1/68. Bleeding disorder with abnormal wound healing, acid-soluble clots and normal factor XIII. An unusual bleeding disorder clinically resembling factor xiii deficiency is presented. The only detectable coagulation abnormality was rapid clot dissolution in 1% monochloroacetic acid. This abnormality was ascribed to the sustained increase of a pepsin-like plasma protease which is activated at low pH. Asystematic search for similar phenomena revealed that massive blood transfusion may also enhance plasma-clot solubility in acid, possibly by release of a red cell protease. We conclude that the acid clot solubility test is not a specific indicator of factor xiii deficiency, but this simple assay is recommended for further studies of acid plasma protease activity. The diagnostic relevance and pathophysiologic importance of increased pepsin-like activity in plasma remain to be elucidated. ( info) |
| factor xiii deficiency is an uncommon, inherited bleeding disorder that usually manifests in infancy or early childhood, involving both boys and girls. We present the case of a woman who had experienced two previous intracranial bleeding events, and was treated before and during her current pregnancy with factor XIII concentrate. Her pregnancy was successful, and she experienced an uncomplicated vaginal delivery. To better understand the issues surrounding bleeding, reproductive capacity, and management of factor xiii deficiency during pregnancy, we conducted a systematic literature review using medline from 1966 to December 1998. We also examined the bibliographic references from all articles, and included all cases, case reports, or case series of patients with factor xiii deficiency. We retrieved data on 117 patients from 37 articles, the majority of which had type II deficiency. Among untreated patients with type II factor xiii deficiency, the literature suggests an elevated mortality rate due to uncontrolled bleeding and intracranial hemorrhage. Because of its high degree of efficacy, the evidence supports the use of life long prophylactic therapy with at least monthly infusions of factor XIII concentrate, including during pregnancy. The opinion that women with type II factor xiii deficiency have inevitable recurrent abortions, or that men are sterile, is not well substantiated. No data were found on whether treatment alters male reproductive capacity. A policy of universal factor XIII replacement, starting in childhood, will likely enable more patients to attain reproductive status. The development of an international data registry would optimally address both bleeding risk and reproductive capacity among patients with factor xiii deficiency. ( info) |
3/68. Maternal blood coagulation factor XIII is associated with the development of cytotrophoblastic shell. We analysed the early implantation tissues of normal women and of a patient with congenital factor xiii deficiency in order to study the role of maternal subunit A of factor XIII (XIIIA) in the development of extravillous cytotrophoblast. The patient had received adequate administration of factor xiiia concentrate only up to 7 weeks of gestation (wG). Her pregnancy was maintained until the latter half of 8 wG, but was terminated by intrauterine fetal death at 9 wG. Immunohistochemical staining of cytokeratin, XIIIA and subunit S of factor XIII was performed in the early implantation tissues of normal women and of this patient. Numerous well-formed cytotrophoblastic shells and Nitabuch's layers were detected in implantation tissues at 7-8 wG in normal women, and XIIIA was present in the intercellular space in well-formed cytotrophoblastic shells, while the cytotrophoblastic shells and Nitabuch's layers in this patient's implantation tissue were poorly-formed. Furthermore, XIIIA was not detected around them. It is suggested that when the maternal plasma activity of factor XIII is low, the concentration of XIIIA at the placental bed is also low, leading to the insufficient formation of cytotrophoblastic shell and therefore an increased probability of miscarriage in patients with congenital factor xiii deficiency. ( info) |
| Inherited factor XIII (FXIII) deficiency is an autosomal recessive disorder which results in a serious bleeding diathesis, problems with wound healing and a very high risk of recurrent miscarriage in deficient females. We have analysed the molecular basis of factor xiii deficiency in two patients and their parents, who originate from the North of pakistan. Four sequence changes were identified: an AGC-->AGG (Ser-->Arg) FXIII deficiency-causing mutation in codon 295; G-->A at position -246 upstream of exon 1; T-->C and C-->T at positions -23 and -24, respectively, in intron 9. Using molecular modelling we predict that the Ser295Arg mutation would prevent the FXIIIA molecule from folding correctly and thus result in an unstable FXIIIA mutant polypeptide. The sequence changes -246G-->A, -23T-->C and -24C-->T are normal polymorphisms. RT-PCR analysis demonstrates that the intronic sequence changes do not appear to affect the accuracy of FXIIIA rna processing. ( info) |
5/68. Identification of a new mutation (Gly420Ser), distal to the active site, that leads to factor xiii deficiency. The molecular defects of the factor XIII A subunit gene were studied in a patient with factor xiii deficiency. mutation analysis was performed on amplified dna from each exon of this gene by single-strand conformation polymorphism (SSCP) and dna sequencing techniques. A substitution of guanine by adenine at nucleotide 1258 in exon 10 of the coagulation factor XIII A subunit gene has been identified in the patient. The mutation results in the replacement of Gly420 by Ser in the core domain of the enzyme. Restriction enzyme analysis of amplified exon 10 dna confirmed that the patient was homozygous for this mutation. A family study revealed that the mutation was inherited from both parents, who were first cousins. The potential effects of the mutation were predicted by molecular modeling of the amino acid substitution within the coordinates of the crystal structure. The substitution occurred within the core domain of the enzyme at a residue completely conserved among all known members of the transglutaminase family. The model of the mutant protein suggests that although the substitution of Gly420 by Ser causes only minor readjustment of the residues and does not appear to be particularly deleterious in terms of structure, the mutation is, however, likely to decrease the molecule's ability to undergo the conformational change that is thought to be required for full transglutaminase activity. Our data strongly support the previously published information about the functional significance of the residues surrounding, but not forming, the catalytic pocket in the A subunit of factor XIII. ( info) |
6/68. Two novel and one recurrent missense mutation in the factor XIII A gene in two Dutch patients with factor xiii deficiency. Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive disorder, usually attributed to a defect in the FXIII A subunit, whose genetic basis has been studied in a number of cases. We describe here the genetic variations found in two unrelated patients with FXIII deficiency. Both patients, under prophylactic substitution with FXIII concentrate, showed low plasma FXIII A subunit antigen levels with undetectable A subunit antigen in the platelets and normal plasma B antigen levels, which indicate that the defects are present in the A subunit of the molecule. Both probands were heterozygous for a previously reported G-->A transversion in exon 8 of the FXIII A subunit gene (Arg326Gln substitution). Proband 1 was also heterozygous for a novel G-->T transversion in exon 7, which predicts a Val316Phe substitution. Two of her sons were heterozygous for this mutation and showed low FXIII activity and FXIII A subunit antigen levels. Val316 is a well-conserved amino acid among the transglutaminase family, located within the core domain, close to the Cys314 member of the catalytic triad. Proband 2 had a unique 2-bp (TT) insertion in one of the alleles within or adjacent to the -7 to -20 T tail of intron A. This insertion was not found in 50 healthy individuals, which supports this being the second mutation in this patient. ( info) |
| We report a new homozygous CTG-->CCG (Leu-->Pro) mutation at codon 354 in the factor xiiia gene of a patient suffering from FXIII deficiency. Leu354 lies in a pocket within the core domain of the FXIIIA molecule, with its side chain pointing into the structure of the barrel 1 domain. Replacement of leucine with a proline residue gives rise to steric hindrance between the proline ring and the surrounding residues, and rearrangement of these residues would be necessary for proline to be accommodated at this position. Using PCR-RFLP, we have demonstrated the absence of this mutation from 220 normal alleles. Together, these data suggest that Leu354Pro is likely to be the disease-causing mutation in this factor XIII deficient family. ( info) |
8/68. Novel Y283C mutation of the A subunit for coagulation factor XIII: molecular modelling predicts its impaired protein folding and dimer formation. In an Italian patient with severe factor xiii deficiency, a novel mutation, Y283C (TAT to TGT), was identified heterozygously by nucleotide sequencing analysis in exon VII of the gene for the A subunit. The presence of this mutation was confirmed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the proband and his brother. Molecular modelling predicts that the mutant molecule would be misfolded. It is probable that the impaired folding of the mutant Y283C A subunit led to its instability, which is at least in part responsible for the factor xiii deficiency of this patient. ( info) |
9/68. factor xiii deficiency. A family study by measurement of factor XIII subunits A and S. A girl with congenital factor xiii deficiency and her large family have been studied by electroimmunoassay of factor XIII subunits A and S. The homozygote has absence of subunit A and a decreased level of subunit S. The heterozygotes have decreased levels of both subunits, and were more readily identified by measurement of subunit A than by the ratio subunit S/subunit A. The mother of the propositus appears to be a new heterozygote, but heterozygosity on the paternal side is traced through three generations. ( info) |
10/68. Mutations in coagulation factor XIII A gene in three Turkish patients: two novel mutations and a known insertion. Molecular analysis of factor XIII A gene on three unrelated Turkish families identified two novel and one known mutations. One novel mutation is a substitution of cytidine by guanine at codon 541 in exon 12, beta barrel 1 domain of the coagulation factor XIII A subunit gene resulting in the conversion of asparagine to lysine. The mutation alters the restriction site of the enzyme MboII. The second novel mutation, a 4 bp (-CAAA) deletion located in a direct repetitive sequence (CAAACAAA) between codons 466-469, results in premature termination of translation at codon 474. The third mutation is a previously reported single nucleotide (cytidine) insertion at codon 400 in exon 9 of the factor XIII gene. ( info) |