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Development of inhibitory antibodies is perhaps the most serious complication of FVIII replacement therapy, precluding efficient clinical management of patients with haemophilia A ( HA). The development and function of immune system are also regulated by micro RNAs (mi RNAs). Mutations and changes in the level of expression of some mi RNA genes have been associated with the onset and progression of immunological disorders. The aim of this study was to investigate new genetic polymorphisms in loci for mi RNA and their targets to evaluate whether these SNPs may confer susceptibility to inhibitor development in patients with HA. Italian HA patients with and without inhibitors and healthy controls were recruited in this study. For SNP analysis, standard DNA sequencing method was used. We have studied four SNPs, i.e. rs36101366, rs34683807, rs1803603 and rs3024496 located in the 3′ UTR of F8 and IL-10 genes. These SNPs have been checked for their frequencies in patients with and without inhibitors, but no statistically significant differences were found. Then, we have searched for other genetic variants in loci for haematopoietic-specific mi RNAs, i.e. hsa-mir-150, hsa-mir-155, hsa-mir-146a, hsa-mir-142, hsa-mir-181a and in a specific mi RNA, hsa-mir-1184, i.e. predicted to be located in the intron 22 of F8 gene. For all mi RNAs selected, we did not identify any sequence variation in our study population. This is the first study to demonstrate that there was no association between selected SNPs in mi RNAs and their targets and the susceptibility to inhibitor development in people affected by HA. [ABSTRACT FROM AUTHOR]

Background/purpose: We explored determinants of success in a large cohort of patients with pectus excavatum submitted to vacuum bell treatment and compared groups with satisfactory versus unsatisfactory outcomes., Methods: Retrospective case-control study in a single center between May 2013 and January 2020, including patients with pectus excavatum treated with vacuum bell. We classified patients according to their status at closure of data registry (surveillance; withdrawal; complete correction; failure) and according to Obermeyer's classification of degrees of pectus excavatum correction. Determinants of success were calculated using receiver operating characteristic curves., Results: Overall, 186 patients were included. Complete correction was achieved by 17% of the cases, while 45% remained under surveillance. Failure rates were low (n = 9; 5%), whereas withdrawal rates were 34%. Based on Obermeyer's classification of degree of excavation correction, 35% had excellent/good, 25% fair, and 40% poor/worse results. When comparing patients with good/excellent results with those with unsatisfactory results, patients with good/excellent results had a longer treatment duration [19.0 (13.0; 28) months vs. 13.0 (6.5; 22.5) months, p<0.0001], and lower initial pectus depth [1.6 (1.2; 2.0) cm, vs. 2.0 (1.5; 2.6) cm, p = 0.001]. Using ROC curves, the best determinants of success were an initial pectus depth ≤ 1.8 cm and a length of treatment > 12 months., Conclusion: One-third of patients in treatment with a vacuum bell achieved excellent or good outcomes in our cohort. Determinants of success included an initial pectus depth of 1.8 cm or less and a minimum length of treatment of 12 months., Type of Study: retrospective comparative study LEVEL OF EVIDENCE: III., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immune-mediated thrombotic thrombocytopenic purpura is a rare and challenging hematological disease caused by the antibody anti-ADAMTS13. Though the mortality rate has decreased considerably in recent years, fatalities still remain unacceptable. This study aimed at further adding to the existing knowledge of this medical challenge. We enrolled 89 consecutive patients observed in six Italian centers (from 8 August 2013 to 28 May 2021) with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura. Clinical information and blood parameters were collected for all patients. We describe clinical manifestations and laboratory data, possible risk factors and the therapeutic management of first episodes or relapses. A total of 74 first episodes and 19 relapses (median 3 years (interquartile range (IQR): 2-7)) were recorded. Seventy percent of patients enrolled at the first episode showed neurological signs and/or symptoms. All the patients enrolled at the first episode were treated with plasma exchange (median = 12; IQR: 8-19.5) and methylprednisolone (1 mg/kg/day). Rituximab (375 mg/m 2 weekly for four weeks) and caplacizumab were given to 15 (20.2%) and 2 patients (2.6%), respectively. We observed an overall mortality of 5.4% in the follow-up (median 60 months; IQR: 36.0-103.5). All fatalities occurred after a diagnostic delay. Present data point to the importance of the early detection of factors mostly associated with poor outcomes. It is likely that use of caplacizumab could improve the prognosis in those patients.

Background: Endothelial dysfunction, coupled with inflammation, induces thrombo-inflammation. In COVID-19, this process is believed to be associated with clinical severity. Von Willebrand factor (VWF), and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS-13), are strong markers of endothelial dysfunction. We evaluated the impact of the VWF/ADAMTS-13 fraction on COVID-19 severity and prognosis., Materials and Methods: A cohort study including 74 COVID-19 patients, with 22 admitted to the intensive care unit (ICU) and 52 to the medical ward (MW), was carried out. We also evaluated, in a group of 54 patients who were prospectively observed, whether variations in VWF/ADAMTS-13 correlated with the degree of severity and routine blood parameters., Results: A VWF:RCo/ADAMTS-13 fraction above 6.5 predicted in-hospital mortality in the entire cohort. At admission, a VWF:RCo/ADAMTS-13 fraction above 5.7 predicted admission to the ICU. Furthermore, the VWF:RCo/ADAMTS-13 fraction directly correlated with C-reactive protein (CRP) (Spearman r: 0.51, p < 0.0001) and D-dimer (Spearman r: 0.26, p = 0.03). In the prospective cohort, dynamic changes in VWF:RCo/ADAMTS-13 and the CRP concentration were directly correlated (Spearman r, p = 0.0014). This relationship was significant in both groups (ICU: p = 0.006; MW: p = 0.02)., Conclusions: The present findings show that in COVID-19, the VWF/ADAMTS-13 fraction predicts in-hospital mortality. The VWF/ADAMTS-13 fraction may be a helpful tool to monitor COVID-19 patients throughout hospitalization.

Background: May-Hegglin anomaly is an autosomal dominant inherited condition, characterized by thrombocytopenia, giant platelets and Dohle-like bodies. Incidence is unknown and affected individuals can show from mild to moderate-severe haemorrhagic symptoms. The cyst of cavum veli interpositi (a virtual space filled with fluid within the third ventricle) is rarely reported in the foetal period. Furthermore, it is unclear whether isolated cavum veli interpositi cysts are a normal variant or developmental malformations. The simultaneous presence of these two anomalies was never described., Case Presentation: We describe a very rare case of a twin monochorionic pregnancy in a woman with the May-Hegglin anomaly, whose foetuses carried cavum veli interpositi cysts. Since childhood, our patient had shown macro-thrombocytopenia, deafness and bleeding (epistaxis and menorrhagia), but she was misdiagnosed until the age of 30 years when our Centre identified a de novo allelic variant in the gene MYH9 coding for the non-muscle myosin heavy chain IIa. Our patient bled neither during the pregnancy, nor in the peripartum period. Children are now eight-months-old and have never bled, although both inherited the MYH9 variant and have thrombocytopenia with giant platelets. Furthermore, none of them developed psychomotor disorders., Conclusions: To the best of our knowledge, this is the sixth case of twin pregnancy in a woman carrying May-Hegglin anomaly and the first one with cavum veli interpositi cysts in the neonates. We speculate that MYH9 could have, at least in part, played a role in the development of both conditions, as this gene has a pleiotropic effect.

Automated methodologies allowing for rapid detection of Factor V Leiden and Factor II G20210A variants are desirable, due to a high number of tested patients. Here, we report a preliminary validation of a CE-marked in vitro diagnostic (IVD) certified method for simultaneous detection of Factor V Leiden and Factor II G20210A variants on whole blood samples. The novel method is based on Loop-mediated isothermal AMPlification (LAMP) applied for a duplex detection of Factor V Leiden and Factor II G20210A variants without requiring prior DNA extraction, whereas the routine one is a TaqMan SNP genotyping targeting genomic DNA. We tested routine patients for both variants using novel and current methods and estimated concordance rate. Patients were tested under similar laboratory procedures. One hundred and eight patients referred for the thrombophilia testing in the period between 9th December 2019 to 27th February 2020 represented the study population. We routinely identified for the Factor V Leiden variant 163 wild-type, 17 heterozygotes and no homozygote. Concerning the Factor II G20210A variant, we identified 170 wild-type, nine heterozygotes and one homozygous carrier. Two heterozygotes carried both variants (double heterozygotes). The LAMP method showed a 100% concordance rate, detecting rightly all genotypes. The LAMP for a duplex detection of common thrombophilia variants shows analytic performances as good as those of the standard method.

Competing Interests: Conflict of Interest None declared.

This study was carried out to explore hemostasis modifications occurring in pregnant women and thromboelastography profiles in those taking antithrombotic drugs. An exploratory study was carried out in the period from March 2017 to May 2018. Caucasian women from Southern Italy were recruited during a routine obstetric assessment. Participants were divided into four groups: T1 (gestational week <14 weeks), T2 (14-28 weeks), T3 (29-42 weeks) and T4 in the postpartum period. We investigated thromboelastography profile in 19 and 5 women administered with low-molecular-weight heparin or low-dose aspirin, respectively. "MA" value observed in the T1 group was significantly greater than that observed in the T3 and the T4 groups, while "K" in the T1 group was significantly longer than that in the T3 and the T4 groups, indicating a gradual development of a prothrombotic state (in all cases Mann-Whitney U test, p<0.05). Significant differences within "R" were observed between the T2 and the T3 and between the T3 and the T4 ("R" parameter) (Mann-Whitney U test, p<0.05). "LY30" parameter resulted to be significantly higher in the T1 group (Mann-Whitney U test, p=0.01) compared with the T4 one, indicating fibrinolysis decreases throughout pregnancy and until post partum. No significant variations were found in women administered with prophylactic doses of low-molecular-weight heparin. Significantly higher fibrinolysis (p<0.01) was observed for "LY30" parameter in women taking low-dose aspirin versus women not taking any treatments. Our data contribute to better interpret thromboelastography profile in the context of peripartum complications, which are often unpredictable and need prompt therapies., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Antiphospholipid (aPL) antibodies are recognised risk factors for adverse obstetric outcomes. Recently, carriers of the M2 haplotype in the Annexin A5 gene have been shown to have a higher susceptibility to develop aPL antibodies. In a general obstetric population, we prospectively evaluated the possible relationship between: (1) aPL antibodies and M2 haplotype; and (2) aPL antibodies and/or M2 haplotype and obstetric outcomes. From a cohort of 3,097 consecutive pregnant women, 1,286 samples were analysed for the presence of both anti-cardiolipin and anti-human β2-glycoprotein I antibodies; samples with available DNA ( n  = 606) were also investigated for the M2 haplotype. Overall, 41/1,286 (3.2%) women showed the presence of aPL antibodies. Among them, 2 (4.8%) experienced a pregnancy loss and 38 (92.7%) gave birth to live-born babies ( p -value = non-significant vs. those without aPL antibodies). M2 haplotype was identified in 140 (23.1%) out of 606 women with DNA available: 3/140 (2.1%) M2 carriers and 17/466 (3.6%) non-carriers tested positive for aPL antibodies, respectively ( p -value = non-significant). In total, 15/150 (10%) M2 and/or aPL antibody carriers, and 38/445 (8.5%) non-aPL antibody and/or M2 carriers suffered from obstetric complications, respectively ( p -value = non-significant). No relationship between aPL antibodies and M2 haplotype was found. Furthermore, neither aPL antibodies nor the M2 haplotype is associated with obstetric complications., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders., Materials and Methods: Ten subjects were referred to our Centre because of likely hypo/dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms., Results: We identified one afibrinogenaemic patient (alpha p.Arg178* homozygote) with bleeding/thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: p.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall., Discussion: All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.

Pregnancies after assisted reproductive technologies (ART) have been associated with an increased risk of venous thromboembolism (VTE). On the contrary, the magnitude of this risk in unsuccessful ART cycles (not resulting in a clinical pregnancy) has not yet been clearly defined. In this study, we evaluated the incidence of VTE in unsuccessful cycles and compared it with that recorded in successful cycles in the same study population. From a cohort of 998 women consecutively referred by local Fertility Clinics to our Atherosclerosis and Thrombosis Unit (April 2002-July 2011), we identified and included women with at least one cycle of ovarian stimulation and a negative history for VTE. Overall, 661 women undergone 1518 unsuccessful and 318 successful cycles of ovarian stimulation, respectively, were analysed. VTE events occurred in 2/1518 (1.3‰) unsuccessful cycles compared with 3/318 (9.4‰) successful cycles, (Two-tailed Fisher exact test, p = 0.04, OR 0.14, 95% CI 0.02-1.02). Both cases observed in unsuccessful cycles were isolated pulmonary embolism occurred after OHSS; no antithrombotic prophylaxis had been prescribed. At logistic regression analysis, the occurrence of successful cycle and BMI were significantly and independently associated with the occurrence of VTE with an OR of 13.94 (95% CI 1.41-137.45) and 1.23 (95% CI 1.01-1.49), respectively. VTE incidence is significantly lower in unsuccessful cycles as compared to that of successful ones. However, although rare, thrombotic risk during ovarian stimulation cannot be excluded and, when it occurs, can be life-threatening. Therefore, particular attention should be paid to these women, independently of ART outcome.

Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency., Competing Interests: The authors declare no conflict of interest.

This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients., Competing Interests: The authors declare no conflict of interest.

Purpose: In placentae from uneventful pregnancies a direct relationship between expression of tissue factor (TF) and tissue-factor pathway inhibitor type 2 (TFPI2) was found, as well as between TF and vascular endothelial growth factor (VEGF). Furthermore, placentae from gestational vascular complications (GVCs) lack these correlations. Aims of the present study are (1) to evaluate a possible role of low-molecular-weight-heparins (LMWHs) in the modulation of the expression of TF, TFPI, TFPI2 and VEGF in placentae from thrombophilic women and (2) to study the possible role of endothelium in the placental expression of markers involved in haemostasis and angiogenesis., Methods: Fourteen pregnancies in thrombophilic women and 11 uneventful pregnancies in non-thrombophilic women were studied and placentae collected. From each placenta total RNA was obtained. Expression of TF, TFPI, TFPI2 and VEGF was evaluated. Human Vein Endothelial Cells were incubated with increasing doses of LMWH and expression of TF, TFPI and VEGF was measured., Results: Expression of all the markers analyzed in placentae from treated pregnancies was similar to that observed in placentae from uneventful ones. A significant direct relationship between TF and TFPI2, as well as TF and VEGF, was observed in cases treated with LMWHs and controls. Furthermore, the expression of TF and its inhibitors and VEGF in endothelial cells was modulated by LMWH., Conclusion: Present data suggest that LMWH during pregnancy in thrombophilic women restores the relationship between markers of haemostasis and angiogenesis. Furthermore, the endothelium is likely to play an important role in this phenomenon.

Coagulation disorder associated with essential thrombocythemia may exacerbate the prothrombotic state physiologically occurring during pregnancy. We report a case of a severe postpartum haemorrhage in a 35-year-old woman previously diagnosed with essential thrombocythemia and carrying the somatic calreticulin mutation. She was referred to our Thrombosis and Haemostasis Unit for pregnancy management. A treatment with low-dose aspirin was prescribed until the labour started, as the platelets count raised above 1000 × 10/l. At the time of bleeding, no residual placenta was detected at the revision of the uterine cavity.Although the postpartum is a high-risk period for thrombotic events, we have to carefully evaluate in women with essential thrombocythemia the likelihood of developing a hemorrhagic complication.

Pectus carinatum is a chest wall deformity, sometimes associated with physical signs and symptoms, but always associated to significant psychological distress. Surgical correction used to be the only solution, and was therefore only indicated for the most severe cases. Non-surgical approaches have been developed and improved during the last 15-20 years. A paradigm shift occured when the medical community realized that, despite the wall deformity, the chest wall was not completely rigid, but flexible and capable of remodeling. Several bracing devices and protocols are available as of today. This article will focus specifically in the FMF ® Dynamic Compressor System (DCS), which was developed in Argentina in 2001 and is currently used worldwide., Competing Interests: Conflicts of Interest: Bruno Strappa is a full time employee at Pampamed S.R.L. Marcelo Martinez-Ferro is also owner of Pampamed S.R.L, an argentine company holding the license for commercialization of the FMF® Dynamic Compressor System. The other authors have no conflicts of interest to declare.

Objective: Knowledge about risk factors for venous thromboembolism (VTE) is still limited. A recently found haplotype within the natural anticoagulant protein annexin A5 (ANXA5) exerts an important modulating effect on gene expression., Study Design: Eighty-three nonanticoagulated patients with a documented 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 logistic regression analysis, correcting for potential confounders (age at which the thrombotic event occurred, factor V Leiden, and factor IIA20210 variants) showed a significant increase (odds ratio, 3.4; 95% confidence interval, 1.7-6.7) of the occurrence of VTE in carriers of the M2 haplotype as compared with noncarriers., Conclusion: The M2 haplotype within the ANXA5 gene may represent a new thrombophilic risk factor for pregnancy-related VTE., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Introduction: Preeclampsia (PE) and fetal growth restriction (FGR) are multifactorial diseases, whose pathogenesis is largely unknown. A significant relationship between haemostasis and angiogenesis in placentae from uneventful pregnancies was previously shown., Materials and Methods: RNA expression of haemostasis (TF, TFPI, TFPI-2, PAI-2, Anx V, TM) and angiogenesis (Ang-1, Ang-2, PlGF, VEGF) markers in placentae from PE (n=12), PE+FGR (n=17) and FGR (n=20) in respect of placentae from uncomplicated pregnancies (n=21) were investigated., Results: Placentae from complicated pregnancies showed a significant lower expression (p

Inherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancy-related hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls, 195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic regression, correcting for age, gravidity and parity showed that the ANXA5 haplotype is significantly and independently associated with the occurrence of RFL (3.1; 95%CI: 1.1-9.5; p = 0.047) and pregnancy-related hypertensive disorders (2.1; 95%CI: 1.2-3.5; p = 0.008). The M2 haplotype might be a new and relevant risk factor for obstetric complications.

In a group of placentas from patients with preeclampsia or fetal growth restriction, reduced annexin V gene expression in those carrying the M2 haplotype was observed. This is the first "ex vivo" demonstration that annexin V gene expression in placentas is dependent on the M2 haplotype.

Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.

Introduction: Few studies have been carried out to investigate whether distinct areas of full term placenta express different amounts of markers involved in the placental haemostasis and angiogenesis. A possible relationship between the expression of genes involved in the haemostasis and angiogenesis of human placenta has not been investigated., Materials and Methods: Twenty-eight fresh human placentas (35-41 weeks of gestation) from uneventful pregnancies were dissected with two different methods. Quantitative mRNA expression of the tissue factor (TF), TF pathway inhibitor (TFPI), TFPI-2, plasminogen activator inhibitor (PAI-2), annexin V (Anx V), vascular endothelial growth factor (VEGF), and thrombomodulin (TM) genes was evaluated by quantitative real time PCR system. Histology of each sample was graded., Results: Gene expression of all the considered markers was not significantly different in each area, using both the different methods of dissection. A significant correlation (p<0.05) was found between the expression of TF and TFPI-2. TF and TFPI-2 were significantly (p<0.05) associated with VEGF, whereas a stronger association (p<0.01) was found between TFPI and TFPI-2. TFPI and TFPI-2 were strongly associated with PAI-2 expression (p<0.01)., Conclusions: In placentas with central cord insertion, gene expression is not dependent on the method of sampling site. A significant relationship between haemostasis and angiogenesis in at term placentas was shown.