- Email: [email protected]
P-005 Bleeding tendency in Swedish carriers of haemophilia A and B
Abstracts / Thrombosis Research 131, Suppl. 1 (2013) S71–S103
is a loop region which is in contact with the longest helix of PZI. Other regions have been identified, which hold anomalous flexibility associated with potentially protective gene variants. A possible explanation of the effect of the observed gene variants is given, based on the interaction between PZ and PZI.
P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities H.M. Knol 1,2 , A.B. Mulder 3 , D.H. Bogchelman 2 , H.C. Kluin-Nelemans 1 , A.G.J. van der Zee 2 , K. Meijer 1 1 Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen; 2 Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen; 3 Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the Netherlands Introduction: Bleeding disorders have been recognized as an important etiologic and/or contributing factor in women with menorrhagia. Objective: To assess the prevalence of bleeding disorders and symptoms in women with menorrhagia, with and without gynaecological abnormalities. Methods: We included 102 consecutive patients referred for menorrhagia, confirmed by a pictoral bleeding assessment chart score >100. Patients and controls (28 healthy volunteers without menorrhagia) had haemostatic testing in the 1st week after menstruation and a bleeding history was taken. Patients underwent gynaecologic evaluation. Results: 46% of patients were anaemic, 61% had low ferritin. Twenty-six percent of patients had endometrial polyps or submucosal uterine myoma, sufficient to explain menorrhagia. An underlying bleeding disorder was found in 29% vs 11% (p=0.04) of the patients vs controls, and in 31% vs 27% of the women with unexplained vs explained menorrhagia (p=0.75). We diagnosed 6 cases of VWD, 4 cases of FXI deficiency and one FVII deficiency. The only abnormalities found in controls were platelet aggregation defects (11% vs 23% in patients). Patients had a significantly longer aPTT compared to controls (26.5 vs 25.0 sec; p=0.001) caused by lower median levels of FXI (100 vs 124 IU/dL; p<0.001). Although non-menorrhagia bleeding symptoms were more prevalent in patients than in controls, additional bleeding symptoms did not predict for an underlying bleeding disorder in patients. Conclusion: bleeding disorders play an equally important role in the aetiology of menorrhagia with and without gynaecological abnormalities. A novel finding is the occurrence of low, but not deficient levels of factor XI.
P-003 Plasma free DNA and circulating nucleosomes: Preliminary data in normal and pathologic pregnancies S. Bouvier 1,3,4 , L. Grandemange 4 , E. Mousty 2 , S. Ripart-Neveu 2 , P. Marès 2 , E. Cochery-Nouvellon 1,3 , E. Mercier 1,3,4 , J.-C. Gris 1,3,4 1 Departement of Haematology; 2 Department of Gynaecology and Obstetrics, University Hospital, Nîmes; 3 Research Group E.A. 2992; 4 Laboratory of Haematology, Faculty of Pharmacy and Biological Sciences, Montpellier 1 University, Montpellier, France Recent data have analyzed the fundamental coupling between coagulation and innate immunity, indicating the central role of neutrophil-derived circulating nucleosomes on the promotion of coagulation. As pregnancy is an acquired hypercoagulability state, the aim of this exploratory prospective study was to compare plasma cell free DNA and nucleosomes concentrations between non-pregnant women, pregnant women with a normal pregnancy and pregnant women with an obvious clinical complication. Quantification of DNA and circulating nucleosomes were respectively determined by Q-PCR and a commercially available ELISA kit. Age, white blood cell (WBC) and neutrophils counts were documented for each woman. Blood samples from pregnant women were characterized by gestational age and pregnancy-related pathology, if any. We included 124 patients from October 2011 to May 2012: 35 women with a normal pregnancy, 73 women with an abnormal pregnancy and 16 non-pregnant women. We found increased plasma DNA (p<0.0001) and nucleosomes (p=0.02)
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concentrations in pregnant women, concentrations being the highest in abnormal pregnancies. DNA (p<0.0001) and nucleosomes (p=0.002) concentrations differed depending on the type and severity of pregnancy-related complications: very high rates in the ischemic placental disease group. DNA:WBC, nucleosomes:WBC, DNA:neutrophils and nucleosomes:neutrophils ratios were significantly higher in pregnant women with a symptomatic complication. This preliminary study shows high DNA and nucleosomes plasma concentrations during pregnancy which culminate in severe pregnancy complications. Further studies (currently under evaluation) are necessary before working on the putative clinical value of these new parameters which may be released during pregnancy from non-hematologic cells.
P-004 Homocysteine levels in preterm neonates – The impact of genetic and environmental factors M.J. Simchen 1 , A. Maayan-Metzger 2 , A. Lubetsky 3 , J. Kuint 2 , N. Rosenberg 3 , A.A. Kuperman 3,4 , B.-A. Sela 5 , G. Kenet 3 1 The Department of Obstetrics and Gynecology; 2 The Department of Neonatology, The Edmond and Lily Safra Children’s Hospital; 3 The Institute of Thrombosis and Hemostasis and the; 5 Institute of Chemical Pathology, Sheba Medical Center, Tel-Hashomer, affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel:; 4 The Pediatric Hematology Clinic, Thrombosis and Hemostasis Service, Institute of Hematology, Western Galilee Hospital, Naharriya, Israel Background and Objective: Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early postnatal health status. Methods: Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18-month period. Data were collected on maternal history and delivery as well as on postnatal complications. Results: The study cohort included 167 infants whose mean gestational age was 30.98±2.34 weeks (range: 26–36 weeks), mean birth weight 1327.6±327 g, and mean Hcy level 7.99±3.27 (range 2.2–21.2) μmol/L. Maternal intake of folic acid was inversely associated with the babies’ Hcy levels (p=0.0001). Increased Hcy levels positively correlated with birth weight, gestational age (p<0.005), total number of pregnancies (p=0.012), and presence of MTHFR polymorphism. Higher Hcy levels were associated with feeding (p=0.008), especially total parenteral nutrition (p=0.0001). There was no correlation between Hcy levels and any vascular postnatal complications. Conclusions: During their postnatal hospitalization, preterm infants may have relatively high (within the adult normal range) Hcy levels which are influenced by genetic and environmental factors. Despite the fact that no correlation was found between Hcy levels and postnatal complications, these associations should be further studied.
P-005 Bleeding tendency in Swedish carriers of haemophilia A and B A. Olsson 1 , F. Baghaei 1 , E. Berntorp 2 , M. Hellgren 3 1 Department of Haematology and Coagulation disorders; 3 Department of Obstetrics, Sahlgrenska University Hospital; 2 Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden Objectives: Haemophilia is an X-linked recessive disorder caused by the deficiency of coagulation factors VIII (haemophilia A) and IX (haemophilia B). Carriers of moderate and severe haemophilia A (HA) and B (HB) have been studied. Methods: 126 of 298 carries registered at the three Haemophilia Treatment Centres in Sweden were recruited. The carriership was confirmed by DNA analysis. Ninety healthy women without a family history of bleedings served as controls. Bleeding tendency was determined using the MCMDM-
S78
Abstracts / Thrombosis Research 131, Suppl. 1 (2013) S71–S103
1vWD bleeding questionnaire modified by Bowen. A bleeding score (BS) of ≥4 was considered as clinical relevant bleeding tendency. FVIII:C and FIX:C analyses were performed in carriers only. Results: The mean level of FVIII: C (HA carriers) was 0.74±0.32 kIU/L (ref 0.50–2.00 kIU/L) and the mean level of FIX:C (HB carriers) was 0.54±0.27 kIU/L (ref 0.60–1.30 kIU/L). Carriers had higher BS than controls (p <0.0001). BS was weakly correlated to FVIII:C (p=0.01) but not to FIX:C (p=0.17). A median BS ≥4 was seen in HA and HB carriers with a factor VIII:C and IX:C <0.40 kIU/L, respectively. Conclusion Carriers of severe and moderate HA and HB have an increased bleeding tendency according to the BS. BS correlated weakly to FVIII:C but not to FIX:C.
P-006 Polymorphisms of placental alkaline phosphatase gene are associated with recurrent pregnancy loss S. Bouvier #,1,2,3 , M. Vatin #,4 , L. Bellazi 5 , X. Montagutelli 6 , P. Laissue 7 , A. Ziyyat 4 , C. Serres 4 , M.N. Dieudonné 5 , P. de Mazancourt 5 , E. Mornet 5,8 , D. Vaiman 4 , J.-C. Gris 1,2,3 1 Laboratoire d’Hématologie, CHU de Nîmes, France; 2 E.A. 2992, France; 3 Laboratoire d’Hématologie, U.F.R. des Sciences Biologiques et Pharmaceutiques, UM1, Montpellier, France; 4 Université Paris Descartes, Institut Cochin Inserm U1016 CNRS UMR 8104, Paris, France; 5 Unité de pathologie cellulaire et génétique EA2493, Université de Versailles-Saint Quentin en Yvelines, Versailles, France; 6 Institut Pasteur, Unité de Génétique des Mammifères, Paris, France; 7 Unité de Génétique, Faculté de Médecine, Université Del Rosario, Bogota, Colombie; 8 Laboratoire SESEP, Centre Hospitalier de Versailles, Le Chesnay, France # Co-authors Fertility is a quantitative complex character governed by a considerable number of genes. Despite clinical and scientific advances, many cases of human infertility remain unexplained. From the analysis of embryo resorption rates in inter-specific recombinant congenic mice strains, the placental alkaline phosphatase (PLAP) gene (ALPP) was identified as potentially responsible for recurrent miscarriage in women. This placental gene has been reported to be associated with pregnancy diseases such as pre-term delivery, pre-eclampsia and small-for-gestational age infants. However, little information is available regarding the role of PLAP, a known positive proliferative factor in human trophoblastic cells, in recurrent spontaneous abortion (RSA). ALPP was sequenced in a series of 100 control women and 100 RSA women from the same ethnic background. Functional analysis of PLAP variants was achieved in a cell model. We showed that several ALPP alleles and allelic combinations are more frequent in RSA women. One of the haplotype was associated with a ∼5 fold increased risk of developing RSA. By contrast, one of the polymorphism inducing an amino-acid change (ILE89LEU) in the polypeptidic chain, was clinically protective (RR=0.47, univariable analysis). Functional analysis of this variant revealed a significant increase in PLAP activity. This preliminary study confirms that mouse models are helpful to decipher complex multifactorial diseases in humans. ALPP variants and PLAP seem to be associated with RSA. Larger confirmatory studies are currently under evaluation, the model highlighting other critical genes.
P-007 Pregnant women with mechanical prosthetic heart valves – Which anticoagulant is best? I. Wilkins, N.L. Yatim, E. Ciantar Leeds Teaching Hospitals NHS Trust, Leeds, UK Background: The care of pregnant women with mechanical prosthetic heart valves (MPHV) poses many challenges including the choice of anticoagulation to prevent thromboembolism. Warfarin is known to be associated with an increased risk of miscarriage and late foetal loss whereas lowmolecular-weight heparin (LMWH) is associated with serious maternal events, such as valve thrombosis [1,2]. Aim: The aim of this audit was to identify the pregnancy outcomes and the maternal complications in pregnant women with MPHV using three different anticoagulation regimes.
Method: This was a 10-year retrospective observational study of 22 pregnancies in 13 women identified from combined obstetric-cardiology and obstetric-haematology clinics between 2001 and 2011 at the Leeds Teaching Hospitals (tertiary centre). Outcomes were compared according to the three anticoagulation regimes: 1) warfarin throughout pregnancy, 2) LMWH throughout pregnancy and 3) warfarin with LMWH substitutions (during gestational weeks 6–12 and 36 to delivery). Results:
Miscarriage TOP Stillbirth Neonatal death Live birth (>32w) Valve thrombosis
Warfarin only 9 pregnancies
LMWH only 8 pregnancies
Combined 5 pregnancies
5 (56%) 3 (33%) 0 0 1 (11%) 0
1 (13%) 1 (13%) 0 1 (13%) 5 (63%) 2 (25%)
0 0 1 (20%) 0 4 (80%) 1 (20%)
TOP = termination of pregnancy.
Conclusions: No anticoagulation regime is without risk and our result interpretation is limited by the small cohort. However LMWH (either alone or in combination) was associated with a higher rate of successful live birth but a greater risk of maternal valve thrombosis, one of which requiring emergency valve replacement. References: [1] Parvord, S. (2010). Prosthetic heart valves. In: The Obstetric Haematology Manual, Ch 9 (ed. By S. Parvord & S. Hunt), pp. 109–119. Cambridge University Press, Cambridge, UK. [2] Baude, S., Hein, C., Curtis, S., Clark, A. and Trinder, J. (2012). Lowmolecular-weight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study. BJOG: An International Journal of Obstetrics & Gynaecology, 119: 1008–1013.
P-008 Polycystic ovary syndrome: Influence of BMI and insulin resistance on trombin generation in plasma M. Aziz 1 , J.J. Sidelmann 2 , J. Faber 3 , M.L. Wissing 4 , S.O. Skouby 1 1 Dept. of Obstetrics and Gynecology, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen; 2 Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark; 3 Dept. of Endocrinology, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen; 4 Dept. of Obstetrics and Gynecology, Holbæk Hospital, Faculty of Health Sciences, University of Copenhagen Objective:Women with polycystic ovary syndrome (PCOS) defined by the Rotterdam criteria (at least two of the following clinical manifestations: anovulation (Anov), hyperandrogenism (HA), polycystic ovaries (PCO)) are clinically heterogeneous. Our objective was therefore to evaluate the relationship between thrombin generation and four different PCOS phenotypes defined by BMI and insulin resistance (IR) (2525/−IR: 16%; 4) BMI>25/+IR: 39%. The phenotype BMI>25/+IR had the highest endogenous thrombin potential and the highest peak value for thrombin generation with an overall p<0.001 and p<0.038 respectively. Total body fat/height2 had highly significant positive association to all parameters of thrombin generation test (TGT). Conclusions: Additional phenotyping of women with PCOS is required to evaluate the risk of thrombotic disease in terms of thrombin generation. The overweight/obese, IR phenotype had highest level of hypercoagulabil-
is a loop region which is in contact with the longest helix of PZI. Other regions have been identified, which hold anomalous flexibility associated with potentially protective gene variants. A possible explanation of the effect of the observed gene variants is given, based on the interaction between PZ and PZI.
P-002 Underlying bleeding disorders in patients are equally important in menorrhagia with and without gynaecological abnormalities H.M. Knol 1,2 , A.B. Mulder 3 , D.H. Bogchelman 2 , H.C. Kluin-Nelemans 1 , A.G.J. van der Zee 2 , K. Meijer 1 1 Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen; 2 Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen; 3 Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, the Netherlands Introduction: Bleeding disorders have been recognized as an important etiologic and/or contributing factor in women with menorrhagia. Objective: To assess the prevalence of bleeding disorders and symptoms in women with menorrhagia, with and without gynaecological abnormalities. Methods: We included 102 consecutive patients referred for menorrhagia, confirmed by a pictoral bleeding assessment chart score >100. Patients and controls (28 healthy volunteers without menorrhagia) had haemostatic testing in the 1st week after menstruation and a bleeding history was taken. Patients underwent gynaecologic evaluation. Results: 46% of patients were anaemic, 61% had low ferritin. Twenty-six percent of patients had endometrial polyps or submucosal uterine myoma, sufficient to explain menorrhagia. An underlying bleeding disorder was found in 29% vs 11% (p=0.04) of the patients vs controls, and in 31% vs 27% of the women with unexplained vs explained menorrhagia (p=0.75). We diagnosed 6 cases of VWD, 4 cases of FXI deficiency and one FVII deficiency. The only abnormalities found in controls were platelet aggregation defects (11% vs 23% in patients). Patients had a significantly longer aPTT compared to controls (26.5 vs 25.0 sec; p=0.001) caused by lower median levels of FXI (100 vs 124 IU/dL; p<0.001). Although non-menorrhagia bleeding symptoms were more prevalent in patients than in controls, additional bleeding symptoms did not predict for an underlying bleeding disorder in patients. Conclusion: bleeding disorders play an equally important role in the aetiology of menorrhagia with and without gynaecological abnormalities. A novel finding is the occurrence of low, but not deficient levels of factor XI.
P-003 Plasma free DNA and circulating nucleosomes: Preliminary data in normal and pathologic pregnancies S. Bouvier 1,3,4 , L. Grandemange 4 , E. Mousty 2 , S. Ripart-Neveu 2 , P. Marès 2 , E. Cochery-Nouvellon 1,3 , E. Mercier 1,3,4 , J.-C. Gris 1,3,4 1 Departement of Haematology; 2 Department of Gynaecology and Obstetrics, University Hospital, Nîmes; 3 Research Group E.A. 2992; 4 Laboratory of Haematology, Faculty of Pharmacy and Biological Sciences, Montpellier 1 University, Montpellier, France Recent data have analyzed the fundamental coupling between coagulation and innate immunity, indicating the central role of neutrophil-derived circulating nucleosomes on the promotion of coagulation. As pregnancy is an acquired hypercoagulability state, the aim of this exploratory prospective study was to compare plasma cell free DNA and nucleosomes concentrations between non-pregnant women, pregnant women with a normal pregnancy and pregnant women with an obvious clinical complication. Quantification of DNA and circulating nucleosomes were respectively determined by Q-PCR and a commercially available ELISA kit. Age, white blood cell (WBC) and neutrophils counts were documented for each woman. Blood samples from pregnant women were characterized by gestational age and pregnancy-related pathology, if any. We included 124 patients from October 2011 to May 2012: 35 women with a normal pregnancy, 73 women with an abnormal pregnancy and 16 non-pregnant women. We found increased plasma DNA (p<0.0001) and nucleosomes (p=0.02)
S77
concentrations in pregnant women, concentrations being the highest in abnormal pregnancies. DNA (p<0.0001) and nucleosomes (p=0.002) concentrations differed depending on the type and severity of pregnancy-related complications: very high rates in the ischemic placental disease group. DNA:WBC, nucleosomes:WBC, DNA:neutrophils and nucleosomes:neutrophils ratios were significantly higher in pregnant women with a symptomatic complication. This preliminary study shows high DNA and nucleosomes plasma concentrations during pregnancy which culminate in severe pregnancy complications. Further studies (currently under evaluation) are necessary before working on the putative clinical value of these new parameters which may be released during pregnancy from non-hematologic cells.
P-004 Homocysteine levels in preterm neonates – The impact of genetic and environmental factors M.J. Simchen 1 , A. Maayan-Metzger 2 , A. Lubetsky 3 , J. Kuint 2 , N. Rosenberg 3 , A.A. Kuperman 3,4 , B.-A. Sela 5 , G. Kenet 3 1 The Department of Obstetrics and Gynecology; 2 The Department of Neonatology, The Edmond and Lily Safra Children’s Hospital; 3 The Institute of Thrombosis and Hemostasis and the; 5 Institute of Chemical Pathology, Sheba Medical Center, Tel-Hashomer, affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel:; 4 The Pediatric Hematology Clinic, Thrombosis and Hemostasis Service, Institute of Hematology, Western Galilee Hospital, Naharriya, Israel Background and Objective: Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early postnatal health status. Methods: Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18-month period. Data were collected on maternal history and delivery as well as on postnatal complications. Results: The study cohort included 167 infants whose mean gestational age was 30.98±2.34 weeks (range: 26–36 weeks), mean birth weight 1327.6±327 g, and mean Hcy level 7.99±3.27 (range 2.2–21.2) μmol/L. Maternal intake of folic acid was inversely associated with the babies’ Hcy levels (p=0.0001). Increased Hcy levels positively correlated with birth weight, gestational age (p<0.005), total number of pregnancies (p=0.012), and presence of MTHFR polymorphism. Higher Hcy levels were associated with feeding (p=0.008), especially total parenteral nutrition (p=0.0001). There was no correlation between Hcy levels and any vascular postnatal complications. Conclusions: During their postnatal hospitalization, preterm infants may have relatively high (within the adult normal range) Hcy levels which are influenced by genetic and environmental factors. Despite the fact that no correlation was found between Hcy levels and postnatal complications, these associations should be further studied.
P-005 Bleeding tendency in Swedish carriers of haemophilia A and B A. Olsson 1 , F. Baghaei 1 , E. Berntorp 2 , M. Hellgren 3 1 Department of Haematology and Coagulation disorders; 3 Department of Obstetrics, Sahlgrenska University Hospital; 2 Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden Objectives: Haemophilia is an X-linked recessive disorder caused by the deficiency of coagulation factors VIII (haemophilia A) and IX (haemophilia B). Carriers of moderate and severe haemophilia A (HA) and B (HB) have been studied. Methods: 126 of 298 carries registered at the three Haemophilia Treatment Centres in Sweden were recruited. The carriership was confirmed by DNA analysis. Ninety healthy women without a family history of bleedings served as controls. Bleeding tendency was determined using the MCMDM-
S78
Abstracts / Thrombosis Research 131, Suppl. 1 (2013) S71–S103
1vWD bleeding questionnaire modified by Bowen. A bleeding score (BS) of ≥4 was considered as clinical relevant bleeding tendency. FVIII:C and FIX:C analyses were performed in carriers only. Results: The mean level of FVIII: C (HA carriers) was 0.74±0.32 kIU/L (ref 0.50–2.00 kIU/L) and the mean level of FIX:C (HB carriers) was 0.54±0.27 kIU/L (ref 0.60–1.30 kIU/L). Carriers had higher BS than controls (p <0.0001). BS was weakly correlated to FVIII:C (p=0.01) but not to FIX:C (p=0.17). A median BS ≥4 was seen in HA and HB carriers with a factor VIII:C and IX:C <0.40 kIU/L, respectively. Conclusion Carriers of severe and moderate HA and HB have an increased bleeding tendency according to the BS. BS correlated weakly to FVIII:C but not to FIX:C.
P-006 Polymorphisms of placental alkaline phosphatase gene are associated with recurrent pregnancy loss S. Bouvier #,1,2,3 , M. Vatin #,4 , L. Bellazi 5 , X. Montagutelli 6 , P. Laissue 7 , A. Ziyyat 4 , C. Serres 4 , M.N. Dieudonné 5 , P. de Mazancourt 5 , E. Mornet 5,8 , D. Vaiman 4 , J.-C. Gris 1,2,3 1 Laboratoire d’Hématologie, CHU de Nîmes, France; 2 E.A. 2992, France; 3 Laboratoire d’Hématologie, U.F.R. des Sciences Biologiques et Pharmaceutiques, UM1, Montpellier, France; 4 Université Paris Descartes, Institut Cochin Inserm U1016 CNRS UMR 8104, Paris, France; 5 Unité de pathologie cellulaire et génétique EA2493, Université de Versailles-Saint Quentin en Yvelines, Versailles, France; 6 Institut Pasteur, Unité de Génétique des Mammifères, Paris, France; 7 Unité de Génétique, Faculté de Médecine, Université Del Rosario, Bogota, Colombie; 8 Laboratoire SESEP, Centre Hospitalier de Versailles, Le Chesnay, France # Co-authors Fertility is a quantitative complex character governed by a considerable number of genes. Despite clinical and scientific advances, many cases of human infertility remain unexplained. From the analysis of embryo resorption rates in inter-specific recombinant congenic mice strains, the placental alkaline phosphatase (PLAP) gene (ALPP) was identified as potentially responsible for recurrent miscarriage in women. This placental gene has been reported to be associated with pregnancy diseases such as pre-term delivery, pre-eclampsia and small-for-gestational age infants. However, little information is available regarding the role of PLAP, a known positive proliferative factor in human trophoblastic cells, in recurrent spontaneous abortion (RSA). ALPP was sequenced in a series of 100 control women and 100 RSA women from the same ethnic background. Functional analysis of PLAP variants was achieved in a cell model. We showed that several ALPP alleles and allelic combinations are more frequent in RSA women. One of the haplotype was associated with a ∼5 fold increased risk of developing RSA. By contrast, one of the polymorphism inducing an amino-acid change (ILE89LEU) in the polypeptidic chain, was clinically protective (RR=0.47, univariable analysis). Functional analysis of this variant revealed a significant increase in PLAP activity. This preliminary study confirms that mouse models are helpful to decipher complex multifactorial diseases in humans. ALPP variants and PLAP seem to be associated with RSA. Larger confirmatory studies are currently under evaluation, the model highlighting other critical genes.
P-007 Pregnant women with mechanical prosthetic heart valves – Which anticoagulant is best? I. Wilkins, N.L. Yatim, E. Ciantar Leeds Teaching Hospitals NHS Trust, Leeds, UK Background: The care of pregnant women with mechanical prosthetic heart valves (MPHV) poses many challenges including the choice of anticoagulation to prevent thromboembolism. Warfarin is known to be associated with an increased risk of miscarriage and late foetal loss whereas lowmolecular-weight heparin (LMWH) is associated with serious maternal events, such as valve thrombosis [1,2]. Aim: The aim of this audit was to identify the pregnancy outcomes and the maternal complications in pregnant women with MPHV using three different anticoagulation regimes.
Method: This was a 10-year retrospective observational study of 22 pregnancies in 13 women identified from combined obstetric-cardiology and obstetric-haematology clinics between 2001 and 2011 at the Leeds Teaching Hospitals (tertiary centre). Outcomes were compared according to the three anticoagulation regimes: 1) warfarin throughout pregnancy, 2) LMWH throughout pregnancy and 3) warfarin with LMWH substitutions (during gestational weeks 6–12 and 36 to delivery). Results:
Miscarriage TOP Stillbirth Neonatal death Live birth (>32w) Valve thrombosis
Warfarin only 9 pregnancies
LMWH only 8 pregnancies
Combined 5 pregnancies
5 (56%) 3 (33%) 0 0 1 (11%) 0
1 (13%) 1 (13%) 0 1 (13%) 5 (63%) 2 (25%)
0 0 1 (20%) 0 4 (80%) 1 (20%)
TOP = termination of pregnancy.
Conclusions: No anticoagulation regime is without risk and our result interpretation is limited by the small cohort. However LMWH (either alone or in combination) was associated with a higher rate of successful live birth but a greater risk of maternal valve thrombosis, one of which requiring emergency valve replacement. References: [1] Parvord, S. (2010). Prosthetic heart valves. In: The Obstetric Haematology Manual, Ch 9 (ed. By S. Parvord & S. Hunt), pp. 109–119. Cambridge University Press, Cambridge, UK. [2] Baude, S., Hein, C., Curtis, S., Clark, A. and Trinder, J. (2012). Lowmolecular-weight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study. BJOG: An International Journal of Obstetrics & Gynaecology, 119: 1008–1013.
P-008 Polycystic ovary syndrome: Influence of BMI and insulin resistance on trombin generation in plasma M. Aziz 1 , J.J. Sidelmann 2 , J. Faber 3 , M.L. Wissing 4 , S.O. Skouby 1 1 Dept. of Obstetrics and Gynecology, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen; 2 Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark; 3 Dept. of Endocrinology, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen; 4 Dept. of Obstetrics and Gynecology, Holbæk Hospital, Faculty of Health Sciences, University of Copenhagen Objective:Women with polycystic ovary syndrome (PCOS) defined by the Rotterdam criteria (at least two of the following clinical manifestations: anovulation (Anov), hyperandrogenism (HA), polycystic ovaries (PCO)) are clinically heterogeneous. Our objective was therefore to evaluate the relationship between thrombin generation and four different PCOS phenotypes defined by BMI and insulin resistance (IR) (25