Clonal haematopoiesis of indeterminate potential in patients with venous thromboembolism.

Over the last decade, the concept of Clonal haematopoiesis of undetermined potential (CHIP) has emerged. Low frequency somatic mutations in hematopoietic cells can occur with age and might allow formation of clones in individuals with no characterized haematological pathology. These CHIP mutations are associated with an increased risk of cancer or atherothrombosis, and their prevalence are more and more studied in pathologies with an inflammatory component. In our study, we analysed, by next generation sequencing, the prevalence of CHIP mutation in 94 patients with deep venous thrombosis (DVT), distinguishing two clinical phenotypes: provoked distal and non-provoked proximal DVTs. We show that there is no difference in CHIP prevalence between these two groups, nor with a matched-aged control group. The number of mutation per patients and the affected genes remain also the same between the three groups. Consequently and despite the relative small number of patients in each cohort, it seems that CHIP is not a strong concern in venous thromboembolism.

Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort.

Malignancies can be associated with positive antiphospholipid antibodies but the incidence of cancer among women with the purely obstetric form of antiphospholipid syndrome (APS) is currently unknown. Our aim was to investigate the comparative incidence of cancers in women with a history of obstetric APS within a referral university hospital-based cohort (NOH-APS cohort). We performed a 17-year observational study of 1,592 non-thrombotic women with three consecutive spontaneous abortions before the 10th week of gestation or one fetal death at or beyond the 10th week of gestation. We compared the incidence of cancer diagnosis during follow-up among the cohort of women positive for antiphospholipid antibodies (n=517), the cohort of women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n=279) and a cohort of women with negative thrombophilia screening results (n=796). The annualized rate of cancer was 0.300% (0.20%-0.44%) for women with obstetric APS and their cancer risk was substantially higher than that of women with negative thrombophilia screening [adjusted hazard ratio (aHR) 2.483; 95% confidence interval (CI) 1.27-4.85]. The computed standardized incidence ratio for women with obstetric APS was 2.89; 95% CI: 1.89-4.23. Among antiphospholipid antibodies, lupus anticoagulant was associated with incident cancers (aHR 2.608; 95% CI: 1.091-6.236). Our cohort study shows that the risk of cancer is substantially higher in women with a history of obstetric APS than in the general population, and in women with a similar initial clinical history but negative for antiphospholipid antibodies.

Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study.

An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D-dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non-surviving patients, area under the receiver-operator characteristic curve (AUCROC ): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non-survivors using each of the three FGMs. A dose-effect relationship was observed between ISTH DIC scores and non-survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non-survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUCROC values testing the ability of the ISTH DIC score to predict non-survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially-available automated assays, automated FM is the FGM best related with late prognosis.

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes.

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10-2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047).

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study.

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study.

The incidence of pregnancy outcomes for women with the purely obstetric form of antiphospholipid syndrome (APS) treated with prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) has not been documented. We observed women without a history of thrombosis who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week. We compared the frequencies of complications during new pregnancies between treated women with APS (n = 513; LMWH + LDA) and women negative for antiphospholipid antibodies as controls (n = 791; no treatment). Among APS women, prior fetal loss was a risk factor for fetal loss, preeclampsia (PE), premature birth, and the occurrence of any placenta-mediated complication. Being positive for anticardiolipin immunoglobulin M antibodies was a risk factor for any placenta-mediated complication. Among women with a history of recurrent abortion, APS women were at a higher risk than other women of PE, placenta-mediated complications, and neonatal mortality. Among women with prior fetal loss, LMWH + LDA-treated APS women had lower pregnancy loss rates but higher PE rates than other women. Improved therapies, in particular better prophylaxis of late pregnancy complications, are urgently needed for obstetric APS and should be evaluated according to the type of pregnancy loss.

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study.

The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.

Reference values of coagulation assays performed for thrombophilia screening after a first venous thrombosis and their intra-patient associations.

INTRODUCTION: No reference values are currently available for coagulation assays performed for thrombophilia screening prescribed according to guidelines, after a first venous thromboembolic (VTE) event, and we have no idea of the intra-patient associations between results. METHODS: We performed a retrospective study of consecutive prescriptions fulfilling guidelines in a French university hospital from 2010 to 2019 (n = 3842) from the Glims® laboratory information system. We collected results of 12 parameters: aPTT, PT, fibrinogen (Fg), one-stage clotting methods for factors VIII, IX, XI and II (FVIII, FIX, FXI, FII), antithrombin (using an amidolytic assay: AT), protein C and S (using clotting assays: PC and PS) and mixing tests of a lupus-anticoagulant sensitive aPTT and of DRVVT. RESULTS: We show the results of the 12 parameters from 3603 individual files with less than 6 missing values, then describe these distributions and correlations between results from 2930 files with no missing value. We give the frequency of results described as indicating a risk of first VTE or of VTE recurrence. We propose 2 quantitative scores linking the 12 parameters at the individual level and reflecting their degree of dispersion with respect to their mean, describe the values of these scores and their associations with thrombophilic results. CONCLUSIONS: These normal values should help laboratory workers to validate process results and to assess their degree of originality. Our 2 scores should help to determine the intra-patient plausibility of associations of results. The usefulness of these laboratory scores for predicting clinically-relevant outcomes deserves to be investigated.

[Is haemostasis assessment mandatory in case of pregnancy loss?]. / Faut-il faire un bilan d'hémostase en cas de pertes foetales?

Pregnancy losses must be categorised into biochemical loss, early embryonic loss, late foetal loss and stillbirth cases. No haemostasis-related investigations are necessary for biochemical losses. Antiphospholipid antibodies must be checked for three early losses or one late loss. A complete blood count will reveal the rare essential thrombocytemias, a functional fibrinogen assay the exceptional dysfibrinogenemia cases. Vitamin B12 and intracellular folates levels must be checked in case of clinical or biological suspicion. Constitutive thrombophilias must not be routinely assessed because a therapeutic option is not definitively demonstrated. Screening for constitutive thrombophilias should be only indicated for clinical research purposes, only for late foetal loss and stillbirth cases.

Early ADAMTS13 testing associates with pre-eclampsia occurrence in antiphospholipid syndrome.

INTRODUCTION: Women with obstetric antiphospholipid syndrome (oAPS) still develop placental diseases, mainly pre-eclampsia (PEcl), which diagnosis is associated with reduced ADAMTS13 levels. Testing ADAMTS13 in newly pregnant oAPS may provide evidence for risk stratification. MATERIALS AND METHODS: We retrospectively investigated the prognostic value of ADAMTS13 activity, antigen and antibodies on stored plasma samples obtained prior to beginning low-molecular weight heparin-low dose aspirin treatment in 513 oAPS women. RESULTS: Some women had evidences of early positive ADAMTS13 antibodies and low ADAMTS13 activity:antigen ratio, suggestive of ADAMTS13 dysfunction. Women with a subsequent PEcl had higher ADAMTS13 antibodies (p < 0.0001), and lower ADAMTS13 activity and activity:antigen ratios (p < 0.0001). In multivariate analysis, these markers were significant risk factors for PEcl and for the most devastating PEcl subgroups (early-onset PEcl, severe PEcl, PEcl with no living child after 28 days). ADAMTS13-related markers showed acceptable discrimination power to predict clinical events, particularly for ADAMTS13 activity:antigen ratio in predicting PEcl cases with no living child after 28 days (AUC: 0.844 (0.712-0.974), p < 0.0001), with excellent negative predictive value (0.990). CONCLUSIONS: The characterization of ADAMTS13 in newly pregnant women with oAPS depicts the risk of PEcl occurrence. ADAMTS13 might help identify pregnant women with oAPS not requiring escalating treatment strategies to prevent PEcl.

The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples.

The endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10(th) week > or = foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.

Urinary Placental Growth Factor for Prediction of Placental Adverse Outcomes in High-Risk Pregnancies.

OBJECTIVE: To evaluate whether urinary levels of placental growth factor (PlGF) during pregnancy are associated with the subsequent development of composite adverse outcomes (preeclampsia, fetal growth restriction, placental abruption, perinatal death, maternal death) occurring at less than 34 weeks of gestation. METHODS: This is a preplanned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive either low-molecular-weight (LMW) heparin or aspirin alone. For this substudy we measured urinary levels of PlGF and urinary creatinine at the following gestational windows: 10-13 6/7, 14-17 6/7, 18-21 6/7, 22-25 6/7, 26-29 6/7, 30-33 6/7, and 34-37 6/7 weeks of gestation. RESULTS: Urine samples were available from 187 patients: LMW heparin plus aspirin (n=93) and aspirin alone (n=94). The two groups had comparable baseline characteristics and had similar adverse composite outcomes at less than 34 weeks of gestation (14/93 [15.1%] vs 11/94 [11.7%]; P=.50). There were no significant differences in urine PlGF levels in the patients who received LMW heparin plus aspirin compared with those who received aspirin alone. However, median [interquartile range] urinary PlGF/creatinine concentrations (pg/mg) measured at mid-pregnancy (22-26 weeks of gestation) were significantly lower among women who developed composite adverse outcome at less than 34 weeks of gestation (42.7 [32.4-80.8] vs 255.6 [118.7-391.8] P<.001) and significantly lower among women who developed preeclampsia at less than 34 weeks of gestation (42.7 [27.5-80.7] vs 244.6 [112.9-390.6] P<.001). For a fixed false-positive rate of 10% the sensitivity of urinary PlGF concentrations at mid-pregnancy was 75.2% (area under the curve 0.93) for the subsequent development of composite adverse outcomes. CONCLUSION: Decreased urinary PlGF at mid-gestation (22-26 weeks of gestation) is associated with the subsequent development of preeclampsia-related adverse outcomes at less than 34 weeks of gestation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00986765.

The role of haemostasis in placenta-mediated complications.

Normal pregnancy is associated with an increasing state of activation of the haemostatic system. This activation state is excessive in women with placenta-mediated pregnancy complications (PMPCs), including preeclampsia (PE). Platelet activation plays a crucial pathophysiological role in PE. The very early activation of coagulation in the intervillous space is mandatory for placental growth and morphogenesis but its excesses and/or inadequate control may participate to the emergence of the trophoblastic phenotype of PE. Extracellular vesicles, of endothelial but also of trophoblastic origin, can favour key cellular reactions of preeclampsia, acting as proactive cofactors. The understanding of this intricate relationship between haemostasis activation and PMPCs may provide interesting keys for new pathophysiological therapeutic developments.

Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study.

OBJECTIVES: Case reports describe neuropsychiatric manifestations associated with antiphospholipid antibodies (aPlAbs). In patients sharing the same symptoms fulfilling the antiphospholipid syndrome (APS) clinical criteria, the prevalence of common mental disorders has, however, never been studied. METHODS: We observed women with three consecutive abortions before the 10th week of gestation or one foetal loss at or beyond the 10th week. We compared the prevalence of common psychiatric disorders detected through screening using the Mini International Neuropsychiatric Interview, 10 years after inclusion, in women with APS (n = 506), women negative for aPlAbs but carrying the F5rs6025 or F2rs1799963 thrombogenic polymorphism (n = 269), and women with negative thrombophilia screening results as controls (n = 764). RESULTS: Similar prevalence values were obtained for controls and women bearing one of the two thrombogenic polymorphisms. Women with APS more frequently had mood disorders (relative risk (RR) 1.57 (1.262-1.953), P = .0001) and anxiety (RR 1.645 (1.366-1.979), P < .0001). Within the APS group, lupus anticoagulant (LA) and anti-ß2GP1 IgG, or triple positivity, were strong risk factors for mood disorders. CONCLUSIONS: Women with obstetric APS have a higher risk of positive screening for common mental disorders than women without APS.

Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort.

Severe postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6-17) and 4.7 (1.5-15) respectively), independent of caesarean section delivery and low-molecular-weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively). Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis.

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.

OBJECTIVE: To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction. METHODS: This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks. RESULTS: Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery. CONCLUSION: Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00986765.

Monocyte IL-10 produced in response to lipopolysaccharide modulates thrombin generation by inhibiting tissue factor expression and release of active tissue factor-bound microparticles.

Lipopolysaccharide (LPS)-stimulated monocytes are known to have a procoagulant effect. This property is currently explained by the fact that monocytes, in response to LPS, can express tissue factor (TF) and undergo a process of membrane microvesiculation. Interleukin-10 (IL-10) has been shown to downregulate TF expression and inhibit procoagulant activity (PCA). In order to further characterize the inhibitory effect of IL-10 on LPS-induced PCA, we used the integrated system of analysis of kinetics of thrombin generation in normal plasma (thrombinography). For this, we developed an original method of elutriation allowing to obtain a highly purified monocyte preparation, under endotoxin-free conditions. Thrombin generation was measured using a highly sensitive and specific fluorogenic method which we adapted to inhibit the contact factor pathway. Results show that recombinant human IL-10 decreased the kinetics of thrombin generation in a dose-dependent manner. Furthermore, the inhibition of endogenous IL-10 released by monocytes in response to LPS is associated with an increase in the kinetics of thrombin generation. We demonstrated that this effect was a consequence of the up-regulation of TF expression and TF-bound microparticle release. In conclusion, we report that IL-10 can regulate thrombin generation in conditions close to physiology as allowed by thrombinography, and that endogenous IL-10 regulates TF expression and release of active TF-bound microparticles by a negative feed back loop through IL-10 receptor alpha.

Interleukin-10 promoter polymorphism and venous thrombosis: a case-control study.

The human interleukin-10 promoter gene is highly polymorphic. IL-10 polymorphisms have been associated with various autoimmune and lymphoproliferative disorders. Although IL-10 has been shown to modulate thrombin generation in several experimental models, it is not known whether IL-10 polymorphisms could be a risk factor for venous thrombosis. We therefore conducted a case-control study comparing 74 consecutive patients who experienced at least one episode of documented venous thromboembolic event and 100 healthy controls. All subjects were Caucasians. Five polymorphisms of the IL-10 promoter gene were studied: two highly polymorphic dinucleotide repeats, IL-10 R and IL-10G, and three single nucleotide polymorphisms at position -1082, -819 and -592. Factor VG1691C Leiden mutation was systematically determined. Multivariate logistic regression analysis showed that IL-10 G13 and G10 alleles are independent risk factors for venous thrombosis (Odds ratio:OR = 3.33, p = 0.003 and OR = 2.83, p = 0.03, respectively). Furthermore, IL-10 G10 allele is more frequent in recurrent disease.

The association between hereditary thrombophilias and pregnancy loss.

The correlation between hereditary thrombophilia and fetal loss is supported by several observations. In murine models, the protein C system has been shown to be essential for the maintenance of pregnancy, as it indirectly acts as a growth factor for trophoblast cells and protects them from apoptosis. In humans, it has been shown that the placenta replaces the yolk sac as an essential source of blood supply to the embryo during the 8th and 9th weeks of gestation. Furthermore, meta-analysis of epidemiological data demonstrates a correlation between thrombophilic polymorphisms such as factor V Leiden and prothrombin 20210G-->A and isolated or recurrent fetal losses. Finally, therapeutic non-controlled trials indicate the benefits and safety of low-molecular weight heparins as secondary prophylaxis. However, it is still necessary to further clarify the association between thrombophilia and fetal loss, especially during a first pregnancy, with regard to the type of pregnancy loss and with respect to other related factors.