The effect of graduated compression stockings on blood velocity in the deep venous system of the lower limb in the postnatal period.

Venous thromboembolism (VTE) is the leading cause of maternal mortality in the UK and is also a major cause of long-term morbidity. Recent UK national guidelines recommend thromboprophylaxis, which includes the use of graduated compression stockings (GCS), for high-risk women to reduce the risk of VTE in both the antenatal and postpartum period. This study of 17 women examined the effects of GCS on the deep venous system in the immediate postpartum period and found a statistically significant reduction in the diameter of the common femoral vein (CFV) (pre- versus post stocking diameter: mean 10.39 mm [SD 2.09] versus mean 9.69 mm [SD 1.99]) and an increase in the rate of blood velocity in the CFV (pre- versus post stocking velocity: mean 10.0 cm/s [SD 2.7] versus 13.9 cm/s [SD 4.2]) 30 minutes after application of thigh length GCS in women 1 or 2 days following a singleton vaginal delivery at term. This confirms reduction in venous stasis in the deep venous system in the immediate postpartum woman by the use of GCS, supporting their use in improving venous function in this context.

The role of factor V Leiden in maternal health and the outcome of pregnancy.

There is growing evidence that women with thrombophilia are at increased risk of pregnancy related venous thromboembolism and of adverse pregnancy outcome including pregnancy loss, pre-eclampsia, intrauterine growth retardation and placental abruption. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4-to 8-fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80-fold increase in relative risk of thrombosis. The relationship between factor V Leiden and adverse pregnancy outcome has been studied in the recent literature, however the size of the estimated risks varies between individual studies due to heterogeneity of study design and small sample size in many cases. The management of women with factor V Leiden in pregnancy with low molecular weight heparin has been shown to be both safe and effective in preventing venous thromboembolism and improving pregnancy loss. Large scale, randomised controlled studies are required to confirm these findings. Selective screening for factor V Leiden based on prior venous thromboembolism has been shown to be marginally more cost-effective than universal screening in pregnancy and a recent consensus statement has recommended screening for thrombophilia based on a strong personal or family history of venous thromboembolism. There is now some evidence that placental problems may be associated with factor V Leiden in the fetus. There has also been an observed association between maternal factor V Leiden and fetal or neonatal stroke. These areas require further study and at present there is no evidence-based approach to investigation, prevention or management.

Anaesthetic considerations in a parturient with critical coronary artery disease and a drug-eluting stent presenting for caesarean section.

A parturient presented with her first symptoms of coronary artery disease at 18 weeks' gestation. Following an angiogram, a drug-eluting stent was inserted, resulting in resolution of her symptoms. The patient was prescribed anti-platelet medication including clopidogrel. She was delivered by elective caesarean section at 35 weeks under general anaesthesia. The anaesthetic management is discussed and a review of the literature presented.

Increased nitrotyrosine in the diabetic placenta: evidence for oxidative stress.

OBJECTIVE: To evaluate the presence of nitrotyrosine (NT) residues in placental villous tissue of diabetic pregnancies as an index of vascular damage linked to oxidative stress. RESEARCH DESIGN AND METHODS: Villous tissue was collected and flash frozen after delivery from 10 class C and D IDDM patients (37.9+/-3.2 weeks) and 10 normotensive pregnant individuals (37.5+/-3.8 weeks). Serial sections of tissue were immunostained with specific antibodies to NT, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and manganese superoxide dismutase (MnSOD). Sections were scored for intensity of immunostaining (0-3) by three observers blinded to the identity of tissue. RESULTS: All tissues demonstrated immunostaining for eNOS in both syncytiotrophoblast and stem villous vascular endothelium with no apparent differences between groups. Immunostaining for iNOS was seen in the villous stroma, but again was not different between the two groups. Significantly more intense NT staining was apparent in vascular endothelium and villous stroma (both P < 0.02) of diabetic placentas. The endothelium of large villous vessels of diabetic tissues also showed more intense immunostaining for MnSOD (P < 0.01). CONCLUSIONS: In these diabetic pregnancies, we were unable to show increased eNOS, unlike previous findings in preeclamptic pregnancies. The presence of NT may indicate vascular damage in the diabetic placenta due to peroxynitrite action formed from increased synthesis/interaction of nitric oxide and superoxide. The apparently paradoxical increase in MnSOD expression may be an adaptive response to increased superoxide generation.

Interaction of the protein C/protein S anticoagulant system, the endothelium and pregnancy.

Normal pregnancy is associated with significant changes in haemostasis, lipid metabolism and endothelial function. This suggests that maternal adaptation in these systems is required for successful pregnancy outcome. A number of acquired and heritable prothrombotic abnormalities are associated with complications in pregnancy. A common feature of these abnormalities is their ability to alter endothelial function or the protein C/protein S system and increase thrombin generation. In this review the normal function of the endothelium and the protein C/protein S system is detailed. The changes which characterize normal and complicated pregnancies are outlined and the evidence for the impact of heritable and acquired disorders of the protein C/protein S system on pre-eclampsia and fetal loss are discussed.

Placental proopiomelanocortin gene expression, adrenocorticotropin tissue concentrations, and immunostaining increase throughout gestation and are unaffected by prostaglandins, antiprogestins, or labor.

The objective of this study was to demonstrate the ontogeny of POMC gene expression, the distribution of immunoreactive ACTH, and tissue peptide content within the placenta and fetal membranes and to investigate the regulatory effects of PGs and progesterone during the first trimester and of labor at term. Tissues were collected from the following groups: 1) women undergoing first trimester (gestation 5-12 weeks) therapeutic abortion (by suction curettage with and without the synthetic PGE1 analogue, gemeprost administered vaginally 2-4 h before the procedure or with 600 mg mifepristone 48 h before receiving 1 mg gemeprost vaginally); 2) women undergoing second trimester therapeutic abortion (600 mg mifepristone; 1 mg gemeprost); 3) in association with delivery at term by spontaneous labor; 4) induced labor; or 5) elective caesarean section. ACTH was immunolocalized to the placental cytotrophoblasts in the first trimester and to the syncytiotrophoblasts in the second and third trimester. The intensity of the staining increased with advancing gestation. ACTH immunoreactivity also was localized in the epithelial layer of the amnion, the reticular layer of the chorion, and the decidual stroma. ACTH content measured by RIA in placental extracts increased significantly in the third trimester. In situ hybridization demonstrated expression of POMC messenger RNA in syncytiotrophoblasts and cytotrophoblasts from the first trimester and also demonstrated a significant increase in POMC gene expression with advancing gestation. The localization and staining intensity for ACTH and POMC gene expression were not affected by the administration of PGs or mifepristone or by labor at term. These data demonstrate the localization of ACTH immunoreactivity within the placenta throughout pregnancy, supporting the hypothesis that the placenta may activate and maintain the maternal and/or fetal hypothalamo-pituitary-adrenal axis throughout pregnancy.

Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein.

A detailed longitudinal examination of plasma lipoprotein subfraction concentrations and compositions in pregnancy was performed with the objective of discovering the pattern of change in lipoprotein subfractions. Plasma triglyceride, cholesterol, very low density lipoprotein (VLDL1), very low density lipoprotein (VLDL2), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and its subfractions (LDL-I, LDL-II, LDL-III), and high density lipoprotein-cholesterol (HDL cholesterol) were quantified in 10 normal pregnant women from 10 weeks of gestation and at 5 weekly intervals thereafter, until 35 weeks of gestation, together with circulating hepatic lipase (at 10 and 35 weeks) and serum estradiol concentration. Median concentrations of VLDL1 (19-109 mg/dL), VLDL2 (17-103 mg/dL) and IDL (26-124 mg/dL) increased in parallel (maximum increase around 5-fold) as plasma triglyceride increased with advancing gestation. This contrasts with observations in the normal non-pregnant female, where higher concentrations of plasma triglyceride are associated with preferentially higher VLDL1 concentrations. The rise in IDL was also remarkable as this does not normally accompany changes in plasma triglyceride. LDL mass increased by 70% (200-353 mg/dL) between 10 and 35 weeks, and in 6 of the 10 women studied, the LDL subfraction pattern was modified towards a smaller denser pattern in a manner suggestive of a "threshold" transition, with the proportion of LDL-III increasing at the expense of LDL-II, whereas in the other 4 women, LDL subfraction profile remained unchanged throughout pregnancy. Interestingly, this "threshold" transition, if it occurred, did so at varying gestational ages and triglyceride concentrations for different women. The likelihood of LDL subfraction change and the final concentration of small, dense. LDL-III were related to the 10-week triglyceride concentration (R2 = 36.7%, P = 0.063) and to the rate of change in triglyceride for a given increment in estrogen (R2 = 48.6%, P = 0.025). In addition, VLDL1 mass exceeded 100 mg/dL during pregnancy only in those individuals in whom LDL profile perturbation was evident (chi 2, P < 0.001). LDL profile change was evident at the lowest triglyceride concentrations in the 2 individuals with the highest increments in triglyceride corrected for estrogen. On the basis of these longitudinal observations, we conclude the following: 1) as plasma triglyceride increases in pregnancy, there are parallel rises in median concentrations of VLDL1, VLDL2 and IDL, around 5-fold; 2) as a result of this progressive increase in plasma triglyceride, in particular in VLDL1, the LDL profile is altered in some individuals towards smaller, dense particles; 3) in general, the higher the initial (booking) fasting plasma triglyceride concentration or the larger the rate of change in triglyceride for a given increment in estradiol, the greater the probability of change in LDL profile towards smaller denser species; 4) significantly, LDL subclass perturbation towards smaller denser species occurs not in a gradual and progressive manner but exhibits "threshold" behavior; and finally, 5) this threshold is achieved at differing gestational ages and triglyceride concentrations for different women.

The effect of type 1 diabetes mellitus on vascular responses to endothelin-1 in pregnant women.

Diabetes is associated with vascular dysfunction, which may be due in part to altered vascular responses to endogenous peptides such as endothelin-1. These altered responses may also contribute to the decreased maternal peripheral resistance in pregnancy. The aim of this study was to examine the effect of diabetes on the vasoconstrictor response to endothelin-1 in pregnant women. Small arteries were isolated from nine healthy pregnant, seven type 1 diabetic pregnant women, and five healthy nonpregnant women. Contraction curves were performed on a wire myograph for noradrenaline (1 nM to 30 microM) and endothelin-1 (1 pM to 0.3 microM). Maximum responses and sensitivity were compared by t test. No differences in maximum response to noradrenaline or potassium were seen among the three groups. The maximum response to endothelin-1 was significantly increased in pregnancy (P < 0.05), whereas endothelin-1 sensitivity was reduced in the diabetic compared with the nondiabetic pregnant women (P < 0.05). Pregnant women have an increased maximum vasoconstriction response to endothelin-1 compared with nonpregnant women, whereas diabetic pregnant women demonstrate reduced sensitivity to endothelin-1. These observations suggest that endothelin-1 may play a role in maintaining peripheral vascular tone in normal pregnancy, and the decreased sensitivity seen in pregnant women with diabetes may reflect abnormal vascular reactivity.

Lipid and lipoprotein concentrations in pregnancies complicated by intrauterine growth restriction.

Previous studies have shown that in preeclampsia, plasma lipids climb substantially above levels seen in normal pregnancies. Such lipid changes may play a role in the endothelial damage characteristic of preeclampsia. Pregnancies complicated by intrauterine growth restriction (IUGR), without preeclampsia, have similar placental pathology to preeclampsia despite the absence of the maternal systemic manifestations of hypertension and proteinuria. The aim of this study was to perform a cross-sectional study of lipid and lipoprotein concentrations in the third trimester, from normal pregnancies, and those complicated by IUGR without preeclampsia. Our hypothesis was that, in contrast to the exaggerated lipid changes seen in preeclampsia, lipid and lipoprotein concentrations in IUGR would be similar to those of matched healthy pregnant controls. Fasting blood samples for lipids and lipoprotein fractions were taken in the third trimester, from eight women with IUGR; and eight women with uncomplicated pregnancies, matched as a group for age, booking weight, parity, and gestational age at sampling. There were no significant differences (P > 0.05) in the median concentrations of triglyceride, high-density lipoprotein, and very-low-density lipoprotein 1 (VLDL1), between cases and controls. However, women with IUGR pregnancies had significantly lower cholesterol [4.95 mmol/L (3.35-7.10) vs. 7.47 (5.75-8.45); median (range) for IUGR patients and controls, respectively; P < 0.01], low-density lipoprotein (LDL)-cholesterol [2.45 mmol/L (0.95-3.60) vs. 4.25 (3.35-5.60); P < 0.01], VLDL2 mass [59.0 mg/dL (37-87) vs. 103.0 (64-168); P < 0.01], intermediate-density lipoprotein mass [56.0 mg/dL (31-110) vs. 125.6 (91-157); P < 0.01], and total LDL mass [221.0 mg/dL (104-237) vs. 380.3 (267-534); P < 0.01]. In addition, it was noteworthy that, with respect to LDL-cholesterol and total LDL mass, there was little or no overlap in the ranges of concentrations measured between cases and controls. Because VLDL2 and intermediate-density lipoprotein are the synthetic precursors to LDL in the circulation, their significantly lower median concentrations imply a failure of appropriate LDL synthesis in IUGR pregnancies. Whatever the mechanism, if our results are confirmed in larger studies and longitudinal investigations, then LDL-cholesterol measurements (when LDL-cholesterol fails to rise appropriately or is low in the third trimester) may be of use in identifying mothers with, or at risk of, a pregnancy complicated by IUGR.

Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre-eclampsia.

Lipoprotein (a) (Lp(a)) is recognised as a risk factor for arterial and venous thrombosis, a property which may relate to its structural similarity to plasminogen. Pregnancy is associated with a hypofibrinolytic state. Elevated Lp(a) may influence fibrinolysis and have an unfavourable role in pregnancy outcome. In this study alterations in plasma Lp(a) concentrations during normal pregnancy was examined, in a detailed longitudinal investigation, in ten women together with changes in other lipid parameters. In addition, Lp(a) concentrations were examined in subjects with pre-eclampsia (n=10) relative to matched controls (n=10), since it has recently been reported that a substantial increase in circulating Lp(a) occurs in this disorder. Lp(a) concentration increased steadily in normal pregnancy between 10 and 35 weeks with a doubling of the median value from 14.5 to 27.0 mg/dl (P=0.01). A significant increase in Lp(a) values was observed in all subjects with increasing gestation (median rise 190%, range 117-340%). This increase was intermediate to those seen in plasma triglyceride and cholesterol. No significant difference in Lp(a) values was observed in subjects with pre-eclampsia, compared with matched normal pregnancy controls (median 14 mg/dl [IQR 4.7-69.0] in pre-eclampsia vs 20 mg/dl [9.0-56. 3] in controls; P=0.57), at a median gestation of 32 weeks. In conclusion, there is a 2-fold increase in Lp(a) during normal pregnancy, which may influence fibrinolysis. Circulating Lp(a) is not significantly elevated in women with pre-eclampsia, and thus is unlikely to play a role in the pathophysiology of this disorder.

Fetal cord plasma lipoprotein status in uncomplicated human pregnancies and in pregnancies complicated by pre-eclampsia and intrauterine growth restriction.

Maternal lipids have been studied extensively in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) but little is known about fetal lipids. We hypothesised that the maternal lipid perturbations in PE and IUGR pregnancies would result in similar alterations in the fetal lipid profile. We performed a cross-sectional case control study of maternal and fetal (delivery venous cord blood) lipid and lipoprotein concentrations in third trimester uncomplicated pregnancies (n = 81) and in pregnancies complicated by PE (n = 23) or IUGR (n = 17). In uncomplicated pregnancies, fetal log total cholesterol (TC), log triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were significantly affected by mode of delivery. Fetal log TC (r = 0.37, P = 0.02), log TG (r = 0.34, P = 0.04) and TC/HDL-C ratio (r = 0.31, P = 0.05) were positively correlated with placental weight. Maternal TC (r = 0.35, P = 0.03) and LDL levels (r = 0.36, P = 0.02) were associated with fetal HDL-C levels. Maternal TC was significantly elevated in PE [mean 6.75 (standard deviation 1.14) mmol/L] compared to BMI-matched controls [5.94 (0.89) mmol/L P = 0.04]. In PE, fetal log TC [mean 0.36 (0.23) versus 0.11 (0.15) log mmol/L, P = 0.03], fetal log TG [-0.21 (0.32) versus -0.49 (0.26) log mmol/L, P = 0.02] and fetal TC/HDL-C ratio [3.64 (1.62) versus 1.80 (0.86), P = 0.001] were higher than in controls, after adjustment for mode of delivery. In IUGR, fetal log TG [-0.17 (0.35) versus -0.57 (0.10) log mmol/L, P = 0.01] was higher than controls, after adjustment for mode of delivery. There were no correlations between maternal and fetal lipid levels, or between fetal birth weight and either maternal or fetal lipids in the PE or IUGR groups. We conclude that although fetal lipids do not show a direct correlation with maternal lipids in PE or IUGR, these complications of pregnancy significantly impact upon fetal lipid levels possibly due to increased fetal stress or compromised placental lipid transport. Our findings are potentially pertinent to understanding the future cardiovascular health of the offspring.

Mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells.

OBJECTIVE: To determine whether changes in haemodynamic load, simulated in vitro by mechanically stretching cultured vascular smooth muscle cells, could be transduced into biochemical signals similar to those produced by growth factors. DESIGN: A system was developed which was capable of stretching cultured vascular smooth muscle cells from 0 to 20%. The effect of stretching quiescent vascular smooth muscle cells on both c-fos messenger RNA (mRNA) expression and release of total inositol phosphates was determined over a time interval of 0-360 min. METHODS: Rat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Induction of the proto-oncogene, c-fos, was determined by Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells. RESULTS: A 20% fixed stretch resulted in a rapid induction of c-fos mRNA which reached maximal levels by 15 min. The amount of c-fos mRNA detected was dependent on the degree of stretch, with maximum induction obtained for 15 and 20% stretch. The effects of mechanical stretch were also assessed on phosphoinositide turnover by measuring [3H]-inositol phosphates released from prelabelled cells. A 20% fixed stretch of vascular smooth muscle cells for 20 min resulted in a 3.2-fold increase in total [3H]-inositol phosphates released compared with unstretched cells. CONCLUSIONS: Our results show that mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells in vitro. These observations suggest that mechanical stretch and growth factors share common signal transduction pathways which may be important in the development of vascular hypertrophy.

Differential localization of superoxide dismutase isoforms in placental villous tissue of normotensive, pre-eclamptic, and intrauterine growth-restricted pregnancies.

Several isoforms of superoxide dismutase (SOD), including copper/zinc (cytosolic) and manganese (mitochondrial), exist. In the human placenta, SOD may prevent excessive superoxide accumulation and any potential deleterious oxidative effects. In pre-eclampsia, increased levels of lipid peroxide and decreased SOD activity have been described in the placenta. Oxidative stress such as occurs in pre-eclampsia can alter expression of SOD isoforms. The objective of this study was to localize the copper/zinc and manganese SOD isoforms in the placenta using immunohistochemistry and to compare localization and intensity of immunostaining in tissues from normotensive pregnancies with those from pregnancies complicated by pre-eclampsia and/or intrauterine growth restriction (IUGR). Western blotting with specific antibodies recognized a 17-kD copper/zinc and a 23-kD manganese SOD subunit in placental homogenates. Intense immunostaining for the manganese SOD isoform was seen in villous vascular endothelium, but only faint staining was found in the syncytiotrophoblast or villous stroma. In serial sections, intense immunostaining for copper/zinc SOD was seen in certain cells of the villous stroma but only faint immunostaining in syncytiotrophoblast and vascular endothelium. No apparent differences in localization or intensity of immunostaining for either isoform were seen between tissues of normotensive or pre-eclamptic pregnancies, with or without IUGR. The different cellular localizations of the SOD isoforms suggest that they fulfill different functional roles within the placenta.

The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: significance of pregnancy associated activated protein C resistance.

Activated protein C (APC) resistance secondary to Factor V Leiden (FVL) is associated with pregnancy failure and pre-eclampsia (PET). In non-pregnant subjects, the degree of resistance to APC relates to venous thrombosis risk. In pregnancy, resistance to APC occurs in the absence of FVL. We investigated, in an unselected prospective longitudinal study of 1,671 pregnant, non-FVL subjects, the relationship of the APC sensitivity ratio (APC:SR) with demographic variables and pregnancy outcome. Lower APC:SR values at 7-16 weeks gestation were observed in subjects who subsequently developed PET (median APC:SR 2.55, IQR 2.29-2.70 vs 2.69, IQR 2.48-2.93, Mann-Whitney U-test p = 0.003) in the current pregnancy. An APC:SR < the median (2.69) at 7-16 weeks was associated with a 2.95-fold increased risk (CI95 1.2-7.4) of PET in the current pregnancy. No relationship between the APC:SR, at any gestation, and fetal loss was observed. An inverse correlation between the APC:SR and birth weight was noted. Higher APC:SRs were observed in blood group O subjects and smokers. An inverse relationship of the APC:SR with age, diastolic blood pressure and total serum cholesterol was observed.

Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers.

Ketorolac is a potent cyclo-oxygenase inhibitor used for the treatment of postoperative pain. It is known to have anti-platelet properties. The aim of this study was to determine the effect of ketorolac on haemostasis both alone and in combination with low dose heparin in 12 healthy male volunteers. Each volunteer received the following drug combinations in a double blind, placebo controlled, cross over manner: ketorolac placebo/heparin placebo, ketorolac active/heparin placebo, ketorolac active/heparin active and ketorolac placebo/heparin active. Ketorolac significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin cephalin clotting time and increased anti-Xa levels. Ketorolac had no effect on the kaolin cephalin clotting time or anti-Xa levels and no interaction was found between ketorolac and heparin in any of the investigations. The prolongation of bleeding time seen with ketorolac is unlikely, to be of any major clinical significance as almost all subjects remained within the normal range; however, it should be used with caution in subjects with haemostatic problems.

A comparative study of the effects of adrenoceptor antagonists on platelet aggregation and thromboxane generation.

Platelet aggregation and thromboxane A2 have been implicated in the pathogenesis of several forms of vascular disease. The aim of this study was to determine the effect of a wide range of adrenoceptor antagonists on platelet aggregation, and thromboxane A2 production, from normal human platelet rich plasma in vitro. Labetalol, pindolol and propranolol inhibited platelet aggregation to collagen in a dose dependent manner. Increasing the concentration of collagen "shifted" the dose response curve to the right. These 3 drugs also significantly inhibited thromboxane A2 generation in response to collagen but not to arachidonic acid. This effect was independent of any inhibitory effect of these drugs on platelet aggregation, and occurred at a drug concentration close to that obtained in vivo. Atenolol, metoprolol, prazosin and timolol were similarly assessed but had no effect on either platelet aggregation or thromboxane A2 generation. This ability of labetalol, pindolol, and propranolol to inhibit platelet aggregation and thromboxane generation, may be of clinical benefit in view of the increasing evidence implicating thromboxane A2 in the pathogenesis of vascular disease.

Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.

A prospective study of activated protein C sensitivity, protein C, protein S, and other coagulation factors in 239 women during normal pregnancy was carried out. Protein C activity appeared unaffected by gestation, although an elevation of protein C activity was observed in the early puerperium. A fall in total and free protein S with increasing gestation was observed. Activated protein C sensitivity ratio (APC:SR) showed a progressive fall through pregnancy. This fall correlated with changes in factor VIIIc, factor Vc and protein S. 38% of subjects, with no evidence of Factor V Leiden or anticardiolipin antibodies, showed a low APC:SR (APC:SR <2.6) in the third trimester of pregnancy. Aside from a significant reduction in birth weight, no difference in pregnancy outcome was observed between these subjects and those with a normal APC:SR. Activated protein C sensitivity ratio, modified by pre-dilution of patient samples with factor V depleted plasma, showed no consistent trend with gestation.

Risk factors for pregnancy associated venous thromboembolism.

In an attempt to reduce the incidence of pregnancy associated venous thromboembolism (PA-VTE), some researchers have advocated screening of all women for the factor V(Leiden) mutation during early pregnancy. We have conducted a large retrospective study (over 72,000 deliveries) to determine if this would be useful. Sixty-two objectively confirmed venous thrombotic events (51 DVT, 11 PE) were recorded at two maternity units in the UK. The incidence of DVT was 0.71 per 1000 deliveries (95% CI 0.5-0.9) with 0.50 occurring in the antenatal period (95% CI 0.34-0.66) and 0.21 in the puerperium (95% CI 0.11-0.31). The incidence of PE was 0.15 per 1000 deliveries (95% CI 0.06-0.24), 0.07 antenatal (95% CI 0.01-0.13) and 0.08 in the puerperium (95% CI 0.02-0.14). Of these 62, 50 attended for follow-up and thrombophilia screening. 28% of all episodes of PA-VTE had no clinical risk factor for thrombosis or an identifiable thrombophilic abnormality. Deficiency of antithrombin was identified in 12% of individuals (95% CI 3-21) and the factor V(Leiden) mutation in 8% (95% CI 0.5-15.5). Based on estimates of the prevalence of the factor V(Leiden) mutation in the population, we estimate that the thrombotic risk for a woman during pregnancy or the puerperium with the defect is approximately 1 in 400-500. This figure would not lend support to the idea of random screening for the mutation in early pregnancy.

Effect of stanozolol on factors VIII and IX and serum aminotransferases in haemophilia.

The treatment of haemophilia has been dramatically improved since the introduction of factor VIII and IX concentrates, however these concentrates have brought new problems such as hepatitis and A.I.D.S. An oral agent which could raise endogenous levels of factor VIII and IX would be of great benefit. Danazol, an anabolic steroid, has recently been shown to increase levels of factors VIII and IX in haemophilia. We therefore studied the effect of stanozolol, a closely related anabolic steroid, in 15 patients with haemophilia A or Christmas disease over a 2-4 week period. There was no consistent change in factor VIIIc or factor IX, and fibrinolysis was significantly enhanced. No effect was apparent on the incidence of spontaneous bleeds. However serum aminotransferases which were abnormal in 11 of the 15 patients at the start of the study fell significantly with stanozolol therapy. This raises the interesting possibility that anabolic steroids may be beneficial in patients with chronic liver diseases.