Placental Transfer of Vitamin K1 and Its Implications in Fetal Hemostasis

Mandelbrot, Laurent; Guillaumont, M.; Leclercq, M.; Lefrère, Jean‐Jacques; Gozin, D; Daffos, F.; Forestier, F.

doi:10.1055/s-0038-1647631

Cited by 81 publications

(33 citation statements)

References 20 publications

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“…In the majority of cases, maternal vitamin K deficiency was presumed likely based on the medical histories, but not documented. Since fetal vitamin K levels are normally low due to reduced placental transport, a deficiency in the mother would be expected to further reduce fetal vitamin K levels [Mandelbrot et al, 1988]. Finally, eight infants with CDPX1-like phenotypes born to six mothers with systemic lupus erythematosus (SLE) have been described [Kozlowski et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

Nino

Matos-Miranda

Maeda

et al. 2008

American J of Med Genetics Pt A

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X-linked Recessive Chondrodysplasia Punctata (CDPX1) is due to a defect in arylsulfatase E (ARSE), located on Xp22.3. Neither the substrate nor function of the encoded warfarin-sensitive arylsulfatase has been identified and molecular analysis remains the only confirmatory diagnostic test. Nevertheless, the majority of patients evaluated have not had identifiable mutations in ARSE, and thus far 23 patients have been reported. The major clinical features in these patients are also present in a group now recognized as phenocopies, due to vitamin K deficiency in early gestation or maternal autoimmune disease. We evaluated the ARSE gene in 11 patients who met clinical criteria for CDPX1. We amplified all exons and intronic flanking sequence from each patient, and investigated suspected deletions or rearrangements by southern analysis. We identified mutations in seven individuals. Of the remainder, three had maternal conditions that further expand the phenocopy group. Thus, this group might represent a proportion of the mutation-negative patients in previous studies. We extracted clinical information from all prior reports over the past decade and show that there are few distinguishing features on examination between these two groups of patients. This study supports heterogeneity for CDPX1-like phenotypes and sorting these out will help to define the biological pathway and genetic contributors.

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Section: Introductionmentioning

confidence: 99%

Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

Nino

Matos-Miranda

Maeda

et al. 2008

American J of Med Genetics Pt A

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“…5 In these experiments, all missense alleles had negligible activity. 9,10 Considering the phenotypic resemblance of warfarin embryopathy in early gestation to BCP, Franco et al 5 (1995) demonstrated that ARSE activity is inhibited in the presence of warfarin, an anticoagulant drug that decreases amounts of active vitamin K. These findings suggested that cases of BCP without ARSE mutations could be caused by inhibition of a normal ARSE enzyme in fetal development by reducing levels of vitamin K. Because placental transport of vitamin K is normally reduced, 11 vitamin K deficiency in the mother would be expected to result in greater vitamin K deficiency in the fetus. This hypothesis is attractive given that there have been several reports of BCP in offspring of both sexes in which gestational vitamin K deficiency was suspected, including mothers with severe hyperemesis gravidarum, 12 small-intestinal obstruction, 13 small-bowel syndrome, 14 pancreatitis, 15 or biliary lithiasis.…”

Section: Original Research Article © American College Of Medical Genementioning

confidence: 99%

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

Matos-Miranda

Nimmo

B³

et al. 2013

Genetics in Medicine

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Brachytelephalangic chondrodysplasia punctata (BCP) describes a group of heterogeneous conditions with overlapping phenotypes. X-linked recessive BCP (CDPX1) (OMIM no. 302950), originally recognized by Sheffield et al., 1 is a panethnic congenital rare disorder that affects males. The most characteristic clinical features are as follows: 2,3 (i) Chondrodysplasia punctata, or stippled epiphyses, observed on X-ray. These minimally involve the ankle and distal phalanges but can also include long bones, vertebrae, hips, costochondral junctions, hyoid bone, and tracheal and bronchial cartilage. Chondrodysplasia punctata can be observed initially in the second trimester of pregnancy by ultrasound but tends to improve or disappear by age 2-3 years. (ii) Brachytelephalangy, or shortening of the distal phalanges. A characteristic finding on X-ray is an inverted triangle appearance of the distal phalanges, with punctata on either side. (iii) Nasomaxillary hypoplasia, referring to absence or hypoplasia of the anterior nasal spine, causing a flat nasal base, reduced nasal tip protrusion, shortened columella, and vertical grooves within the alae nasi. (iv) Proportionate short stature. Another commonly observed characteristic is mixed conductive and sensorineural hearing loss. Most children have normal intellect and life span, but comorbidities can be present, including compression of the cervical spinal cord associated with cervical vertebral abnormalities or stenosis of the upper and lower airways that result from extensive calcifications within the tracheal and bronchial cartilage. 3,4 Intrafamilial differences in disease severity have also been documented. 3 The only known genetic cause of CDPX1 is defects in arylsulfatase E (ARSE). The ARSE gene is located at Xp22.3, within a cluster of contiguous arylsulfatase genes that share high sequence homology, escape X inactivation, and have pseudogenes on the Y chromosome. 5 There are 17 sulfatases in the human genome; all share extensive sequence homology and contain a highly conserved cysteine that undergoes a unique posttranslational modification essential for their catalytic activity. 6-8 ARSE is localized to the Golgi membranes, 9 and its transcript has been identified in multiple tissues. 5 Its protein product is a 589-amino-acid and 60 kD precursor, which is subject Purpose: The only known genetic cause of brachytelephalangic chondrodysplasia punctata is X-linked chondrodysplasia punctata 1 (CDPX1), which results from a deficiency of arylsulfatase E (ARSE). Historically, ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases. Methods:To further evaluate causes of brachytelephalangic chondrodysplasia punctata, we established a Collaboration Education and Test Translation program for CDPX1 from 2008 to 2010. Of the 29 male probands identified, 17 had ARSE mutations that included 10 novel missense alleles and one single-cod...

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“…The placenta maintains a steep gradient of vitamin K during gestation, with fetal levels approximately one-10th that of maternal (51,52). Evidence for vitamin K deficiency at birth has been reported by many authors (52,53).…”

Section: Coagulation Proteins In the Lambmentioning

confidence: 99%

“…Evidence for vitamin K deficiency at birth has been reported by many authors (52,53). It has been speculated that high concentrations of vitamin K promote mutagenesis of DNA in vitro, and low levels of vitamin K are maintained during fetal development to diminish mutagenic risk in rapidly proliferating cells (54).…”

Section: Coagulation Proteins In the Lambmentioning

confidence: 99%

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Manco‐Johnson

2002

Pediatric Research

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To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p Ͻ 0.0001). Plasma levels of FX, PC, and PS achieved neonatal levels by mid-gestation with mild but significant decreases during mid-and late gestation. Fetal and early neonatal plasma concentrations of these vitamin K-dependent proteins fit a model with both quadratic (p Ͻ 0.01) and linear (p Ͻ 0.01) components. The discrepant levels in mRNA relative to plasma concentration were consistent with regulatory control beyond the level of transcription. In contrast, a simple linear increase in plasma protein levels was determined for the vitamin K-independent coagulation regulatory protein, AT (p for quadratic component Ͼ 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein. The hemostatic systems of the fetus and neonate differ from that of the adult. Plasma concentrations of coagulation proteins mature at different rates during in utero and postnatal development (1-3). In particular, vitamin K-dependent factors, prothrombin, PC, PS, and factors VII, IX, and X, as well as contact factors XI, XII, prekallikrein, and high-molecular-weight kininogen, are present in very low concentrations in the fetus and do not achieve normal adult levels until later infancy to adolescence (2-7). Clinically, the well neonate has a functionally intact hemostatic system. However, the stressed infant demonstrates an increased predisposition to thrombosis, both induced and spontaneous (8). The increased rate of thrombosis in neonates is generally attributed to physiologically low levels of coagulation regulatory proteins, particularly PC, PS, and AT.PC is a vitamin K-dependent serine protease that serves a critical role in the regulation of coagulation. Activated PC, with its cofactor PS, inactivates activated procoagulant factors V and VIII (9). Infants with severe genetic deficiencies of either PC or PS manifest spontaneous thrombosis in utero or within hours of birth (10, 11). Our previous work showed that the mean concentration of PC in the extremely preterm infant is 0.20 U/mL, as compared with 1.00 U/mL in healthy adults (6, 7). An increased risk of catheter-related and spontaneous thrombosis was demonstrated in preterm infants with plasma concentrations of PC Ͻ0.10 U/mL (7).AT is an essential regulatory protein that functions through i...

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Placental Transfer of Vitamin K1 and Its Implications in Fetal Hemostasis

Cited by 81 publications

References 20 publications

Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

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