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0.06b Role of protein S and tissue factor pathway inhibitor in the development of APC resistance early in pregnancy
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Abstracts / Thrombosis Research 127 (2011) S123–S150
Conclusions: GDM is associated with concomitant early-morning activation of extrinsic coagulation pathway and attenuation of contact activation pathway. In the latter, SNS may be one of the mediating mechanisms. The dissociation of AM and vWF–FVIII interaction during pregnancy may refer to unrevealed mechanism contributing to hypercoagulation and thrombosis risk. O.06b Role of protein S and tissue factor pathway inhibitor in the development of APC resistance early in pregnancy S.N. Tchaikovski1,3 *, M.C.L.G.D. Thomassen1 , S.D. Costa3 , L.L.H. Peeters2 , J. Rosing1 . 1 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 2 Department of Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands, 3 Department of Gynecology, Otto-von-Guericke University, Magdeburg, Germany Background: Pregnancy is a risk factor for venous thrombosis. Elevated thrombin generation and resistance to activated protein C (APC) likely contribute to the increased thrombosis risk of pregnant women. Objectives: We studied changes and the determinants of thrombin generation and APC resistance in the first 16 weeks of pregnancy. Additionally, we investigated the influence of pregnancy-induced haemodilution on coagulation. Methods: We measured thrombin generation and APC resistance, as well as plasma levels of prothrombin, factor V, factor X, protein S and tissue factor pathway inhibitor (TFPI) in 21 pregnant women at 8, 12 and 16 weeks of gestation and in 30 non-pregnant controls. Results: Women at 8 weeks pregnancy had higher thrombin generation and APC resistance than non-pregnant controls, and these values increased progressively between 8 and 16 weeks. The main determinants of APC resistance were TFPIfree , protein Sfree and factor X. Changes in the TFPIfree and protein Sfree levels accounted for ~70% of pregnancy-induced APC resistance. At a low tissue factor concentration, thrombin generation was dependent on the levels of protein Sfree , factor X, factor V and TFPIfree . Interestingly, a significant correlation (slope 2.23; 95% CI: 1.56 to 2.91; r= 0.58) was observed between protein Stotal levels and haematocrit. Conclusions: A decrease of the plasma levels of TFPIfree and protein Sfree during pregnancy impairs the function of the TFPI and protein C systems, resulting in elevated thrombin generation and increased APC resistance. Furthermore, our data provide indirect evidence for pregnancy-dependent haemodilution contributing to the decreased peripheral protein S levels. O.06C Oligoamenorrhea, high weight accrual rate, acanthosis and first trimester hypertriglyceridemia are independent predictors of preeclampsia S. Hoirisch Clapauch1 *, P.R. Benchimol-Barbosa2 . 1 Hospital Federal dos Servidores do Estado do Rio de Janeiro, 2 DSc. State University of Rio de Janeiro, Brazil Introduction: Thrombophilia and preeclampsia are related to preterm deliveries and fetal death due to placental thrombosis. Objective: To evaluate predictors of preeclampsia. Methods: We analyzed retrospectively clinical and laboratory data of 106 women with recurrent fetal losses and/or preterm deliveries from 2007– 2009. Women were defined as normotensive (NP, n = 54, 195 pregnancies) or preeclamptic (PP, n = 52, 92 pregnancies). Weight accrual rate was arbitrarily defined as acquired weight since age of 18 until the beginning of pregnancy, divided by elapsed years (WAR, kg/years). A logistic regression analysis identified independent predictors of preeclampsia. Bootstrap resampling assessed data fitness to model. Data was presented as mean±SD or percentage (p < 0.05). Results: In PP, 34% had one episode and 66% had ≥2 episodes of preeclampsia; 10% had eclampsia and/or HELLP. Maternal age (NP = 29.9±5.2; PP = 31.5±6.5), fetal deaths (NP = 50%; PP = 51%), preterm deliveries (NP = 35%, PP = 21%), afro-descendance (NP = 46%; PP = 50%) and antiphospholipid syndrome prevalence (NP = 9%; PP = 8%) were not different, whereas oligoamenorrhea (NP = 28%; PP = 58%; OR = 3.5; p = 0.002), WAR (NP = 0.61±0.78; PP = 1.47±1.21; p = 0.0001), acanthosis (NP = 7%, PP = 53%; OR = 16; p < 0.001), and first trimester triglyceridemia (NP = 106±49; PP = 134±55; p = 0.01) were different between groups. In a multivariate logistic model, oligoamenorrhea (p = 0.01), WAR > 0.8 (p < 0.001), acanthosis (p = 0.02) and first trimester triglyceridemia >150 mg/dL (p < 0.03) were independent predictors of preeclampsia. Preeclampsia predictor index defined as ≥2 of 4 predictors showed a hazard ratio of 48 (95% CI:15–150) to develop preeclampsia (88% specificity, 82% sensitivity, c-statistic 87±4%; p = 0.0001). After 1,000 bootstrap resampling, average coefficients were oligoamenorrhea: 2.7±1.5 (p < 0.001);
WAR > 0.8: 1.7±1.6 (p < 0.001); acanthosis: 2.0±1.8 (p < 0.001); and first trimester triglyceridemia >150 mg/dL: 1.8±1.9 (p < 0.001). In bootstraps, oligoamenorrhea, WAR > 0.8, acanthosis and first trimester triglyceridemia >150 mg/dL predicted preeclampsia in, respectively, 99.4%, 99.9%, 99.2%, and 99.4%. Conclusions: Clinical markers related to insulin resistance and sedentary lifestyle are independent strong predictors of preeclampsia. O.07a Enoxaparin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia: the pilot randomised controlled NOH-PE study J.C. Gris *, C. Chauleur, P. Mares, ` I. Quer ´ e, ´ J.Y. Lefrant, B. Haddad, M. Dauzat. University Hospital and research team EA2992, Nîmes, France Administration of heparin in the secondary prevention of placental vascular complications is still experimental. In women with severe pre-eclampsia during their first pregnancy, we investigated the effectiveness of a LMWH in preventing these complications. Between January 2000 and January 2010, 224 women from the NOHA First cohort, with previous severe preeclampsia and negative for antiphospholipid antibodies, with a second singleton pregnancy, all received low-dose aspirin and were randomised to either a prophylactic daily dose of enoxaparin starting from the positive pregnancy test (n = 112) or no enoxaparin (n = 112). The primary outcome was a composite of at least one of the following: preeclampsia, abruptio placentae, birthweight <5th percentile of foetal loss after 20 weeks. Enoxaparin was associated with a lower frequency of primary outcome: 8.9% (10/112) vs. 25% (28/112), p = 0.0025, adjusted hazard ratio = 0.30, 95% confidence interval 0.13–0.65, p = 0.012. Enoxaparin was safe, with no obvious side-effect. This pilot study shows that enoxaparin, added to low-dose aspirin given early during the second pregnancy, decreases the occurrence of placental vascular complications in women with a previous severe pre-eclampsia. O.07b Low molecular weight heparin versus no treatment in women with previous severe pregnancy complications and placental findings without thrombophilia M. Kupferminc *, E. Rimon, A. Many, S. Maslovitz, J.B. Lessing, R. Gamzu. Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Objectives: Low molecular weight heparin (LMWH) treatment has been recommended for pregnant women with previous adverse pregnancy and who were diagnosed as having a thrombophilia. We now examined the effect of LMWH on pregnant women without thrombophilias who had severe pregnancy complications and placental vasculopathy in an earlier pregnancy. Methods: Seventy-two women with a history of severe preeclampsia, fetal growth restriction (FGR) <5th percentile, severe placental abruption, and/or stillbirth >20 weeks whose thrombophilia workup was negative were enrolled. Placental vasculopathy was defined as villous infarcts, fibrinoid necrosis of decidual vessels, fetal vessel thrombosis, evidence of placental abruption and perivillous fibrin deposition. The study group consisted of 32 pregnant women who were treated with LMWH and 40 pregnant women who were not treated with LMWH (control group) in their ensuing pregnancy in our institution between 2003–2007. Results: The incidences of severe preeclampsia, FGR, placental abruption and stillbirth in the previous pregnancies were similar for both groups. The incidences of severe preeclampsia and placental abruption in the study group in the undex pregnancy were significantly lower than the control group (3.13% vs. 20%, P = 0.03, and 0% vs. 15%, P = 0.03, respectively). The respective incidences of FGR was 6.25% vs. 22.5%, and of overall adverse outcome was 9.4% vs. 60% (P = 0.001). Conclusions: Treatment with LMWH may reduce the rate of the recurrence of severe pregnancy complications and significant placental vasculopathy in women without thrombophilias.
Abstracts / Thrombosis Research 127 (2011) S123–S150
Conclusions: GDM is associated with concomitant early-morning activation of extrinsic coagulation pathway and attenuation of contact activation pathway. In the latter, SNS may be one of the mediating mechanisms. The dissociation of AM and vWF–FVIII interaction during pregnancy may refer to unrevealed mechanism contributing to hypercoagulation and thrombosis risk. O.06b Role of protein S and tissue factor pathway inhibitor in the development of APC resistance early in pregnancy S.N. Tchaikovski1,3 *, M.C.L.G.D. Thomassen1 , S.D. Costa3 , L.L.H. Peeters2 , J. Rosing1 . 1 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 2 Department of Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands, 3 Department of Gynecology, Otto-von-Guericke University, Magdeburg, Germany Background: Pregnancy is a risk factor for venous thrombosis. Elevated thrombin generation and resistance to activated protein C (APC) likely contribute to the increased thrombosis risk of pregnant women. Objectives: We studied changes and the determinants of thrombin generation and APC resistance in the first 16 weeks of pregnancy. Additionally, we investigated the influence of pregnancy-induced haemodilution on coagulation. Methods: We measured thrombin generation and APC resistance, as well as plasma levels of prothrombin, factor V, factor X, protein S and tissue factor pathway inhibitor (TFPI) in 21 pregnant women at 8, 12 and 16 weeks of gestation and in 30 non-pregnant controls. Results: Women at 8 weeks pregnancy had higher thrombin generation and APC resistance than non-pregnant controls, and these values increased progressively between 8 and 16 weeks. The main determinants of APC resistance were TFPIfree , protein Sfree and factor X. Changes in the TFPIfree and protein Sfree levels accounted for ~70% of pregnancy-induced APC resistance. At a low tissue factor concentration, thrombin generation was dependent on the levels of protein Sfree , factor X, factor V and TFPIfree . Interestingly, a significant correlation (slope 2.23; 95% CI: 1.56 to 2.91; r= 0.58) was observed between protein Stotal levels and haematocrit. Conclusions: A decrease of the plasma levels of TFPIfree and protein Sfree during pregnancy impairs the function of the TFPI and protein C systems, resulting in elevated thrombin generation and increased APC resistance. Furthermore, our data provide indirect evidence for pregnancy-dependent haemodilution contributing to the decreased peripheral protein S levels. O.06C Oligoamenorrhea, high weight accrual rate, acanthosis and first trimester hypertriglyceridemia are independent predictors of preeclampsia S. Hoirisch Clapauch1 *, P.R. Benchimol-Barbosa2 . 1 Hospital Federal dos Servidores do Estado do Rio de Janeiro, 2 DSc. State University of Rio de Janeiro, Brazil Introduction: Thrombophilia and preeclampsia are related to preterm deliveries and fetal death due to placental thrombosis. Objective: To evaluate predictors of preeclampsia. Methods: We analyzed retrospectively clinical and laboratory data of 106 women with recurrent fetal losses and/or preterm deliveries from 2007– 2009. Women were defined as normotensive (NP, n = 54, 195 pregnancies) or preeclamptic (PP, n = 52, 92 pregnancies). Weight accrual rate was arbitrarily defined as acquired weight since age of 18 until the beginning of pregnancy, divided by elapsed years (WAR, kg/years). A logistic regression analysis identified independent predictors of preeclampsia. Bootstrap resampling assessed data fitness to model. Data was presented as mean±SD or percentage (p < 0.05). Results: In PP, 34% had one episode and 66% had ≥2 episodes of preeclampsia; 10% had eclampsia and/or HELLP. Maternal age (NP = 29.9±5.2; PP = 31.5±6.5), fetal deaths (NP = 50%; PP = 51%), preterm deliveries (NP = 35%, PP = 21%), afro-descendance (NP = 46%; PP = 50%) and antiphospholipid syndrome prevalence (NP = 9%; PP = 8%) were not different, whereas oligoamenorrhea (NP = 28%; PP = 58%; OR = 3.5; p = 0.002), WAR (NP = 0.61±0.78; PP = 1.47±1.21; p = 0.0001), acanthosis (NP = 7%, PP = 53%; OR = 16; p < 0.001), and first trimester triglyceridemia (NP = 106±49; PP = 134±55; p = 0.01) were different between groups. In a multivariate logistic model, oligoamenorrhea (p = 0.01), WAR > 0.8 (p < 0.001), acanthosis (p = 0.02) and first trimester triglyceridemia >150 mg/dL (p < 0.03) were independent predictors of preeclampsia. Preeclampsia predictor index defined as ≥2 of 4 predictors showed a hazard ratio of 48 (95% CI:15–150) to develop preeclampsia (88% specificity, 82% sensitivity, c-statistic 87±4%; p = 0.0001). After 1,000 bootstrap resampling, average coefficients were oligoamenorrhea: 2.7±1.5 (p < 0.001);
WAR > 0.8: 1.7±1.6 (p < 0.001); acanthosis: 2.0±1.8 (p < 0.001); and first trimester triglyceridemia >150 mg/dL: 1.8±1.9 (p < 0.001). In bootstraps, oligoamenorrhea, WAR > 0.8, acanthosis and first trimester triglyceridemia >150 mg/dL predicted preeclampsia in, respectively, 99.4%, 99.9%, 99.2%, and 99.4%. Conclusions: Clinical markers related to insulin resistance and sedentary lifestyle are independent strong predictors of preeclampsia. O.07a Enoxaparin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia: the pilot randomised controlled NOH-PE study J.C. Gris *, C. Chauleur, P. Mares, ` I. Quer ´ e, ´ J.Y. Lefrant, B. Haddad, M. Dauzat. University Hospital and research team EA2992, Nîmes, France Administration of heparin in the secondary prevention of placental vascular complications is still experimental. In women with severe pre-eclampsia during their first pregnancy, we investigated the effectiveness of a LMWH in preventing these complications. Between January 2000 and January 2010, 224 women from the NOHA First cohort, with previous severe preeclampsia and negative for antiphospholipid antibodies, with a second singleton pregnancy, all received low-dose aspirin and were randomised to either a prophylactic daily dose of enoxaparin starting from the positive pregnancy test (n = 112) or no enoxaparin (n = 112). The primary outcome was a composite of at least one of the following: preeclampsia, abruptio placentae, birthweight <5th percentile of foetal loss after 20 weeks. Enoxaparin was associated with a lower frequency of primary outcome: 8.9% (10/112) vs. 25% (28/112), p = 0.0025, adjusted hazard ratio = 0.30, 95% confidence interval 0.13–0.65, p = 0.012. Enoxaparin was safe, with no obvious side-effect. This pilot study shows that enoxaparin, added to low-dose aspirin given early during the second pregnancy, decreases the occurrence of placental vascular complications in women with a previous severe pre-eclampsia. O.07b Low molecular weight heparin versus no treatment in women with previous severe pregnancy complications and placental findings without thrombophilia M. Kupferminc *, E. Rimon, A. Many, S. Maslovitz, J.B. Lessing, R. Gamzu. Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Objectives: Low molecular weight heparin (LMWH) treatment has been recommended for pregnant women with previous adverse pregnancy and who were diagnosed as having a thrombophilia. We now examined the effect of LMWH on pregnant women without thrombophilias who had severe pregnancy complications and placental vasculopathy in an earlier pregnancy. Methods: Seventy-two women with a history of severe preeclampsia, fetal growth restriction (FGR) <5th percentile, severe placental abruption, and/or stillbirth >20 weeks whose thrombophilia workup was negative were enrolled. Placental vasculopathy was defined as villous infarcts, fibrinoid necrosis of decidual vessels, fetal vessel thrombosis, evidence of placental abruption and perivillous fibrin deposition. The study group consisted of 32 pregnant women who were treated with LMWH and 40 pregnant women who were not treated with LMWH (control group) in their ensuing pregnancy in our institution between 2003–2007. Results: The incidences of severe preeclampsia, FGR, placental abruption and stillbirth in the previous pregnancies were similar for both groups. The incidences of severe preeclampsia and placental abruption in the study group in the undex pregnancy were significantly lower than the control group (3.13% vs. 20%, P = 0.03, and 0% vs. 15%, P = 0.03, respectively). The respective incidences of FGR was 6.25% vs. 22.5%, and of overall adverse outcome was 9.4% vs. 60% (P = 0.001). Conclusions: Treatment with LMWH may reduce the rate of the recurrence of severe pregnancy complications and significant placental vasculopathy in women without thrombophilias.