in gestational hypertension mainly depends on the fluidity of the cell membrane (lipid content). Other factors are the hemoglobin viscosity and the cell membrane surface area/cell volume ratio.
Birth Weight↗
[Hemorheology and hypertension in pregnancy].
Gestational hypertension is characterized by a contracted plasma volume with hemoconcentration and hyperviscosity. Additional rheological parameters are an elevated red blood cell aggregation and impaired erythrocyte deformability. It is possible, that the increase of erythrocyte rigidity may result from a redistribution of cellular calcium metabolism or from interchanges with plasma lipids.
Blood Viscosity↗
[Relation of Doppler ultrasound to hemostaseologic and hemorheologic parameters in pregnancy-induced hypertension].
During this study we investigated 23 patients with preeclampsia and 23 women with normal pregnancies. The hemorheological, the hemostasiological and the dates of doppler ultrasound were evaluated. High values of D-Dimer as a sign for a rapidly turnover of fibrin, are a poor prognostical symptom for gestational hypertension. There is a close correlation between doppler ultrasound indices and the maternal D-Dimer. Nearly 80% of the new born babies with growth retardation suffered by a high blood viscosity of the umbilical artery. We postulate that the changes of maternal and fetal blood viscosity are very important to estimate the doppler flow velocity by patients with gestational hypertension.
Adult↗
[Erythrocyte deformability in pregnancy-induced hypertension].
Erythrocyte deformability and red blood cells characteristics (MCV, MCH, Hct) were studied in 18 patients with gestational hypertension (24 normotensive primigravidae and 20 non-pregnant nulliparous women). The deformability of red cells was determined by red cell filtration in a filtrometer MF4 after prefiltration through cotton wool. We found a statistically reduced deformability in patients with gestational hypertension compared with normal pregnancy and non pregnant controls. Our data suggest a strong correlation between red cell filterability and newborn weight (r = 0.59, p < 0.02). The deformability of erythrocytes in gestational hypertension mainly depends on the fluidity of the cell membrane (lipid contents). Other factors of minor importance are the hemoglobin viscosity and the cell membrane surface area/cell volume ratio. The significantly lower erythrocyte fluidity in patients with gestational hypertension may also be explained by an enlarged metabolic pool of free calcium ions in these red blood cells.
Birth Rate↗
[The Na+/K+ cotransporter of the erythrocyte membrane in pregnancy-induced hypertension].
In erythrocytes, the extrusion of a cellular sodium level load is accomplished by the Ouabain-sensitive Na+/K+ pump and by the furosemide-sensitive Na+/K+ cotransport, which operates against the passive sodium permeability. An abnormal low rate of net sodium extrusion by the Na+/K+ cotransport was observed in pre-eclamptic patients. At the molecular level the cotransport abnormality seems to be consecutive to a diminished apparent affinity for intracellular Na+. The normal pregnancy is characterized by a strong increase of Na+/K+ cotransport efflux. No difference could be detected between the passive sodium permeability of erythrocytes from normotensive pregnant patients and from normotensive controls. Pre-eclampsia seems to be associated with a low passive sodium and potassium permeability. The abnormalities of cotransport and red cell deformability in patients with pre-eclampsia might be interpreted as an early sign of impaired microcirculation and increased vascular reactivity.
Adolescent↗
The Na+/K+ co-transport system in erythrocytes from pregnant patients.
In erythrocytes, the extrusion of a cellular sodium level load is accomplished by the Ouabain--sensitive Na+/K+ pump and by the furosemide-sensitive Na+/K(+)--cotransport, which operates against the passive sodium permeability. An abnormal low rate of net sodium extrusion by the Na+/K+ cotransport was observed in pre-eclamptic patients. At the molecular level the cotransport abnormality seems to be the consequence of an apparent diminished affinity for intracellular Na+. Normal pregnancy is characterized by a strong increase of Na+/K+ cotransport efflux. No difference could be detected between the passive sodium permeability of erythrocytes from normotensive pregnant patients and from normotensive non-pregnant controls. Pre-eclampsia seems to be associated with a low passive sodium and potassium permeability. The abnormalities of cotransport and red cell deformability in patients with pre-eclampsia might be interpreted as an early sign of impaired microcirculation and increased vascular reactivity.
Adolescent↗
[Changes in central hemodynamics and peripheral circulation in pregnancy].
Systemic blood pressure, stroke volume, systolic time intervals (measured via impedance cardiography), rheological properties of blood (hematocrit, plasma viscosity and erythrocyte aggregation) and peripheral flow conditions (measured via occlusive impedance plethysmography) were assessed longitudinally in 21 nonpregnant women and in 49 patients from 5th to 41st week of gestation and 4 to 9 days postpartum. Measurements were taken in the left lateral position. The data showed, that dz/dt, stroke volume and cardiac index rose until the 30th week of gestation and decreased throughout the rest of pregnancy. The same changes were observed in the data on diastolic pressure and Heather Index. Peripheral resistance fell during the first trimester and then increased notably throughout the following time of pregnancy. The systolic time intervals become longer in the last trimester of pregnancy, but were characterised by a markedly shortened left ventricular ejection time (LVET). The reduction of stroke volume in the last trimester is due to diminished venous return or venous outflow by obstruction of the inferior vena cava or by abnormalities in the left ventricular function and/or impaired rheological properties of the blood.
Adult↗
[Hemoglobin--an obstetric risk factor].
The relationship between haemoglobin values (14th to 30th week of gestation), pregnancy outcome and perinatal morbidity was investigated in a prospective study. Subsequently, haemoglobin values, blood pressure, proteinuria and perinatal risk factors, together with the foetal cardiotocogram were abstracted from the obstetrician's records. Preterm birth (25%), intrauterine growth retardation (7.6%) gestational hypertension (31.5%) and low birth weight babies (10.3%) were seen significantly more often in women with haemoglobin > or = 13 g/dl in the 2nd trimester (14-30 wk). We observed a high perinatal morbidity from RDS (9.3%) and newborn hyperviscosity (23.9%) in women with a high haemoglobin level. These results were in agreement with the hypothesis, that a higher blood viscosity or a lack of haemodilution are risk factors for poor placental perfusion.
Adolescent↗
[Rheology and gravidic hypertension].
Gestational hypertension is the development of hypertension and proteinuria after the 20th week of gestation. The most common causes of increased peripheral resistance are the vasoconstriction and hemoconcentration with plasma volume contraction. Additional rheological parameters are an elevated red blood cell aggregation and impaired erythrocyte deformability. Preeclamptic patients showed a significantly low cardiac output and central venous pressure than normal pregnant women. It has already been shown by the studies by Hytten and Paintin (1963) and also by the subsequent studies by Garn et al. (1981), Murphy et al. (1986) that a strong correlation exists between newborn weight and plasma volume. Other authors (Gallery et al. (1979/1981)) show the possibility that plasma volume contraction plays an even larger role than vasoconstriction in the fetal growth retardation that often accompanies maternal hypertension. This possibility is supported by the finding that hypertension and perinatal complications can be reduced in some pregnant women by the admission of oncotic solutions (i.e. hydroxyethyl-starch) that expand plasma volume. Volume expansion with hydroxyethyl-starch appears to be of therapeutic benefit for hypertensive patients and patients with fetal growth retardation with low cardiac output.
Birth Weight↗
[Hemostasis and pre-eclampsia].
A longitudinal study has been undertaken in 125 pregnant women between 25 and 40 weeks of gestation, to provide systematic information on the changes that occur in a wide range of haemostasiological and haemorheological variables. Fibrinogen, D-Dimer, Factor VIIIR: Ag, erythrocyte aggregation and plasma viscosity rose markedly throughout pregnancy. Antithrombin III and alpha 2-antiplasmin were unchanged during pregnancy. There were no significant differences between women in the pre-eclamptic group (N = 16) and the control group. HELLP syndrome (N = 7) was associated with high D-Dimer (p less than 0.05), and TAT (p less than 0.05), low antithrombin III (p less than 0.03), protein C (p less than 0.01) and platelets (p less than 0.001). Our results demonstrate that during pregnancy (also, however, in pre-eclamptic women) alterations of the coagulation system occur, but these changes do not affect the overall haemostatic balance. Findings in patients with "true" HELLP syndrome are consistent with an increased tendency for intravascular coagulation.
Blood Coagulation Factors↗
[Value of hemodilution therapy in pregnancy].
The ability to produce a large increase in plasma volume is one of the hallmarks of a successful pregnancy. Data from Garn et al. (5), Knottnerus et al. (14) and Murphy et al. (15) have shown, that hemoglobin levels above 13 g/dl or hematocrit 38% before admittance to hospital are associated with a high incidence of IUGR (intrauterine growth retardation), gestational hypertension and with a greater perinatal mortality. Patients with an elevated viscosity and hematocrit have increased perinatal risks. In these cases the hemodilution with hydroxy- ethylstarch (HES) improves the blood flow and decreases the incidence of dysmature babies and pregnancy complications. The effect of HES on certain coagulation assays seems qualitatively similar to those of Dextran. In a prospective trial we evaluated the effect of HES in the incidence of thrombosis after cesarean section and we found a 5.9% incidence of thrombosis in patients treated with 6% HES 0.62 compared with a 7.8% incidence in heparin treated patients. Treatment with 1500 ml 6% HES 0.62 before and after cesarean section is similarly effective in preventing deep vein thrombosis as heparin prophylaxis.
Blood Volume↗