Activated protein C resistance in normal pregnancy

This prospective cross-sectional (10 women on each occasion) and longitudinal (20 women) study investigated activated protein C (APC) ratio in normal pregnancy. The APC ratio was measured at booking, 20, 30 and 36 weeks of gestation, and compared with a sample of normal nonpregnant women. No significant difference was found between APC ratios for pregnant women at any gestation and those of the nonpregnant population in either the longitudinal or cross-sectional studies. There was a significant decrease in APC ratios throughout pregnancy, but in all but one case values remained within the normal nonpregnant range. The APC ratio can therefore be used as a screening test for the factor V Leiden mutation during pregnancy.     

Activated protein C resistance and lupus anticoagulant in pregnancy

Thrombophilias, both inherited and acquired, have been reported to be associated with thromboembolic events and severe obstetric complications. This case report examines the case of a patient with two thrombophilias, activated protein C resistance secondary to Factor V Leiden mutation and lupus anticoagulant.     

Activated protein C resistance and lupus anticoagulant in pregnancy

Thrombophilias, both inherited and acquired, have been reported to be associated with thromboembolic events and severe obstetric complications. This case report examines the case of a patient with two thrombophilias, activated protein C resistance secondary to Factor V Leiden mutation and lupus anticoagulant.     

Activated protein C resistance in normal and pre-eclamptic pregnancies

OBJECTIVES: A lower ratio in the classic activated protein C resistance (APC-R) test has been reported during pregnancy, which has been called 'acquired' APC-R. However, little is known about the cause of the lowered ratio, and whether or not there is a correlation with blood coagulation activation. The primary objective of our study was to determine changes in APC-R levels in each of the trimesters of normal pregnancy. The secondary objective was to confirm whether APC-R levels were lower in pregnancies complicated by pre-eclampsia than in a control group. Finally, this prospective study was performed to investigate the prevalence of APC-R among pregnant women and to elucidate its obstetric consequences. METHODS: We enrolled 35 healthy pregnant women and 47 pregnant women affected by pre-eclampsia in our study. The following laboratory tests were performed: prothrombin time, partial thromboplastin time, fibrinogen levels, antithrombin III, plasmatic fibronectin (as a marker of endothelial damage), haptoglobin (as a marker of intravascular haemolysis), a functional test for APC-R and analysis of factor V Leiden mutation by polymerase chain reaction. RESULTS: The activated protein C sensitivity ratio was lower in the pathological group than in the control group (p = 0.008 and p = 0.02, respectively). Plasmatic fibronectin was found to be higher in the pathological group than in the control group (p = 0.05). Finally, the overall prevalence of factor V Leiden mutation was 5.4%, i.e. 2/35 women (5.7%) in the control group and 3/47 women in the pathological group (6.38%). CONCLUSIONS: The APC ratio decreased after 20 weeks of gestation until week 42. This decrease was most pronounced in the third trimester, in which resistance was demonstrated in 34.2% of control group patients. In pre-eclampsia, we found a greater reduction of the APC ratio than in controls. We hypothesise that this is due to a decrease in the plasmatic levels of coagulation inhibitors and an increase in coagulatory factors.     

Activated protein C resistance during in vitro fertilization treatment

Acquired resistance to the anticoagulant action of activated protein C (APC) has been proposed to explain the increased risk of venous thrombosis associated with pregnancy, hormone replacement therapy and the use of oral contraceptives. In this study, we have investigated whether the hormonal changes induced during in vitro fertilization (IVF) treatment are also associated with acquired APC resistance. Twenty-nine women, who were planned for an IVF cycle, donated blood at four time points during treatment, i.e. at baseline, down-regulation, hyperstimulation and luteal support. In the plasma samples, APC sensitivity ratios (APCsr) and the levels of progesterone and estradiol were measured. The changes in plasma concentrations of hormones were in accordance with literature. The APCsr increased significantly during hyperstimulation and remained high during luteal support. The extent of APC resistance occurring during IVF treatment was comparable to that observed during the use of second generation OC and was less pronounced than that occurring during pregnancy. The change in estradiol between baseline and hyperstimulation correlated with the change in APCsr. Although this suggests that plasma estrogen levels are an important determinant for acquired APC resistance, it remains to be established which plasma proteins are responsible for estrogen-induced APC resistance.     

Activated protein C resistance in Turkish women with severe preeclampsia

The purpose of this study was to investigate the occurrence rate of APC resistance (APC-R) with severe preeclampsia in Turkish women. Thirty-two consecutive women having severe preeclampsia were included in the study. Thirty-two healthy pregnant women served as the control group. APC-R assays were performed in the third trimester of pregnancy, and 3 and 9 months after delivery. APC-R was demonstrated in the third trimester, 3 months and 9 months after delivery in 27 (84.4%), 23 (71.9%) and 5 (15.6%) of 32 preeclamptic patients, respectively. APC-R rates were significantly higher in preeclamptic group than in normal pregnant women in the third trimester of pregnancy (p < 0.05). Decreased mean APC activity and also increased APC-R rate was still persisting in preeclamptic group for 3 months after delivery. Nine months after delivery, the mean APC activity and also APC-R rates approached to the normal pregnant women; however, there was a significant difference between both groups (p < 0.05). Our results indicate that acquired APC-R may be a contributory factor in the pathogenesis of preeclampsia.     

Activated protein C resistance in cord blood from healthy and complicated newborns

Objectives. Newborns are susceptible to thrombosis secondary to the immature hemostatic system and maternal and fetal complications. The contribution of activated protein C resistance (APCR) to thrombosis tendency has not yet been established. This study was conducted to investigate the effects of maternal and fetal complications on APCR levels.

Methods. APCR levels were determined in cord blood from healthy term infants and compared with those in healthy preterm and complicated neonates as well as that in adult venous blood.

Results. The mean value of APCR in cord blood from healthy term infants (166 ± 40 s) was not significantly different from that in adult venous blood (173 ± 40 s). No significant differences in the mean cord blood APCR values were observed between healthy term and preterm infants, infants with vaginal and cesarean delivery, infants from preeclamptic and non-eclamptic mothers, and infants with or without perinatal asphyxia. The activity levels of protein C, protein S, and antithrombin III were not significantly different between these groups except for lower levels in preterm babies.

Conclusions. The level of APCR in cord blood is comparable to that in adults and not influenced by maternal and fetal complications. It appears that APCR does not contribute to the thrombotic tendency in newborns.     

Activated protein C resistance (APCR) and placental fibrin deposition

Activated protein C resistance (APCR) results in an ineffective anticoagulant response leading to an increased risk of thrombosis, particularly during pregnancy. Adverse pregnancy outcomes including pre-eclampsia (PET), intrauterine growth restriction (IUGR), recurrent miscarriage and placental abruption have been linked with thrombotic lesions compromising the utero-placental circulation. Using histological staining including Martius Scarlet Blue (MSB) and Haematoxylin and Eosin (H&E) and microscopy, we studied placental fibrin deposition and histological abnormalities in subjects (n=23) with APCR (APCR group), based on a ratio of less than or equal to 2.1s with the Coatest((R)) classic test and subjects (n=11) with an APC ratio in the normal range, greater than 2.1s (APCN group). Fibrin deposition was significantly higher (3.3-fold) in the APCR group compared to the APCN group. An inverse correlation between APC ratio and placental fibrin deposition was determined for the study group. Histological abnormalities were more than 2-fold higher in the APCR group compared to the APCN group. Molecular screening identified common thrombophilic mutations, FVL and FII-G20210A in the APCR group but not in the APCN group.     

Activated protein C resistance in cord blood from healthy and complicated newborns.

OBJECTIVES: Newborns are susceptible to thrombosis secondary to the immature hemostatic system and maternal and fetal complications. The contribution of activated protein C resistance (APCR) to thrombosis tendency has not yet been established. This study was conducted to investigate the effects of maternal and fetal complications on APCR levels. METHODS: APCR levels were determined in cord blood from healthy term infants and compared with those in healthy preterm and complicated neonates as well as that in adult venous blood. RESULTS: The mean value of APCR in cord blood from healthy term infants (166 +/- 40 s) was not significantly different from that in adult venous blood (173 +/- 40 s). No significant differences in the mean cord blood APCR values were observed between healthy term and preterm infants, infants with vaginal and cesarean delivery, infants from preeclamptic and non-eclamptic mothers, and infants with or without perinatal asphyxia. The activity levels of protein C, protein S, and antithrombin III were not significantly different between these groups except for lower levels in preterm babies. CONCLUSIONS: The level of APCR in cord blood is comparable to that in adults and not influenced by maternal and fetal complications. It appears that APCR does not contribute to the thrombotic tendency in newborns.     

C-reactive protein in normal pregnancy

Maternal serum C-reactive protein (CRP) has been studied extensively as an adjunct in the diagnosis of subclinical infection among pregnant women with preterm labor or preterm rupture of membranes. However, before the utility of CRP can be studied in pregnancies with these complications, the effects of normal pregnancy and labor on maternal serum CRP levels must be established. We determined CRP levels serially from 22 weeks' gestation until delivery in healthy pregnant women without antepartum complications. Median CRP values for women not in labor ranged from 0.7-0.9 mg/dL, depending on gestational age; 95% of the values were 1.5 mg/dL or lower. No consistent change in CRP levels with gestational age was found among serially sampled women not in labor. The median CRP value for women in labor at term was 1.3 mg/dL, and 32% of values were over 1.5 mg/dL. Median CRP values in normal pregnancies appear to be higher than standardized values for nonpregnant individuals, and CRP values are further elevated in labor. Understanding the physiology and temporal course of the increase in CRP in normal pregnancy and labor may help to clarify the appropriate use of CRP in complicated pregnancies.     

Activated protein C resistance associated with maternal floor infarction treated with low-molecular-weight heparin

Factor V Leiden with activated protein C resistance is found in up to 5% of the population. It is associated with current adverse pregnancy outcomes. Maternal floor infarction is a lesion in which fibrin is deposited throughout the placenta, leading to necrosis of villi, and (50% of the time) fetal demise. It is also often recurrent. There is no known etiology of maternal floor infarction, nor is there a known treatment. We report a case of a 34-year-old G5, P2 with multiple pregnancy losses, including two fetal deaths. Placental pathology was obtained from one of the losses and was notable for maternal floor infarction. In the index pregnancy, she was evaluated for thrombophilia and found to have a significant protein C resistance of 1.59, consistent with a factor V Leiden. She was treated with low-molecular-weight heparin, enoxaparin, 40 mg twice a day, titrated to achieve an activated factor Xa activity level of 0.2 prior to her next dose. Her pregnancy was unremarkable until 39 weeks, when she developed a decreased amniotic fluid index. A 2995-kg healthy infant was delivered. The placenta showed no evidence of maternal floor infarction. This case demonstrates an association between maternal floor infarction and activated protein C resistance. It is also notable for a successful treatment of recurrent maternal floor infarction with prophylactic heparin. A single case report can only raise a question regarding associations. As we become more familiar with the thrombophilias, we may better understand the association of thrombophilias and placental disease as well as develop successful treatments.     

C-reactive protein during normal pregnancy

Serum C-reactive protein (CRP) is determined in a prospective longitudinal study of 60 low-risk pregnant women. CRP is also measured in umbilical-cord blood after delivery. The serum CRP concentrations seem to be independent of pregnancy and gestational age. The 95th percentile is estimated to be 20 mg/l, and this value is considered as the upper limit of normal. A rise in CRP level is considered more predictive of infection than a determination of a single high value. CRP does not cross the placental barrier, and may therefore be useful in diagnosing infections in newborns.     

妊娠不同时期脂肪细胞因子的动态变化与胰岛素抵抗的关系

目的探讨妊娠不同时期脂肪细胞因子的动态变化及其与孕妇胰岛素抵抗的关系。方法选择2004年10月—2005年10月在我院门诊行产前检查的正常孕妇67例,其中妊娠早期18例(妊娠早期组),妊娠中期19例(妊娠中期组),妊娠晚期30例(妊娠晚期组);另选同期正常非孕妇女46例为对照组。采用酶联免疫吸附试验检测各组妇女血清中可溶性肿瘤坏死因子α受体(sTNFR)-Ⅰ、Ⅱ水平;采用放射免疫法测定各组妇女血清中瘦素、脂联素水平;采用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接(SP)法检测妊娠晚期组妇女胎盘及脂肪组织中sTNFR定位与阳性表达。结果(1)妊娠早、中、晚期组及对照组妇女血清中sTNFR-Ⅰ水平分别为(799±173)、(1003±241)、(1278±306)及(729±167)ng/L,妊娠中、晚期组明显高于对照组,分别比较,差异有统计学意义(P<0·001)。(2)妊娠早、中、晚期组及对照组妇女血清中sTNFR-Ⅱ水平分别为(1383±305)、(1772±293)、(1933±498)及(1002±221)ng/L,妊娠早、中、晚期组明显高于对照组,分别比较,差异均有统计学意义(P<0·001)。并随孕期的增加,sTNFR-Ⅱ水平不断升高。(3)妊娠早、中、晚期组及对照组妇女血清中瘦素水平分别为(65±37)、(70±40)、(89±57)及(61±37)μg/L,妊娠晚期组明显高于对照组,两组比较,差异有统计学意义(P<0·05)。(4)妊娠早、中、晚期组及对照组妇女血清中脂联素水平分别为(13±6)、(9±5)、(10±4)及(14±7)mg/L,妊娠中、晚期组明显低于对照组,分别比较,差异有统计学意义(P<0·05)。(5)妊娠晚期组妇女胎盘及脂肪组织中sTNFR-Ⅰ、Ⅱ均呈阳性表达,无阴性表达;sTNFR-Ⅰ阳性染色颗粒主要定位于胎盘绒毛组织中的合体滋养细胞以及细胞滋养细胞中的胞质和胞膜,sTNFR-Ⅱ阳性染色颗粒主要定位于胎盘血管内皮细胞中的胞质和胞膜。结论孕妇血清中sTNFR-Ⅰ、Ⅱ及瘦素水平随孕期的增加不断升高;而脂联素水平则随孕期的增加有所下降,上述变化可能与孕妇的胰岛素抵抗有关。     

Reduction in protein S activity during normal pregnancy

We investigated the serial changes in blood protein S (PS) and related proteins in 11 normal pregnant women. The PS activity decreased significantly in the third trimester and reached minimum levels (23.3%) one hour after delivery. Although the PS activity was reduced markedly below the normal limits, all the women delivered safely. The mechanisms that cause the reduction in PS activity and the clinically dangerous conditions involving PS activity during pregnancy warrant further investigation.     

Longitudinal evaluation of activated protein C resistance among normal pregnancies of Hispanic women

OBJECTIVE: This study was undertaken to describe pregnancy-associated activated protein C resistance and the presence of the factor V Leiden mutation in a sample population of pregnant Hispanic women. STUDY DESIGN: Twenty healthy Hispanic women with single intrauterine pregnancies were randomly selected. Blood samples were taken before 8 weeks' gestation, every 4 weeks during pregnancy, and at 6 weeks post partum. Samples were collected, separated, and stored at -70 degrees C until assay. Standard and modified partial thromboplastin time-based assays were used to evaluate response to activated protein C. A sensitivity ratio < or =2 indicated resistance to activated protein C. Repeated measures analysis of variance and unpaired t tests were used as appropriate. P <.05 was considered significant. RESULTS: Mean (+/-SEM) maternal age was 29 +/- 5 years, and most women were multiparous. Mean gestational age at delivery was 38 weeks' gestation, and the mean birth weight was 3000 g. According to the standard assay, 10 women (50%) acquired activated protein C resistance by 13 weeks' gestation, and this condition persisted through delivery and resolved post partum. Another two had preexisting activated protein C resistance. Results of the standard assay were significantly different for women with preexisting and pregnancy-associated activated protein C resistance (1.55 vs 2.18; P =.01). The modified assay distinguished between women with preexisting and pregnancy-associated activated protein C resistance at 8 weeks' gestation, 24 weeks' gestation, and post partum. The pregnancies of the women with preexisting activated protein C resistance were complicated by oligohydramnios at 34 weeks' gestation and required delivery at 36 weeks' gestation. One infant was small for gestational age. Allele-specific polymerase chain reaction analysis demonstrated that both patients with preexisting activated protein C resistance carried one copy of the factor V Leiden mutation. CONCLUSION: The incidences of pregnancy-associated and factor V Leiden mutation-associated activated protein C resistances in our cohort of gravid Hispanic women was higher than previously reported. Factor V Leiden-associated activated protein C resistance in two patients was associated with adverse perinatal outcome.