Inflammation and Thrombophilia in Pregnancy Complications: Implications for Risk Assessment and Clinical Management

Author(s): Francesca La Farina, Valeria Raparelli, Laura Napoleone, Fiorella Guadagni, Stefania Basili, Patrizia Ferroni

Journal Name: Cardiovascular & Hematological Disorders-Drug Targets
Formerly Current Drug Targets - Cardiovascular & Hematological Disorders

Volume 15 , Issue 3 , 2015

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


In Italy, each year 500000 couples refer to specialized centers due to reproductive problems. Among them, recurrent pregnancy loss (RPL) represents a problem of great importance, given that it affects up to 5% of women of childbearing age. Infertility, on the other hand, is a condition that currently covers 10-20% of couples of reproductive age, being idiopathic in 20% of cases. Accumulating evidence support the concept that changes of blood coagulation, generically defined as the presence of a thrombophilic state (congenital or acquired), are the basis of 40-70% of cases of multiple abortions or infertility. Several evidences support the hypothesis that endothelial dysfunction, a hallmark of a condition of low-grade inflammation, is one of the earliest manifestations of thrombotic phenomena. To date, it’s believed that, while the antiinflammatory Th2 cytokines (i.e. interleukin-10) can exert a protective role in pregnancy, the pro-inflammatory Th1 ones (i.e. interferon-γ, tumor necrosis factor-α,) have deleterious effects on pregnancy outcome, including fertilization and implantation failure. Moreover, development of many pregnancy complications, first and foremost venous thromboembolism (VTE), recognizes similar mechanism(s). As VTE is the main preventable cause of mortality during pregnancy, thromboprophylaxis is mandatory according to individual VTE risk, influenced by the presence of thrombophilic conditions. In this review, we will analyze the relationship between thrombophilia and pregnancy complications, with particular focus on the role of inflammation. Subsequently, we will consider some issues related to the thromboembolic risk in pregnancy. Finally, the role of thromboprophylaxis in pregnancy will be discussed.

Keywords: Anticoagulant drugs, cytokines, hypercoagulability, heparin, infertility, pregnancy loss, recurrent, thromboprophylaxis, venous thromboembolism.

Daher, S.; Shulzhenko, N.; Morgun, A.; Mattar, R.; Rampin, G.F.; Camano, L.; DeLima, M.G. Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J. Reprod. Immunol., 2003, 58(1), 69-77.
Girardi, G. Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome. Clin. Rev. Allergy Immunol., 2010, 39(3), 160-165.
Clifford, K.; Rai, R.; Watson, H.; Regan, L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum. Reprod., 1994, 9(7), 1338-1332.
Isaksson, R.; Titinen, A. Present concept of unexplained infertility. Gynecol. Endocrinol., 2004, 18(5), 278-290.
Mastrolia, S.A.; Mazor, M.; Holcberg, G.; Leron, E.; Beharier, O.; Loverro, G.; Erez, O. The physiologic anticoagulant and anti-inflammatory role of heparins and their utility in the prevention of pregnancy complications. Thromb. Haemost., 2015, 113(6), 1236-1246.
De Santis, M.; Cavaliere, A.F.; Straface, G.; Di Gianantonio, E.; Caruso, A. Inherited and acquired thrombophilia: Pregnancy outcome and treatment. Reprod. Toxicol., 2006, 22(2), 227-233.
Greer, I.A. Thrombophilia: implications for pregnancy outcome. Thromb. Res., 2003, 109(2-3), 73-81.
Coriu, L.; Ungureanu, R.; Talmaci, R.; Uscatescu, V.; Cirstoiu, M.; Coriu, D.; Copaciu, E. Hereditary thrombophilia and thrombotic events in pregnancy: single-center experience. J. Med. Life, 2014, 7(4), 567-571.
Bombell, S.; McGuire, W. Cytokine polymorphisms in women with recurrent pregnancy loss: Meta-analysis. Aust. N. Z. J. Obstet. Gynaecol., 2008, 48(2), 147-154.
Granot, I.; Gnainsky, Y.; Dekel, N. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction, 2012, 144(6), 661-668.
Christiansen, O.B.; Nielsen, H.S.; Kolte, A.M. Inflammation and miscarriage. Semin. Fetal Neonatal Med., 2006, 11(5), 302-308.
Zolti, M.; Ben-Rafael, Z.; Meirom, R.; Shemesh, M.; Bider, D.; Mashiach, S.; Apte, R.N. Cytokine involvement in oocytes and early embryos. Fertil. Steril., 1991, 56(2), 265-272.
Arslan, E.; Colakoglu, M.; Celik, C.; Gezginc, K.; Acar, A.; Capar, M.; Azoz, M.; Akyurek, C. Serum TNF-alpha, IL-6, lupus anticoagulant and anticardiolipin antibody in women with and without a past history of recurrent miscarriage. Arch. Gynecol. Obstet., 2004, 270(4), 227-229.
Lee, B.E.; Jeon, Y.J.; Shin, J.E.; Kim, J.H.; Choi, D.H.; Jung, Y.W.; Shim, S.H.; Lee, W.S.; Kim, N.K. Tumor necrosis factor-α gene polymorphisms in Korean patients with recurrent spontaneous abortion. Reprod. Sci., 2013, 20(4), 408-413.
Van der Pool, T.; Jansen, P.M.; Vanzee, K.J.; Welborn, B.M.; De Jong, I.; Moldawer, L.L. Tumor necrosis factor-alpha induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor. Blood, 1996, 88(3), 922-927.
Esmon, C.T. Inflammation and thrombosis. J. Thromb. Haemost., 2003, 1(7), 1343-1348.
Cheng, S.B.; Sharma, S. Interleukin-10: a pleiotropic regulator in pregnancy. Am. J. Reprod. Immunol., 2015, 73(6), 487-500.
Triplett, D.A.; Harris, E.N. Anthiphospholipid antibodies and reproduction. Am. J. Reprod. Immunol., 1989, 21(3-4), 123-131.
Sanson, B.J.; Friederich, P.W.; Simioni, P.; Zanardi, S.; Hilsman, M.V.; Girolami, A.; ten Cate, J.W.; Prins, M.H. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb. Haemost., 1996, 75(3), 387-388.
Rai, R.S.; Regan, L.; Chirolie, A.; Donald, J.G.; Conen, H. Placental thrombosis and second trimester miscarriage in association with activated protein C resistance. Br. J. Obstet. Gynaecol., 1996, 103(8), 842-844.
Grandone, E.; Margaglione, M.; Colaizzo, D.; Cappucci, G.; Paladini, D.; Martinelli, P.; Montanaro, S.; Pavone, G.; Di Minno, G.; Factor, V. Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb. Haemost., 1997, 77(6), 1052-1054.
Martinelli, I.; Taioli, E.; Cetin, I.; Merinoni, A.; Gerosa, S.; Villa, M.V.; Bozzo, M.; Mannucci, P.M. Mutations in coagulation factors in women with unexplained late fetal loss. N. Engl. J. Med., 2000, 343(14), 1015-1018.
Preston, F.E.; Rosendaal, F.R.; Walker, I.D.; Brie, E.; Berntorp, E.; Conard, J.; Legnanic, C.; Scharrer, I. Increased fetal loss in women with heritable trombophilia. Lancet, 1996, 348(9032), 913-916.
Santoro, R.; Iannaccaro, P.; Sottilotta, G. Prothrombotic gene mutations in women with recurrent abortions and intrauterine fetal death. Minerva Ginecol., 2005, 57(4), 447-450.
Behjati, R.; Modarressi, M.H.; Jeddi-Tehrani, M.; Dokoohaki, P.; Ghasemi, J.; Zarnani, A.H.; Aarabi, M.; Memariani, T.; Ghaffari, M.; Akhondi, M.A. Thrombophilic mutations in Iranian patients with infertility and recurrent spontaneous abortion. Ann. Hematol., 2006, 85(4), 268-271.
Settin, A.; Alkasem, R.; Ali, E.; El Baz, R.; Mashaley, A.M.; Factor, V. Leiden and prothrombin gene mutations in Egyptian cases with unexplained recurrent pregnancy loss. Hematology, 2011, 16(1), 59-63.
Isaoglu, U.; Ulug, P.; Delibas, I.B.; Yilmaz, M.; Kumtepe, Y.; Dogan, H.; Tasdemir, S. The association between inherited thrombophilia and recurrent pregnancy loss in Turkish women. Clin. Exp. Obstet. Gynecol., 2014, 41(2), 177-181.
Gao, H.; Tao, F.B. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb. Res., 2015, 135(2), 339-346.
D’Uva, M.; Di Micco, P.; Strina, I.; Ranieri, A.; Alviggi, C.; Mollo, A.; Fabozzi, F.; Cacciapuoti, L.; Di Frega, M.T.; Iannuzzo, M.; De Placido, G. Etiology of hypercoagulable state in women with recurrent fetal loss without other causes of miscarriage from Southern Italy: new clinical target for antithrombotic therapy. Biologics, 2008, 2(4), 897-902.
Ghee, C.B.; Burrows, R.F. Prothrombin G20210A mutation is not associated with recurrent miscarriages. Aust. N. Z. J. Obstet. Gynaecol., 2002, 42(2), 167-169.
Parand, A.; Zolghadri, J.; Nezam, M.; Afrasiabi, A.; Haghpanah, S.; Karimi, M. Inherited thrombophilia and recurrent pregnancy loss. Iran. Red Crescent Med. J., 2013, 15(12)e13708
Goodman, C.S.; Coulam, C.B.; Jeyendran, R.S.; Acosta, V.A.; Roussev, R. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am. J. Reprod. Immunol., 2006, 56(4), 230-236.
Ren, A.; Wang, J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil. Steril., 2006, 86(6), 1716-1722.
Yousefian, E.; Kardi, M.T.; Allahveisi, A. Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism in Iranian Women With Idiopathic Recurrent Pregnancy Losses. Iran. Red Crescent Med. J., 2014, 16(7)e16763
Wu, O.; Robertson, L.; Twaddle, S.; Lowe, G.D.; Clark, P.; Greaves, M.; Walker, I.D.; Langhorne, P.; Brenkel, I.; Regan, L.; Greer, I. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis Risk and Economic Assessment of Thrombophilia Screening(TREATS) study. Health Technol. Assess., 2006, 10(11), 1-110.
Ferroni, P.; La Farina, F.; Palmirotta, R.; Martini, F.; Raparelli, V.; Nigro, C.; Riondino, S.; Rampini, M.R.; Basili, S.; Guadagni, F. Predictive value of thrombopath determination in women with infertility and pregnancy complications. Chim. Clin. Acta, 2010, 411(1-2), 37-42.
Mathonnet, F.; de Mazancourt, P.; Denninger, M.H.; Morot, M.; Benattar, N.; Giudicelli, Y. Role of factor VIII on activated protein C resistance ratio in inflammatory diseases. Br. J. Haematol., 1996, 95(2), 423-425.
Miller, C.H.; De Staercke, C.; Benson, J.; Hooper, W.C.; Dilley, A.; Evatt, B.L.; Benito, C.; Patterson-Barnett, A.; Eller, D.; Philipp, C.S. Elevated factor VII as a risk factor for recurrent fetal loss. Relationship to factor VII gene polymorphism. Thromb. Haemost., 2005, 93(6), 1089-1094.
Riondino, S.; Ferroni, P.; La Farina, F.; Martini, F.; Palmirotta, R.; Guadagni, F.; Basili, S. Factor seven activating protease activity levels in women with recurrent pregnancy loss. Reprod. Sci., 2012, 19(3), 317-321.
Zhou, L.; Li, R.; Wang, R.; Huang, H.X.; Zhong, K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil. Steril., 2008, 89(5), 1166-1176.
Tiboni, G.M.; Giampietro, F.; Gabriele, E.; Di Donato, V.; Impicciatore, G.G. Impact of a single endometrial injury on assisted reproductive technology outcome: a preliminary observational study. J. Reprod. Med., 2011, 56(11-12), 504-506.
Kalinka, J.; Radwan, M. The impact of dydrogesterone supplementation on serum cytokine profile in women with threatened abortion. Am. J. Reprod. Immunol., 2006, 55(2), 115-121.
Thum, M.; Abdalla, H.I.; Bhaskaran, S.; Harden, E.L.; Ford, B.; Sumar, N.; Shehata, H.; Bansal, A. The relationship of systemic TNF-alpha and INF-gamma with IVF treatment outcome and peripheral blood NK cells. Am. J. Reprod. Immunol., 2007, 57(3), 210-217.
Toder, V.; Fein, A.; Carp, H.; Torchinsky, A. TNF-alpha in pregnancy loss and embryo maldevelopment: a mediator of detrimental stimuli or a protector of the fetoplacental unit? J. Assist. Reprod. Genet., 2003, 20(2), 73-81.
Clark, D.A.; Ding, J.W.; Chaouat, G.; Coulam, C.B.; August, C.; Levy, G.A. The emerging role of immunoregulation of fibrinogen-related procoagulant Fgl2 in the success or spontaneous abortion of early pregnancy in mice and human. Am. J. Reprod. Immunol., 1999, 42(1), 37-43.
Gorczynsky, R.M.; Hadidi, S.; Yu, G.; Clark, D.A. The same immunoregolatory molecules contribute to successful pregnancy and transplantation. Am. J. Reprod. Immunol., 2002, 48(1), 18-26.
Thaxton, J.E.; Sharma, S. Interleukin-10: A Multi-Faceted Agent of Pregnancy. Am. J. Reprod. Immunol., 2010, 63(6), 482-491.
Brogin Moreli, J.; Cirino Ruocco, A.M.; Vernini, J.M.; Rudge, M.V.; Calderon, I.M. Interleukin 10 and Tumor Necrosis Factor-Alpha in Pregnancy: Aspects of Interest in Clinical Obstetrics. ISRN Obstet. Gynecol., 2012, 2012230742
Kwak-kim, J.Y.; Chung-Bang, H.S.; Ng, S.C.; Ntrivalas, E.I.; Mangubat, C.P.; Beaman, K.D.; Beer, A.E.; Gilman-Sachs, A. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum. Reprod., 2003, 18(4), 767-773.
Bohiltea, L.C.; Radoi, E.V. Interleukin-6 and interleukin-10 gene polymorphisms and recurrent pregnancy loss in Romanian population. Iran. J. Reprod. Med., 2014, 12(9), 617-622.
Babbage, S.J.; Arkwright, P.D.; Vince, G.S.; Perrey, C.; Pravica, V.; Quenby, S.; Bates, M.; Hutchinson, I.V. Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J. Reprod. Immunol., 2001, 51(1), 21-27.
Kamali-Sarvestani, E.; Zolghadri, J.; Gharesi-Fard, B.; Sarvari, J. Cytokine gene polymorphisms and susceptibility to recurrent pregnancy loss in Iranian women. J. Reprod. Immunol., 2005, 65(2), 171-178.
Palmirotta, R.; La Farina, F.; Ferroni, P.; Ludovici, G.; Nigro, C.; Savonarola, A.; Raparelli, V.; Riondino, S.; Rampini, M.R.; Guadagni, F.; Basili, S. TNFA gene promoter polymorphisms and susceptibility to recurrent pregnancy loss in Italian women. Reprod. Sci., 2010, 17(7), 659-666.
Vialard, F.; El Sirkasi, M.; Tronchon, V.; Boudjenah, R.; Molina-Gomes, D.; Bergere, M.; Mauduit, C.; Wainer, R.; Selva, J.; Benahmed, M. Tumor necrosis factor-308 polymorphism increases the embryo implantation rate in women undergoing in vitro fertilization. Hum. Reprod., 2013, 28(10), 2774-2783.
Bahadori, M.; Zarei, S.; Zarnani, A.H.; Zarei, O.; Idali, F.; Hadavi, R.; Jeddi-Tehrani, M. IL-6, IL-10 and IL-17 gene polymorphisms in Iranian women with recurrent miscarriage. Iran. J. Immunol., 2014, 11(2), 97-104.
Reid, J.G.; Simpson, N.A.; Walker, R.G.; Economidou, O.; Shillito, J.; Gooi, H.C.; Duffy, S.R.; Walker, J.J. The carriage of pro-infiammatory cytokine gene polymorphisms in recurrent pregnancy loss. Am. J. Reprod. Immunol., 2001, 45(1), 35-40.
Hill, J.A.; Choi, B.C. Maternal immunological aspects of pregnancy success and failure. J. Reprod. Fertil. Suppl., 2000, 55(1), 91-97.
Prigoshin, N.; Tambutti, M.; Larriba, J.; Gozorza, S.; Testa, R. Cytokine gene polymorphism in recurrent loss of unknown cause. Am. J. Reprod. Immunol., 2004, 52(1), 36-41.
Han, A.R.; Ahn, H.; Vu, P.; Park, J.C.; Gilman-Sachs, A.; Beaman, K.; Kwak-Kim, J. Obstetrical outcome of anti-inflammatory and anticoagulation therapy in women with recurrent pregnancy loss or unexplained infertility. Am. J. Reprod. Immunol., 2012, 68(5), 418-427.
Pinheiro, M.B.; Gomes, K.B.; Ronda, C.R.; Guimarães, G.G.; Freitas, L.G.; Teixeira-Carvalho, A.; Martins-Filho, O.A.; Dusse, L.M. Severe preeclampsia: association of genes polymorphisms and maternal cytokines production in Brazilian population. Cytokine, 2015, 71(2), 232-237.
Mustafa, R.; Ahmed, S.; Gupta, A.; Venuto, R.C. A comprehensive review of hypertension in pregnancy. J. Pregnancy, 2012, 2012, 1-19.
Kalkunte, S.; Lai, Z.; Norris, W.E.; Pietras, L.A.; Tewari, N.; Boij, R.; Neubeck, S.; Markert, U.R.; Sharma, S. Novel approaches for mechanistic understanding and predicting preeclampsia. J. Reprod. Immunol., 2009, 83(1-2), 134-138.
Vural, P.; Degirmencioglu, S.; Saral, N.Y.; Demirkan, A.; Akgul, C.; Yildirim, G.; Issever, H.; Eroglu, H. Tumor necrosis factor alpha, interleukin-6 and interleukin-10 polymorphisms in preeclampsia. J. Obstet. Gynaecol. Res., 2010, 36(1), 64-71.
De Groot, C.J.; Jansen, M.W.; Bertina, R.M.; Schonkeren, J.J.; Helmerhost, F.M.; Huizinga, T.W. Interleukin 10 -2849AA genotype protects against pre-eclampsia. Genes Immun., 2004, 5(4), 313-314.
Scottish Intercollegiate Guidelines Network (SIGN). Prophylaxis of venous thromboembolism: a national clinical guideline. SIGN publication 122. (accessed September 09, 2015).
James, A.H.; Jamison, M.G.; Brancazio, L.R.; Myers, E.R. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am. J. Obstet. Gynecol., 2006, 194(5), 1311-1315.
Greer, I.A. Clinical Practice. Pregnancy Complicated by Venous Thrombosis. N. Engl. J. Med., 2015, 373(6), 540-547.
Bates, S.M.; Greer, I.A.; Middeldorp, S.; Veenstra, D.L.; Prabulos, A.M.; Vandvik, P.O. American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest,, 2012, 141(2), e691S-736S.
Royal College of Obstetricians and Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. Green-top Guideline No. 37a, April 2015.
Bauersachs, R.M. Treatment of venous thromboembolism during pregnancy. Thromb. Res., 2009, 123(2), S45-S50.
Greer, I.A.; Nelson-Piercy, C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood, 2005, 106(2), 401-407.
Bain, E.; Wilson, A.; Tooher, R.; Gates, S.; Davis, L.J.; Middleton, P. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst. Rev., 2014, 2CD001689
Lindqvist, P.G.; Bremme, K.; Hellgren, M. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet. Gynecol. Scand., 2011, 90(6), 648-653.
Romualdi, E.; Dentali, F.; Rancan, E.; Squizzato, A.; Steidl, L.; Middeldorp, S.; Ageno, W. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J. Thromb. Haemost., 2013, 11(4), 270-281.
Pettila, V.; Kaaja, R.; Leinonen, P.; Ekblad, U.; Kataja, M.
Ikkala, E. Thromboprophylaxis with low molecular weight heparin(dalteparin) in pregnancy. Thromb. Res., 1999, 96(4), 275-282.
Blondon, M.; Perrier, A.; Nendaz, M.; Righini, M.; Boehlen, F.; Boulvain, M.; De Moerloose, P. Thromboprophylaxis with low-molecular-weight heparin after cesarean delivery. Thromb. Haemost., 2010, 103(1), 129-137.
Nelson-Piercy, C.; MacCallum, P.; Mackillop, L. on behalf of the Guidelines Committee of the Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. RCOG 2009 Green-top Guideline No. 37a. Royal College of Obstetricians and Gynaecologists. London.
American College of Obstetricians and Gynecologists (ACOG). Thromboembolism in pregnancy. Washington (DC), American College of Obstetricians and Gynecologists (ACOG); Sep. 12, 2011.
Mazzolai, L.; Hohlfeld, P.; Spertini, F.; Hayoz, D.; Schapira, M.; Duchosal, M.A. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood, 2006, 108(5), 1569-1570.
Gerhardt, A.; Zotz, R.B.; Stockschlaeder, M.; Scharf, R.E. Fondaparinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and heparinoids. Thromb. Haemost., 2007, 97(3), 496-497.
Harenberg, J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb. Res., 2007, 119(3), 385-388.
Wijesiriwardana, A.; Lees, D.A.; Lush, C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul. Fibrinolysis, 2006, 17(2), 147-149.
Knol, H.M.; Schultinge, L.; Erwich, J.J.; Meijer, K. Fondaparinux as an alternative anticoagulant therapy during pregnancy. J. Thromb. Haemost., 2010, 8(8), 1876-1879.
Elsaigh, E.; Thachil, J.; Nash, M.J.; Tower, C.; Hay, C.R.; Bullough, S.; Byrd, L. The use of fondaparinux in pregnancy. Br. J. Haematol., 2015, 168(5), 762-764.
Winger, E.E.; Reed, J.L. A retrospective analysis of fondaparinux versus enoxaparin treatment in women with infertility or pregnancy loss. Am. J. Reprod. Immunol., 2009, 62(4), 253-260.
Dempfle, C.E. Minor transplacental passage of fondaparinux in vivo. N. Engl. J. Med., 2004, 350(18), 1914-1915.
Bujold, E.; Roberge, S.; Lacasse, Y.; Bureau, M.; Audibert, F.; Marcoux, S.; Forest, J.C.; Giguere, Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet. Gynecol., 2010, 116(1), 402-414.
Askie, L.M.; Duley, L.; Henderson-Smart, D.J.; Stewart, L.A. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet, 2007, 369(9575), 1791-1798.
Duley, L.; Henderson-Smart, D.J.; Meher, S.; King, J.F. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst. Rev., 2007, (2)CD004659
Farquharson, R.G.; Quenby, S.; Greaves, M. Antiphospholipid syndrome in pregnancy: a randomized.; controlled trial of treatment. Obstet. Gynecol., 2002, 100(3), 408-413.
Baglin, T.; Barrowcliffe, T.W.; Cohen, A.; Greaves, M. for the British Committee for Standards in Haematology.Guidelines on the use and monitoring of heparin. Br. J. Haematol., 2006, 133(1), 19-34.
Okoroh, E.M.; Azonobi, I.C.; Grosse, S.D.; Grant, A.M.; Atrash, H.K.; James, A.H. Prevention of venous thromboembolism in pregnancy: a review of guidelines. 2000-2011. J. Womens Health (Larchmt.), 2012, 21(6), 611-615.
Patel, J.P.; Green, B.; Patel, R.K.; Marsh, M.S.; Davies, J.G.; Arya, R. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation, 2013, 128(13), 1462-1469.
De Stefano, V.; Leone, G.; Mastrangelo, S.; Tripodi, A.; Rodeghiero, F.; Castaman, G.; Barbui, T.; Finazzi, G.; Bizzi, B.; Mannucci, P.M. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb. Haemost., 1994, 71(6), 799-800.
Friederich, P.W.; Sanson, B.J.; Simioni, P.; Zanardi, S.; Huisman, M.V.; Kindt, I.; Prandoni, P.; Büller, H.R.; Girolami, A.; Prins, M.H. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann. Intern. Med., 1996, 125(12), 955-960.
Bonnar, J.; Norris, L.; Greene, R. Inherited thrombophilia: the obstetric prospective. Semin. Thromb. Hemost., 1998, 24(1), 49-53.
Lockwood, C.J. Inherited thrombophilias in pregnant patient: detection and treatment paradigm. Obstet. Gynecol., 2002, 99(2), 333-334.
Gohil, R.; Peck, G.; Sharma, P. The genetics of venous thromboembolism. A meta- analysis involving approximately 120,000 cases and 180,000 controls. Thromb. Haemost., 2009, 102(2), 360-370.
Ziakas, P.D.; Poulou, L.S.; Pavlou, M.; Zintzaras, E. Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk. Eur. J. Obstet. Gynecol. Reprod. Biol., 2015, 191, 106-111.
Pabinger, I.; Grafenhofer, H.; Kyrle, P.A.; Quehenberger, P.; Mannhalter, C.; Lechner, K.; Kaider, A. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood, 2002, 100(3), 1060-1062.
Brill-Edwards, P.; Ginsberg, J.S.; Gent, M.; Hirsh, J.; Burrows, R.; Kearon, C.; Geerts, W.; Kovacs, M.; Weitz, J.I. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N. Engl. J. Med., 2000, 343(20), 1439-1444.
Pabinger, I.; Grafenhofer, H.; Kaider, A.; Kyrle, P.A.; Quehenberger, P.; Mannhalter, C.; Lechner, K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J. Thromb. Haemost., 2005, 3(5), 949-954.
De Stefano, V.; Martinelli, I.; Rossi, E.; Battaglioli, T.; Za, T.; Mannucci, P.M.; Leone, G. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br. J. Haematol., 2006, 135(3), 386-391.
Rodger, M.A.; Betancourt, M.T.; Clark, P.; Lindqvist, P.G.; Dizon-Townson, D.; Said, J.; Seligsohn, U.; Carrier, M.; Salomon, O.; Greer, I.A. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med., 2010, 7(6)e1000292
Pasquier, E.; de Saint Martin, L.; Bohec, C.; Chauleur, C.; Bretelle, F.; Marhic, G.; Le Gal, G.; Debarge, V.; Lecomte, F.; Denoual-Ziad, C.; Lejeune-Saada, V.; Douvier, S.; Heisert, M.; Mottier, D. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood, 2015, 125(14), 2200-2205.
Rodger, M.A.; Hague, W.M.; Kingdom, J.; Kahn, S.R.; Karovitch, A.; Sermer, M.; Clement, A.M.; Coat, S.; Chan, W.S.; Said, J.; Rey, E.; Robinson, S.; Khurana, R.; Demers, C.; Kovacs, M.J.; Solymoss, S.; Hinshaw, K.; Dwyer, J.; Smith, G.; McDonald, S.; Newstead-Angel, J.; McLeod, A.; Khandelwal, M.; Silver, R.M.; Le Gal, G.; Greer, I.A.; Keely, E.; Rosene-Montella, K.; Walker, M.; Wells, P.S. TIPPS Investigators. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS), a multinational open-label randomised trial. Lancet, 2014, 384(9955), 1673-1683.
Kaandorp, S.P.; Goddijn, M.; van der Post, J.A.; Hutten, B.A.; Verhoeve, H.R.; Hamulyák, K.; Mol, B.W.; Folkeringa, N.; Nahuis, M.; Papatsonis, D.N.; Büller, H.R.; van der Veen, F.; Middeldorp, S. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N. Engl. J. Med., 2010, 362(17), 1586-1596.
de Jong, P.G.; Kaandorp, S.; Di Nisio, M.; Goddijn, M.; Middeldorp, S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst. Rev., 2014, 7CD004734
Clark, P.; Walker, I.D.; Langhorne, P.; Crichton, L.; Thomson, A.; Greaves, M.; Whyte, S.; Greer, I.A. Scottish Pregnancy Intervention Study (SPIN) collaborators. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood, 2010, 115(21), 4162-4167.
Gris, J.C.; Mercier, E.; Quéré, I.; Lavigne-Lissalde, G.; Cochery-Nouvellon, E.; Hoffet, M.; Ripart-Neveu, S.; Tailland, M.L.; Dauzat, M.; Marès, P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood, 2004, 103(10), 3695-3699.
de Jong, P.G.; Quenby, S.; Bloemenkamp, K.W.; Braams-Lisman, B.A.; de Bruin, J.P.; Coomarasamy, A.; David, M.; DeSancho, M.T.; van der Heijden, O.W.; Hoek, A.; Hutten, B.A.; Jochmans, K.; Koks, C.A.; Kuchenbecker, W.K.; Mol, B.W.; Torrance, H.L.; Scheepers, H.C.; Stephenson, M.D.; Verhoeve, H.R.; Visser, J.; de Vries, J.I.; Goddijn, M.; Middeldorp, S. ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia - study protocol for a randomized controlled trial. Trials, 2015, 16, 208.
Nissen, N.N.; Shankar, R.; Gamelli, R.L.; Singh, A.; DiPietro, L.A. Heparin and heparin sulphate protect basic fibroblast growth factor from non-enzymic glycosylation. Biochem. J., 1999, 338(Pt 3), 637-642.
Elsayed, E.; Becker, R.C. The impact of heparin compounds on cellular inflammatory responses: a construct for future investigation and pharmaceutical development. J. Thromb. Thrombolysis, 2003, 15(1), 11-18.
Bazzoni, G.; Beltrán Nuñez, A.B.; Mascellani, G.; Bianchini, P.; Dejana, E.; Del Maschio, A. Effect of heparin, dermatan sulfate, and related oligderivatives on human polymorphonuclear leukocyte functions. J. Lab. Clin. Med., 1993, 121(2), 268-275.
Silvestro, L.; Viano, I.; Marcario, M.; Colangelo, D.; Montrucchio, G.; Panico, S.; Fantozzi, R. Effects of heparin and its desulfated derivatives on leucocyte-endothelial adhesion. Semin. Thromb. Hemost., 1994, 20(3), 254-258.
Lever, R.; Hoult, J.R.; Page, C.P. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leukocytes to vascular endothelium in vitro. Br. J. Pharmacol., 2000, 129(3), 533-540.
Nelson, R.M.; Cecconi, O.; Roberts, W.G.; Aruffo, A.; Lindhardt, R.J.; Bevilacqua, M.P. Heparin oligosaccharides bind L- and P- selectin and inhibit acute inflammation. Blood, 1993, 82(11), 3253-3258.
Young, E.; Venner, T.; Ribau, J.; Shaughnessy, S.; Hirsh, J.; Podor, T. Binding of unfractionated heparin and low molecular weight heparin to thrombin-activated human endothelial cells. Thromb. Res., 1999, 96(5), 373-381.
Gao, Y. Li. N.; Fei. R.; Chen. Z.; Theng. S.; Zeng. X. P-selectin- mediated acute inflammation can be blocked by chemically modified, RO-heparin. Mol. Cells, 2005, 19(3), 350-355.
Peter, K.; Schwarz, M.; Conradt, C.; Nordt, T.; Moser, M.; Kubler, W.; Bode, C. Heparin inhibits ligand binding to leukocyte integrin Mac-1(CD11b/CD18). Circulation, 1999, 100(14), 1533-1539.
Wulczyn, F.G.; Krappmann, D.; Scheidereit, C. The NF-κB/Rel and I kappa B gene families: mediators of immune response and inflammation. J. Mol. Med., 1996, 74(12), 749-769.
Letourneur, D.; Caleb, B.L.; Castellot Jr, J.J. Heparin binding, internalization and metabolism in vascular smooth muscle cells: II. Degradation and secretion in sensitive and resistant cells. J. Cell. Physiol., 1995, 165(3), 687-695.
Thourani, V.H.; Brar, S.S.; Kennedy, T.P.; Thornton, L.R.; Watts, J.A.; Ronson, R.S.; Zhao, Z.Q.; Sturrock, A.L.; Hoidal, J.R.; Vinten-Johansen, J. Nonanticoagulant heparin inhibits NK-κB activation and attenuates myocardial reperfusion injury. Am. J. Physiol. Heart Circ. Physiol., 2000, 278(6), H2084-H2093.
Manduteanu, I.; Voinea, M.; Antohe, F.; Dragomir, E.; Capraru, M.; Radulescu, L.; Simionescu, M. Effect of enoxaparin on high glucose- induced activation of endothelial cells. Eur. J. Pharmacol., 2003, 477(3), 269-276.
Hecht, I.; Hershkoviz, R.; Shivitel, S.; Lapidot, T.; Cohen, I.R.; Lider, O.; Cahalon, L. Heparin-dissacharide affects T cells: inhibition of NF kappaB activation, cell migration, and modulation of intracellular signaling. J. Leukoc. Biol., 2004, 75(6), 1139-1146.
Hochart, H.; Jenkins, P.V.; Smith, O.P.; White, B. Low molecular weight and unfractionated heparins induce a downregulation of inflammation: decreased levels of proinflammatory cytokines and nuclear factor-κB in LPS-stimulated human monocytes. Br. J. Haematol., 2006, 133(1), 62-67.
Mousavi, S.; Moradi, M.; Khorshidahmad, T.; Motamedi, M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv. Pharmacol. Sci., 2015, 2015507151

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2015
Published on: 01 January, 2016
Page: [187 - 203]
Pages: 17
DOI: 10.2174/1871529X16666160101122530
Price: $65

Article Metrics

PDF: 97