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• W2023183073 abstract "Recurrent pregnancy loss is a common problem, with two or more losses in up to 5% of women, and recurrent (three or more consecutive losses) affecting 1–2% of women. Markers of coagulation activation (D‐dimer and fibrinopeptide A) are known to increase preceding spontaneous abortion [1Woodhams B.J. Candotti G. Shaw R. Kernoff P.B. Changes in coagulation and fibrinolysis during pregnancy: evidence of activation of coagulation preceding spontaneous abortion.Thromb Res. 1989; 55: 99-107Abstract Full Text PDF PubMed Scopus (46) Google Scholar], and there is a strong association with antiphospholipid antibodies (aPA) [2Rai R.S. Clifford K. Cohen H. Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies.Hum Reprod. 1995; 10: 3301-4Crossref PubMed Scopus (259) Google Scholar] and some hereditary thrombophilia [3Preston F.E. Rosendaal F.R. Walker I.D. Briet E. Berntorp E. Conard J. Fontcuberta J. Makris M. Mariani G. Noteboom W. Pabinger I. Legnani C. Scharrer I. Schulman S. Van Der Meer F.J. Increased fetal loss in women with heritable thrombophilia.Lancet. 1996; 348: 913-6Abstract Full Text Full Text PDF PubMed Scopus (623) Google Scholar]. However, the majority of cases of unexplained pregnancy loss occur in the absence of aPA or hereditary thrombophilic defects. Activated protein C (APC) resistance during normal pregnancy is well documented [4Cumming A.M. Tait R.C. Fildes S. Yoong A. Keeney S. Hay C.R. Development of resistance to activated protein C during pregnancy.Br J Haematol. 1995; 90: 725-7Crossref PubMed Scopus (209) Google Scholar] and acquired APC resistance (measured by a clotting test), independent of the factor V Leiden mutation (FVL), is a risk factor for pregnancy loss [5Brenner B. Mandel H. Lanir N. Younis J. Rothbart H. Ohel G. Blumenfeld Z. Activated protein C resistance can be associated with recurrent fetal loss.Br J Haematol. 1997; 97: 551-4Crossref PubMed Scopus (162) Google Scholar, 6Rai R. Shlebak A. Cohen H. Backos M. Holmes Z. Marriott K. Regan L. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage.Hum Reprod. 2001; 16: 961-5Crossref PubMed Scopus (153) Google Scholar] and pre‐eclampsia [7Paternoster D.M. Stella A. Simioni P. Girolami A. Snijders D. Activated protein C resistance in normal and pre‐eclamptic pregnancies.Gynecol Obstet Invest. 2002; 54: 145-9Crossref PubMed Scopus (14) Google Scholar]. Tissue factor pathway inhibitor (TFPI) is known to be a major determinant of thrombin generation‐based APC sensitivity [8De Visser M.C. Van Hykkama Vlieg A. Tans G. Rosing J. Dahm A.E. Sandset P.M. Rosendaal F.R. Bertina R.M. Determinants of the APTT‐ and ETP‐based APC sensitivity tests.J Thromb Haemost. 2005; 3: 1488-94Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar], i.e. low TFPI levels are associated with APC resistance. We therefore studied the role of endogenous thrombin potential (ETP) and TFPI antigen levels in women with recurrent pregnancy loss. The study population comprised 22 women with a history of recurrent early pregnancy loss (three or more consecutive losses at < 24 weeks, n = 17) or intrauterine fetal death (IUFD; n = 5). Six of the women had the antiphospholipid syndrome (APS), while the other 16 had no detectable aPA. All samples were taken in the non‐pregnant state, at least 6 weeks after the end of pregnancy. The following women were excluded from the study: those with protein C or S deficiency, FVL, or who were receiving oral anticoagulation, heparin or oral contraceptives at the time of testing. Thrombin generation was measured with and without exogenous human recombinant APC, using a method based on that of Rosing et al. [9Rosing J. Tans G. Nicolaes G.A. Thomassen M.C. Van Oerle R. Van Der Ploeg P.M. Heijnen P. Hamulyak K. Hemker H.C. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second‐ and third‐generation oral contraceptives.Br J Haematol. 1997; 97: 233-8Crossref PubMed Scopus (314) Google Scholar]. Briefly, coagulation was triggered by the addition of 7 pm tissue factor (Innovin, Marburg, Germany), 20 μm phospholipid (Rossix, Mölndal, Sweden) and 16 mm CaCl2 to defibrinated plasma. The ETP, calculated from the area under the curve, was measured continuously by cleavage of a chromogenic substrate (Pefachrome TG, Pentapharm, Basel, Switzerland) using the ACL9000 (Instrumentation Laboratory, Milan, Italy). This was performed with and without the addition of 5 nm APC (Eli Lilly, Indianapolis, IN, USA). Results were expressed as ratios relative to pooled normal plasma (PNP): ETP = thrombin formed in patient plasma/thrombin formed in PNP, with no APC. ETP+APC = thrombin formed in patient plasma/thrombin formed in PNP, with 5 nm APC. Total TFPI antigen was assayed using the IMUBIND® Total TFPI ELISA kit (American Diagnostica Inc, Stamford, CT, USA) a quantitative sandwich ELISA, which recognizes full‐length, truncated and conjugated forms of TFPI [10Bognacki J. Hammelburger J. Functional and immunologic methods for the measurement of human tissue factor pathway inhibitor.Blood Coagul Fibrinolysis. 1995; 6: S65-72Crossref Scopus (37) Google Scholar]. The Mann–Whitney U‐test was used to test the differences between the medians and statistical significance was defined as P < 0.05. Normal reference ranges were established in citrated plasma from 20 normal non‐pregnant women: ETP median 0.91 (95% reference range 0.70–1.07), ETP+APC 0.96 (0.76–1.07) TFPI antigen 89 ng mL−1 (75–120 ng mL−1). Both ETP and ETP+APC were significantly higher in the women with previous pregnancy morbidity than in normal subjects (median ETP 1.07, P < 0.0001; median ETP+APC 1.32, P < 0.0001). The median TFPI was 75.4 ng mL−1 (range 31.5–120 ng mL−1, P = 0.007), with low TFPI antigen levels in 10 out of 22 (45%) of the women with previous pregnancy morbidity, all of whom had raised ETP and/or ETP+APC (Table 1). Although there was a tendency towards higher ETP and lower TFPI antigen levels in the women with APS, antiphospholipid antibody status had no statistically significant effect on ETP, ETP+APC or TFPI antigen levels. Both ETP+APC and ETP showed a negative correlation with TFPI antigen level (r = −0.48 and −0.24, respectively). Furthermore, the addition of increasing amounts of a polyclonal antibody (rabbit antihuman TFPI IgG; American Diagnostica Inc.), that blocked TFPI function, caused a dose‐dependent increase in ETP+APC of up to 50% in normal plasma and a modest increase in ETP (approximately 10%).Table 1Clinical and laboratory data for the studied patientsIDDiagnosisAntiphospholipid antibodiesETP+APCETPTFPI ng mL−11IUFD+1.271.2275.42IUFD + pre‐eclampsia+1.951.2959.03RM+0.831.2572.04IUFD + placental ischemia−1.261.0431.55REPL−1.000.92115.06REPL−1.560.9748.07REPL−2.001.1092.88REPL−1.581.2434.29REPL−1.561.07103.010REPL−1.421.0978.811REPL−1.661.1988.012REPL−0.940.70104.013REPL+1.641.3274.014REPL+1.360.8540.215REPL−0.800.8484.416REPL+0.981.0693.017REPL−0.921.13120.018REPL−0.880.86112.019IUFD−1.250.8455.820REPL+1.881.2471.021REPL−1.200.8880.322IUFD−1.391.1169.3Median1.321.0877.1Minimum0.800.7031.5Maximum2.001.32120.0IUFD, interuterine fetal death; REPL, recurrent early pregnancy loss; Anti‐β2GP‐I, anti‐β2 glycoprotein‐I antibody; TFPI, total tissue factor pathway inhibitor antigen. Open table in a new tab IUFD, interuterine fetal death; REPL, recurrent early pregnancy loss; Anti‐β2GP‐I, anti‐β2 glycoprotein‐I antibody; TFPI, total tissue factor pathway inhibitor antigen. The mechanisms responsible for the association between thrombophilia and pregnancy morbidity are unclear [11Sarig G. Blumenfeld Z. Leiba R. Lanir N. Brenner B. Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss.Thromb Haemost. 2005; 94: 980-5Crossref PubMed Scopus (32) Google Scholar]. Our preliminary data suggest that low levels of plasma TFPI, increased thrombin generation and resistance to APC may be a common finding in women with pregnancy loss/morbidity. We have demonstrated an association between TFPI levels and APC resistance, and have shown that blocking TFPI activity in vitro causes APC resistance. It is clear that the causes of acquired APC resistance are complex. It has been reported that the APC‐resistant phenotype observed during hormone replacement therapy is associated with a decrease in both TFPI and protein S levels [12Hoibraaten E. Mowinckel M.C. De Ronde H. Bertina R.M. Sandset P.M. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double‐blind, placebo‐controlled trial.Br J Haematol. 2001; 115: 415-20Crossref PubMed Scopus (96) Google Scholar]. Furthermore, Hackeng et al. [13Hackeng T.M. Sere K.M. Tans G. Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor.Proc Natl Acad Sci USA. 2006; 103: 3106-11Crossref PubMed Scopus (241) Google Scholar] have recently described an interaction between TFPI and protein S in the regulation of thrombin formation. Inhibitory antibodies to TFPI have been found in women with APS, and these are associated with pregnancy loss [14Martinuzzo M. Iglesias Varela M.L. Adamczuk Y. Broze G.J. Forastiero R. Antiphospholipid antibodies and antibodies to tissue factor pathway inhibitor in women with implantation failures or early and late pregnancy losses.J Thromb Haemost. 2005; 3: 2587-9Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. While an autoimmune mechanism for reduced TFPI antigen cannot be excluded, the majority of the women in our study were aPA negative, so an alternative cause is more likely. For several years, low‐molecular‐weight heparin (LMWH) treatment has been used in the treatment of recurrent pregnancy loss associated with APS [2Rai R.S. Clifford K. Cohen H. Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies.Hum Reprod. 1995; 10: 3301-4Crossref PubMed Scopus (259) Google Scholar, 15Backos M. Rai R. Baxter N. Chilcott I.T. Cohen H. Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin.Br J Obstet Gynaecol. 1999; 106: 102-7Crossref PubMed Scopus (188) Google Scholar, 16Rai R. Cohen H. Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).BMJ. 1997; 314: 253-7Crossref PubMed Scopus (982) Google Scholar], although the precise mechanisms for the protective effect in this setting are unclear. LMWH is frequently used for the treatment of high‐risk pregnancies associated with hereditary thrombophilia and it has been reported that this improves the live birth rate [17Dolitzky M. Inbal A. Segal Y. Weiss A. Brenner B. Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.Fertil Steril. 2006; 86: 362-6Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 18Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE‐ENOX study.J Thromb Haemost. 2005; 3: 227-9Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] although no placebo‐controlled trials have been performed to date. It is known that placental TFPI may be decreased in gestational vascular complications and this may be restored by maternal LMWH treatment [19Aharon A. Lanir N. Drugan A. Brenner B. Placental TFPI is decreased in gestational vascular complications and can be restored by maternal enoxaparin treatment.J Thromb Haemost. 2005; 3: 2355-7Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. However, sub‐therapeutic anti‐Xa levels during treatment of high‐risk pregnancies appear to be associated with low levels of plasma TFPI and an increased risk of pregnancy loss [11Sarig G. Blumenfeld Z. Leiba R. Lanir N. Brenner B. Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss.Thromb Haemost. 2005; 94: 980-5Crossref PubMed Scopus (32) Google Scholar]. In purified systems, TFPI prolongs the lag period and acts synergistically with the protein C pathway to inhibit thrombin generation [20Van‘t Veer C. Golden N.J. Kalafatis M. Mann K.G. Inhibitory mechanism of the protein C pathway on tissue factor‐induced thrombin generation. Synergistic effect in combination with tissue factor pathway inhibitor.J Biol Chem. 1997; 272: 7983-94Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. This is consistent with our finding of TFPI deficiency as a common contributory factor for an APC‐resistant phenotype associated with recurrent pregnancy loss. As APC has both anticoagulant and anti‐inflammatory properties, it seems probable that reduced sensitivity to protein C could contribute to adverse pregnancy outcome as a result of thrombotic and/or inflammatory processes. Our data suggest that TFPI deficiency associated with ETP‐dependent APC resistance could be a risk factor for pregnancy loss, and imply a potential role for heparin in the treatment of this condition. The authors state that they have no conflict of interest." @default.
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• W2023183073 title "Pregnancy loss, tissue factor pathway inhibitor deficiency and resistance to activated protein C" @default.
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