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PubMed2005

Factor XIII deficiency: new nonsense and deletion mutations in the human factor XIIIA gene.

We identified five disease-causing mutations in six factor XIII deficient patients from four unrelated families: two novel nonsense mutations (nucleotide 979C-->T corresponding to Arg326Stop; and nucleotide 2075G-->A corresponding to Trp691 Stop), one novel deletion of a single nucleotide (nucleotide 708G or 709G), one previously reported missense mutation (nucleotide 888C-->G corresponding to Ser295Arg), and a previously reported splice site mutation (nucleotide 319G-->T at the last position of exon 3). The phenotypic consequences of these mutations are discussed.

Adolescent↗
PubMed2006

Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder.

In 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 delG, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.

Adolescent↗
PubMed1992

Congenital factor XIII deficiency.

Clinical and hematological data of 9 cases with factor XIII deficiency is highlighted. The age at first bleed ranged from 3 days of life to 1 year. Seven of these 9 cases had bleeding from the umbilicus, 3 had recurrent subcutaneous and muscle hematomas, while 4 cases had CNS bleeds of which 3 expired. Routine coagulogram was normal, while clot solubility in 5 molar urea solution was abnormal in all cases. Factor XIII assay was not done in any. Patients were treated with plasma transfusion during episodes of bleeding. No patient received plasma transfusion as prophylactic therapy. The cumulative Indian data so far documented, inclusive of this series, shows a very high incidence of CNS bleeds (33%) in patients with this inherited coagulation disorder.

Cerebral Hemorrhage↗
PubMed1988

Clinical experience with a pasteurised human plasma concentrate in factor XIII deficiency.

A three-day-old infant presented with umbilical haemorrhage. Factor XIII deficiency was diagnosed. When one month old she commenced prophylactic injections of pasteurised factor XIII concentrate of human plasma origin. During two and a half years treatment there were no haemorrhagic episodes and factor XIII concentrate was well tolerated. Satisfactory post infusion factor XIII levels were achieved. Three transient elevations of aspartate transaminase occurred, the cause of which has not been established. There was no evidence of transmission of hepatitis or H.I.V. infection. A brother, born one year later, is also affected and commenced prophylactic therapy with the same factor XIII concentrate. Experience in these two infants suggests the product is efficacious.

Aspartate Aminotransferases↗
PubMed2004

Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families.

BACKGROUND: Hereditary factor (F)XIII deficiency is a rare bleeding disorder mostly due to mutations in FXIII A subunit. OBJECTIVES: We studied the molecular basis of FXIII deficiency in patients from 10 unrelated families originating from Israel, India and Tunisia. METHODS: Exons 2-15 of genomic DNA consisting of coding regions and intron/exon boundaries were amplified and sequenced. Structural analysis of the mutations was undertaken by computer modeling. RESULTS: Seven novel mutations were identified in the FXIIIA gene. The propositus from the Ethiopian-Jewish family was found to be a compound heterozygote for two novel mutations: a 10-bp deletion in exon 12 at nucleotides 1652-1661 (followed by 22 altered amino acids and termination codon) and Ala318Val mutation. The propositus of the Tunisian family was homozygous for C insertion after nucleotide 863 within a stretch of six cytosines of exon 7. This insertion results in generation of eight altered amino acids followed by a termination codon downstream. The propositus from Indian-Jewish origin was found to be homozygous for G to T substitution at IVS 11 [+1] resulting in skipping of exons 10 and 11. In addition to the Ala318Val mutation, three of the novel mutations identified are missense mutations: Arg260Leu, Thr398Asn and Gly210Arg each occurring in a homozygous state in an Israeli-Arab and two Indian families, respectively. CONCLUSIONS: Structure-function correlation analysis by computer modeling of the new missense mutations predicted that Gly210Arg will cause protein misfolding, Ala318Val and Thr398Asn will interfere with the catalytic process or protein stability, and Arg260Leu will impair dimerization.

Catalysis↗
PubMed1989

[Anesthesia for a patient with Ehlers-Danlos syndrome and factor XIII deficiency].

Emergency anesthesia was carried out for a patient with Ehlers-Danlos syndrome (type IV) and factor XIII deficiency. The operation was a ligation of the bleeding right subclavian artery. One month later, a transverse colectomy and splenectomy was performed for a necrotic perforation of the colon, but the wound did not heal completely. The patient died of another perforation of the intestine two months later. Anesthetic management of a patient with Ehlers-Danlos syndrome and factor XIII deficiency was reviewed. Particular problems concerning a genetic disease were also discussed.

Adult↗
PubMed2008

Spontaneous splenic rupture in a patient with factor XIII deficiency and a novel mutation.

We report a novel mutation in factor XIIIA gene that caused severe congenital factor XIII deficiency in a 6 year and 8 month old male. The mutation is a GA deletion in the core domain leading to a premature stop at codon 502. The child had severe deficiency with two episodes of intracerebral hemorrhage. He also developed spontaneous splenic rupture, an unusual complication of this disorder.

Child↗
PubMed1977

[Factor XIII deficiency in adults with acute leukemia: results of a substitution therapy with factor XIII (author's transl)].

A decrease in fibrin stabilizing factor (Factor XIII) is the most frequent coagulation disorder seen in adults with acute leukemia. Patients with prominent reduction of factor XIII (FSF) (less than 50%) were substituted with a factor XIII concentrate from human placenta, and factor XIII plasma concentration and bleeding tendency were followed up during the course of the disease. After substitution plasma, factor XIII activity went up to normal levels in most of the patients. As compared to the course of 12 patients with distinct factor XIII reduction without factor XIII therapy, there were less bleeding complications in 13 courses of patients with prominent reduction of factor XIII substituted with factor XIII concentrate and in 11 with normal or only slightly reduced factor XIII levels.

Acute Disease↗
PubMed1999

[An infant with umbilical cord and intracranial hemorrhage--severe factor XIII deficiency].

Based on the description of a severe bleeding disorder in a young child a short overview on the genetics, the epidemiology, the pathophysiology, the clinical manifestations and the laboratory diagnosis of factor XIII deficiency is presented. The impressive clinical signs with bleeding starting in the neonatal period (prolonged bleeding from the umbilical cord), followed by severe, life-threatening episodes of intracranial hemorrhages should raise the clinical suspicion of FXIII deficiency. Difficulty of laboratory diagnosis is stressed. The importance of repeating initially negative screening tests and of performing a quantitative FXIII assay in the presence of strong clinical suspicion is strengthened. The diagnosis of factor XIII deficiency is difficult but has important therapeutic consequences: patients with documented severe deficiency should be put on regular substitution with factor XIII concentrates. Appropriately timed periodic infusions of such factor XIII concentrates enable patients to live normal lives, free from catastrophic bleeding episodes.

Blood Coagulation Tests↗
PubMed1989

The subunit composition of factor XIII proteins in normal and factor XIII deficient plasma and serum analysed by line immunoelectrophoresis.

Line immunoelectrophoresis was used for the characterization of human coagulation factor XIII in normal and factor XIII-deficient plasma and serum. In normal plasma, two immunoreactive factor XIII proteins termed XIII-p (Mr 330,000 Da) and XIII-s (Mr 170,000 Da) were identified within the beta-globulin fraction. Their reactions with monospecific antisera against known factor XIII subunits, suggests that the factor XIII-p and -s proteins recognized represent the factor XIII a2b2 tetramer and -b2 dimer, respectively. The concentration of the XIII-p protein was, in normal plasma, approximately 6 mg/l, in plasma from a case of congenital factor XIII, approximately 1 mg/l and in normal serum approximately 3 mg/l. The concentration of the XIII-s protein (approximately 18 mg/l) was unaffected by the coagulation process and normal in plasma and serum from the case of congenital factor XIII deficiency. Thus, the present investigation indicates the presence of an excess of the anticatalytic, DNA-binding factor XIII carrier protein in normal as well as in factor XIII-deficient plasma and serum.

Factor XIII↗
PubMed1985

A case of congenital factor XIII deficiency.

The case of a 53 years old woman was described in whom a congenital factor XIII deficiency was suspected because of deforming scars and hemorrhagic diathesis. A thromboelastographic declination of elasticity as well as decreased factor XIII level up to 5% of normal range were only found in all hemostatic examinations. In 2 children factor XIII decreased to half of its normal level, whereas in the youngest daughter that level was 25%. Sporadically the girl had mild diathesis. No changes in thromboelastograms were observed in members of the patient's family. The platelet function was unchanged in all examined cases.

Factor XIII Deficiency↗
PubMed1996

ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group.

A questionnaire was sent out in 1993 to more than 350 European institutions caring for patients with hemorrhagic disorders with the request to provide data of patients with congenital factor XIII deficiency, to pursue the following aims: (1) establish a registry of congenital factor XIII deficiency patients, (2) promote exchange between clinicians and basic researchers, (3) improve diagnostic and therapeutic approaches, and (4) stimulate research on gene defects and their impact on factor XIII function. So far, 72 patient questionnaires from 60 families have been collected. Their bleeding pattern is typical, with frequent involvement of the umbilical cord and the central nervous system. Forty-nine patients receive regular factor XIII replacement, but obviously some patients with mild symptoms do not require prophylactic substitution, despite low factor XIII levels. On the other hand, 18 patients had factor XIII activities of > or = 5% of normal, but only 3 of those patients were reported to have no bleeding symptoms. Furthermore, 17 symptomatic, apparently heterozygous relatives in eight families were observed. Seven out of 30 females aged over 18 years had experienced spontaneous abortions; wound healing problems were seen in 26 patients. Currently, a second questionnaire is being distributed to obtain more detailed information on bleeding and other symptoms, diagnostic approaches, and exclusion of concurrent other bleeding diatheses. Future activities will be validation and standardization of assays, and study of gene defects and their impact on the structure of factor XIII and symptoms of patients. We intend to expand the survey to countries outside Europe.

Abortion, Habitual↗
PubMed1978

Subunits A and S inheritance in four families with congenital factor XIII deficiency.

Previous studies of the inheritance of the two molecular subunits of fibrin stablizing factor (factor XIII) refer to isolated cases. The present work investigates the hereditary mode of transmission of subunits A and S, measured by the Laurell technique, in seven homozygotes and in 29 heterozygotes belonging to four families with factor XIII deficiency. The results indicate that the homozygotes were devoid of immunologically identifiable A subunit, whereas the heterozygotes could be identified by measuring this protein. The subunit S has been found to be decreased both in homozygous and in heterozygous patients, so that it seems that the two subunits, even if their synthesis is controlled by different genes, are genetically related. The mode of transmission of this disorder, supported by quantitative determinations of plasma subunit A, is autosomal recessive.

Factor XIII↗
PubMed2002

Factor XIII deficiency mistaken for battered child syndrome: case of "correct" test ordering negated by a commonly accepted qualitative test with limited negative predictive value.

We report herein a case of Factor XIII deficiency that remained undiagnosed until 2 years of age. Part of the delay in diagnosis was a consequence of testing that was performed on a blood sample obtained after plasma transfusion therapy for a life-threatening bleeding episode. Due to insufficient family follow-up after discharge from the hospital, the diagnosis was delayed 1 year until the child was rehospitalized and a pre-transfusion plasma sample was tested. The commonly accepted approach of using only a qualitative test for the diagnosis of factor XIII deficiency is challenged by this case report.

Battered Child Syndrome↗