OBSTETRICS Role of the M2 haplotype within the annexin A occurrence of pregnancy-related venous throm Elvira Grandone, MD; Giovanni Tiscia, ScD; Donatella Colaizzo, ScD; Elena Chinni, PhD; Daniela Pisanelli, ScD; Valeria Bafunno, PhD; Maurizio Margaglione, MD OBJECTIVE: Knowledge about risk factors for venous thromboembo- lism (VTE) is still limited. A recently found haplotype within the natural anticoagulant protein annexin A5 (ANXA5) exerts an important modulat- ing effect on gene expression. STUDY DESIGN: Eighty-three nonanticoagulated patients with a docu- mented pregnancy-related VTE and 195 controls were investigated. The presence of the ANXA5 haplotypes was determined. RESULTS: Twenty-seven patients (32.5%) carried the M2 haplotype. Among them, 17 (63.0%) had a history of VTE in puerperium and 10 (37.0%) during pregnancy. The prevalence of the M2 haplotype was different as compared with that recorded among controls (odds ratio, 2.7; 95% confidence interval, 1.5– 4.9, P ⬍ .001). A logis sion analysis, correcting for potential confounders (age at which the thrombotic event occurred, factor V Leiden, and factor II ants) showed a significant increase (odds ratio, 3.4; 95% interval, 1.7– 6.7) of the occurrence of VTE in carriers of type as compared with noncarriers. CONCLUSION: The M2 haplotype within the ANXA5 gene may sent a new thrombophilic risk factor for pregnancy-relate Key words: annexin A5, deep venous thrombosis, haplot pregnancy-related deep venous thrombosis Cite this article as: Grandone E, Tiscia G, Colaizzo D, et al.Role of the M2 haplotype within the annexin A5 gene in the occurrence of pregnancy-re thromboembolism. Am J Obstet Gynecol 2010;203:461.e1-5. V enous thromboembolism (VTE) is common in whites, affecting 1 of 1000individualseveryyear and is strongly associated with life-threatening pulmonary embolism (PE), which is still the leading cause of maternal mortality in developed countries. 1 Pregnancy itself is a risk factorfor VTE, and this tendency can be enhanced by inherited or acquired thrombophilia. Indeed, women with thrombophilia are at increased risk of developing VTE, 2 which is an important cause of morbid- ity and mortality during pregnancy. The incidence of antenatal deep vein throm- bosis (DVT) is about 0.61 per 1000 preg- nancies in women younger than 35 years and 1.21 per 1000 in women older than 35 years. 3 The risk of VTE is similar in all 3 trimesters of pregnancy, 4 and the risk of VTE after hospital discharge after de- livery is greater. 5 The incidence of post- partum DVT isabout0.30 per1000 pregnancies in women younger than 35 years, rising to 0.72 per 1000 pregnancies in women older than 35 years. 3 Interestingly age over 35 years, obe- sity,multiparity, prolonged bed rest, mode of delivery (cesarean section, espe- cially urgent ones) significantly increase the risk ofDVT. 1 The association be- tween thrombophilia and pregnancy-re- lated VTE has been addressed: the rela- tive risks are different and depend on the type of inheritedor acquired thrombophilia. 6 The risk of VTE is 4- to 5-fold greater in pregnant than nonpregnant women and can be 20-fold higher in the postpar- tum period. 2 Abnormalities within the gene loci encoding for natural antico- agulants (antithrombin, protein C, and protein S)and fibrinogen have been shown to be rather uncommon risk fac- tors for VTE. 7 In patients from European ancestry, a common mutation within th gene of the coagulation factor V (FV; Le den mutation) and one within the facto II (FII) gene (a G-to-A transition at nu- cleotideposition20210)have been shown to account for a large number of cases of thromboembolism. 7 Although the knowledge of a series of major risk factorsfor vein thrombosis hasbeen greatlyimproved,thereexist many thrombotic events whose pathogenesis unclear. Annexinsareproteinswith a high Ca ⫹⫹ -dependent affinityfor anionic phospholipids. Annexin V (ANXA5), the mostabundantmemberof this group of proteins, is found in many tis- sues and in the bloodstream and plays potent antithrombotic role. 8 The circu- lating ANXA5 is probably released from cells present in the vessel wall. After its secretion into plasma, it binds blood ce and probably endothelial cells, account ing for the low levels of free protein in plasma. 9 The activation of platelets and From the Atherosclerosis and Thrombosis Unit, Research Department (Drs Grandone, Tiscia, Colaizzo, Chinni, PisanellI, and Margaglione), Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, S. Giovanni Rotondo, and the Division of Medical Genetics, Department of Biomedical Sciences (Drs Bafunno and Margaglione), Università di Foggia, Foggia, Italy. Received Oct. 8, 2009; revised Feb. 9, 2010; accepted June 7, 2010. Reprints: Elvira Grandone, MD, Unitá di Aterosclerosi e Trombosi, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, S. Giovanni Rotondo Foggia 71013, Italy. e.grandone@operapadrepio.it. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.06.007 Research www. AJOG .org NOVEMBER 2010 American Journal of Obstetrics & Gynecology 461.e1