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Objective: This is a retrospective analysis of the clinical and laboratory features of 17 cases of factor XIII deficiency that were followed in tertiary care hospitals in Riyadh, Kingdom of Saudi Arabia, over 20 years. Cases were referred to these hospitals from other health care centers in the country., Methods: We performed a retrospective analysis of 17 cases of factor XIII deficiency comprising 11 males and 6 females, who were seen over a period of 20 years (1978-1998) in Riyadh, Kingdom of Saudi Arabia. Data variables including age, sex, origin, clinical presentation, bleeding time, prothrombin time, partial thromboplastin time, factor XIII screening and assay, hemoglobin, and platelet count were collected and analyzed. The diagnosis of factor XIII deficiency was made by urea clot lysis test alone in one patient and urea clot lysis test in combination with factor XIII quantitative assay in 16 patients., Results: Eleven patients were males and 6 were females. Median age at the time of diagnosis was 9 years (3-29 years). Ten patients (59%) had a family history of excessive bleeding. Presenting symptoms included ecchymosis and recurrent hematomas in 12 patients (71%), bleeding after circumcision in 6 male patients (55%), umbilical stump bleeding in 7 (41%), poor wound healing and keloids in 3 patients (18%), and intracranial bleeding in 3 patients (18%). Other manifestations included cephalohematoma, abortion, abruptio placenta, and intraperitoneal bleeding (one patient each). Laboratory evaluation revealed a normal prothrombin time, partial thromboplastin time, bleeding time and platelet count in all patients. Factor XIII screening test was positive in all 17 patients tested and assay for factors XIII was <0.06 U/ml in 16 patients tested., Conclusion: Our data confirms that factor XIII deficiency is a rare bleeding disorder characterized by variable bleeding manifestations but consistent laboratory findings. The occurrence of keloid in our patient group may reflect the poor quality of the clotting, associated with loss of tensile strength of fibrin polymers, caused by factor XIII deficiency and leading to abnormally large scar formation.

Objectives: The objectives of this study were 1) to assess the importance of an early diagnosis for factor XIII (FXIII) deficiency, and 2) to investigate the molecular basis and mechanism(s) of disease in the patients under study., Methods: The case histories of 6 FXIII-deficient patients were examined to assess the influence of early versus delayed diagnosis and replacement therapy. The nucleotide sequence of the FXIIIA gene was determined to identify the underlying mutations responsible for the bleeding diathesis in each patient. Molecular modeling was used to predict the mechanism(s) of disease causation for each mutation., Results: All cases presented with umbilical hemorrhage. Patients 1 to 3 were diagnosed, and their prophylactic therapy was commenced in infancy. Diagnosis in patients 4 to 6 was considerably delayed and, as a result, they continued to suffer from many bleeding symptoms. The FXIIIA gene mutations identified in these patients were as follows: a homozygous GAA-->AAA mutation in codon 102 (Glu102Lys) in patient 1 and a homozygous AGC-->AGG mutation in codon 295 (Ser295Arg) in patients 2 to 6. These mutations segregate with disease and are absent from the normal population, suggesting that they are likely to be disease-causing sequence changes. Computer modeling indicates that both the Lys102 and Arg295 mutants are unable to fold correctly, and probably result in unstable FXIIIA molecules., Conclusions: We demonstrate the importance of recognizing delayed umbilical hemorrhage as a presenting feature for congenital FXIII deficiency, and the value of early diagnosis and prophylaxis. The bleeding disorder of patient 1 was attributable to a homozygous Glu102Lys mutation in FXIIIA. A homozygous Ser295Arg mutation in FXIIIA was responsible for FXIII deficiency in patients 2 to 6.

Blood coagulation factor XIII (FXIII) plays an important role in the final stage of the blood coagulation process. Thrombelastography (TEG) enables global assessment of the hemostatic function. The present study tested for the first time the specificity and sensitivity of the rotation thrombelastography (ROTEG: rotation thrombelastography) method for the influence of FXIII and the FXIIIVal34Leu polymorphism on thrombelastograms measured in citrated plasma. Three thrombelastographic parameters were determined in (a) citrated pool plasma, (b) FXIII-deficient plasma, (c) different mixtures of both, and (d) in 60 plasma samples genotyped for FXIIIVal34Leu. Thrombelastograms from FXIII-deficient plasma were significantly smaller than those from pool plasma (8 mm vs. 20.9 mm). Increasing amounts of pool plasma added to FXIII-deficient plasma led to an increase in maximum clot firmness (MCF). FXIIIVal34Leu showed an influence on clot formation time (CFT) values, which decreased with increasing number of Leu alleles. The difference between the wild type and the homozygote mutant genotype was statistically significant (median 185.3 vs. 86.0 s, P=.031). ROTEG is a simple but effective method for the investigation of FXIII function in plasma. The ROTEG method has shown to be not only specific for the FXIII influence, as effects exclusively dependent on FXIII could be observed, but also sensitive, as already smallest amounts of FXIII could be detected. Additionally, the impact of a common genetic polymorphism on ROTEG could be shown for the first time.

Congenital factor XIII deficiency is a rare hereditary disorder characterized by a marked tendency to bleeding. We describe a male newborn with inherited factor XIII deficiency. The patient was from a family without known antecedents and presented cephalohematoma as the first manifestation of the disease. This presentation is very unusual. The patient was diagnosed during the neonatal period and was successfully treated with substitution therapy. Early diagnosis and treatment of this disorder are important to prevent complications of severe bleeding.

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.

Background/aims: Coagulation factor XIII, which induces the stabilization of fibrin the final step in the coagulation cascade, has various physiological effects. Among these, its beneficial effect in gastrointestinal bleeding episodes is well known. With the exception of inflammatory bowel disease, however, few data are available about this effect, particularly with regard to its role in diffuse bleeding in tumor patients. The study was designed to carry out prospective follow-up investigations, gathering data concerning factor XIII levels in patients with advanced gastrointestinal tumors and evaluating the course of the disease as well as the incidence of bleeding., Methodology: Sixty patients (22 women, 38 men; median age: 60; range: 29-79) with advanced gastrointestinal tumors were followed-up prospectively. Factor XIII levels were measured using chromogenic substrate. The correlation between the FXIII level and the patients' survival was analyzed using the Cox model., Results: Factor XIII deficiency (below 70%) was seen in only 7 patients (11.6%), 6 of whom died within a median of 1.5 months after the measurement. In all patients however, there was a significant correlation (P = 0.0133) between FXIII levels and the risk of death. Four bleeding episodes occurred in 3 patients, three times with FXIII levels being below the lower normal range. When substitution was attempted, it was only successful in 1 patient in whom the FXIII level was reduced., Conclusions: FXIII may have predictive value as a marker for the prognosis in these patients with advanced tumor disease. Bleeding episodes were rarely seen, but when they do occur they may be associated with reduced levels of FXIII, and substitution may be beneficial as an adjunct or even as the sole therapeutic intervention.

Congenital factor XIII deficiency is a rare hemorrhagic syndrome with an altered fibrin stability, hemorrhagic diathesis and habitual abortions. After a short introduction, a case report is described and the clinical differences between plasmatic and platelet deficiency pointed out.

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.

Congenital factor XIII deficiency is a severe bleeding disorder that is inherited as an autosomal recessive trait. The condition is commonly due to absence of the factor XIII-A subunit protein in the plasma. The case of a baby is reported who showed typical clinical features of factor XIII-A deficiency, including recurrent bleeding from the umbilical stump and a life threatening haemorrhage after circumcision. Family studies were performed and molecular analysis, using a Short Tandem Repeat (STR) marker closely linked to the A subunit gene, allowed antenatal exclusion diagnosis to be undertaken in a subsequent pregnancy. The case highlights the importance of seeking a family history of bleeding disorders before surgery in the neonatal period, particularly if the parents are consanguineous.

A 5-year-old boy had an intracerebral hematoma evacuated from the left parieto-occipital region at a local hospital. There was a difficulty in hemostasis during the operation. Postoperatively his neurological state gradually deteriorated. CT scans showed a gradual increase in intracerebral hemorrhage at the operated site. He was transferred to our clinic for further treatment. The preoperative blood coagulation profile showed that the activity of factor XIII was only 4%. The hematoma was removed without any trouble under administration of factor XIII. Postoperative course was also uneventful although the plasma level of factor XIII did not go up higher than 26% in spite of its daily administration. Although factor XIII administration was terminated one month after cranioplasty, the patient showed good recovery and the level of factor XIII spontaneously normalized in 6 months. The cause of the extremely low level of factor XIII in this case is not known, but it could be ascribed to massive hemorrhage.

We report a case of a 4-week-old female who presented with late hemorrhagic disease of the newborn (HDN). The newborn was previously healthy, and she received 1 mg of intramuscular vitamin K at birth. She was exclusively breast-fed. At 4 weeks she began bleeding at the umbilicus and 4 days after she suffered an intracranial hemorrhage. Coagulation studies showed a deficiency of vitamin K-dependent coagulation factors, and the normalization of all clotting studies after administration of vitamin K confirmed the diagnosis of HDN. Our conclusions are that physicians must be alert to mild bleeding in newborns and that prophylaxis with 1 mg of intramuscular vitamin K at birth may be insufficient to prevent late HDN.

Deficiency of the A subunit of coagulation factor XIII causes a severe bleeding disorder requiring life long replacement therapy. The mutations causing A subunit deficiency appear to be very heterogeneous, and it is impractical to identify each mutation before genetic counselling or prenatal diagnosis can be attempted. In this study we have shown that a highly polymorphic short tandem repeat element, HUMF13A01 (AAAG)n that occurs in the 5' flanking sequence of the factor XIII A subunit gene, can be used to follow the segregation of deficiency causing mutations. We studied 6 families with factor XIII A subunit deficiency from 5 different ethnic groups. All parents were heterozygous for the repetitive element and therefore all the families were informative. The linked polymorphism was used to carry out the first prenatal diagnosis of factor XIII A subunit deficiency. The analysis of this polymorphism by the polymerase chain reaction is rapid, reliable, requires little DNA and is ideal for the genetic analysis of factor XIII A subunit deficiency.

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.

Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the 'a' subunit, which is the active enzyme, and the 'b' subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an epsilon (gamma-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (alpha-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts. Inheritance of factor XIII is autosomal recessive. The majority of patients with the inherited defect show no XIII activity and absence of 'a' subunit protein in plasma, platelets and monocytes. At the molecular level, the defect is not a major gene rearrangement or deletion, but most likely a single point mutation which may be different in each family. Because of the severity of the bleeding diathesis, prophylaxis is desirable and has been shown to be very effective as the in vivo half-life of plasma XIII is long, and low plasma levels are sufficient for haemostasis. Acquired inhibitors have been reported in only two cases with inherited XIII deficiency. Acquired XIII deficiency has been described in a variety of diseases and bleeding has been controlled by therapy with large doses of XIII in such conditions as Henoch-Schönlein purpura, various forms of colitis, erosive gastritis and some forms of leukaemia. Large dose XIII therapy has also been used in an endeavour to promote wound healing after surgery and bone union in non-healing fractures. The use of XIII in these conditions remains controversial. Very rarely a bleeding diathesis results from the development of a specific inhibitor to XIII arising de novo, often as a complication in the course of a disease or in association with long-term drug therapy. The bleeding diathesis in these patients is difficult to treat.

The authors report a new case of congenital deficiency of fibrin stabilizing factor. The defect is transmitted as an autosomal recessive trait. The earliest symptom is umbilical bleeding when the cord separates. The diagnosis is confirmed by the rapid dispersion of the clot in urea 5 M or monochloroacetic acid.

Two patients with factor XIII deficiency, presenting with bleeding disorder since birth, are reported. The condition is rare and is likely to be missed unless clot solubility in 5 M urea is performed as a screening test in all patients with bleeding disorders. A correct diagnosis is essential as prophylactic management is practicable in this disorder.

A boy with umbilical bleeding and severe hemorrhages after minor trauma, without family bleeding history, was studied. Coagulation tests showed abnormalities in FXIII subunits and FVIII/vWF complex. Both parents presented results compatible with a heterozygote state for FXIII deficiency and the father had abnormalities of FVIII/vWF. The propositus was diagnosed as congenital FXIII deficiency associated with vWD. No severe hemorrhagic complication was observed after a prophylactic regimen with cryoprecipitates.

A case report of a 6-year-old boy is presented. The patient suffered from a severe Schönlein-Henoch purpura. It was demonstrated that ureteral stenosis develops during the clinical course of this disease. This complication has to be considered in anaphylactoid purpura, since it is usually self-limiting and does not require surgical intervention. This confirms once again the necessity to look for a decrease of factor XIII activity in these patients and of the value of substituting this compound if there are severe abdominal complaints. The theoretical background of this therapeutical intervention is discussed.

We report an infant with Factor XIII deficiency who had 2 seemingly spontaneous intracranial hemorrhages. It is important to consider Factor XIII deficiency as a possible cause of unexplained intracranial hemorrhages in infancy. Ongoing factor replacement therapy is recommended to prevent further bleeding episodes.

A 33 years old female with ulcerative colitis was admitted with an acute exacerbation of the disease characterised by haematochezia, diarrhoea (10 stools/die) and anaemia (haemoglobin 6.5 g/dl). Therapy with 5-ASA and corticosteroids for six weeks failed to decrease the activity of the disease. Since deficiency of coagulation factor XIII (activity 60%, subunit A 56%) was present, in addition, concentrates of factor XIII (Fibrogammin HS, Behring, F.R.G.) 1250 U/die were given for ten days. The substitution resulted in an immediate increase of reduced F XIII activity (164%) and F XIII subunit A (333%) as well as in a marked improvement of symptoms.

We described a five-year-old boy with congenital deficiency of factor XIII. He had bled from the umbilical and circumcision sites during the first week of life. He had frequent ecchymoses and hematomas within 12-24 hours after trauma. His parents are first cousins. The screening hemostatic tests of this patient and his parents were within normal limits. Factor XIII, known as "fibrin-stabilizing factor", is a transpeptidase that produces strong covalent bonds between soluble fibrin monomers formed during coagulation. Presumptive diagnosis of factor XIII deficiency was made with a clot solubility screening test and confirmation was accomplished by demonstrating the absence of factor XIII by latex agglutination.

An assay for rapid factor XIII activity measurement has been developed based on the determination of the ammonium released during fibrin stabilization. Factor XIII was activated by thrombin and calcium. Ammonium was measured by an ammonium-sensitive electrode. It was demonstrated that the assay procedure yields accurate and precise results and that factor XIII-catalyzed fibrin stabilization can be measured kinetically. The amount of ammonium released during the first 90 min of fibrin stabilization was found to be 7.8 +/- 0.5 moles per mole fibrinogen, which is in agreement with the findings of other authors. In 15 normal subjects and in 15 patients suffering from diseases with suspected factor XIII deficiency there was a satisfactory correlation between the results obtained by the "ammonium-release-method', Bohn's method, and the immunological assay (r1 = 0.65; r2 = 0.70; p less than 0.01). In 3 of 5 patients with paraproteinemias the values of factor XIII activity determined by the ammonium-release-method were markedly lower than those estimated by the other methods. It could be shown that inhibitor mechanisms were responsible for these discrepancies.

A case with chronic continuous bleeding on an eleven year old girl with lack of F. XIII with positive family antecedents and without declarate consanguinity is presented. Analytic data are widely clear as well as parent's research which shows the heterocygosity but with doubts exposed.

Factor XIII was determined by enzymatic and immunochemical methods in 3 patients with congenital factor XIII deficiency. Factor XIII activity measured by trans-glutaminase assay was below 1% of normal value in each of these cases. Immunelectrophoresis determination revealed the absence of the functionally active subunit A, whereas subunit S was only slightly diminished (30 to 50% of the normal value). Substitution with factor XIII concentrate caused a parallel increase of factor XIII activity and subunit A concentration. No uptake of factor XIII activity or of subunit. A by platelets could be demonstrated. Despite discontinuous substitution over a period of six years no antibody against factor XIII activity could be demonstrated in one patient with congenital factor XIII deficiency.

Fibrin clots formed from normal plasma dissolve readily in 1% monochloroacetic acid at 37 C. However, if the clots are washed thoroughly before the acid is added, they are no longer soluble. The agent present in the serum which causes dissolution of the fibrin clot was isolated and identified as pepsinogen. Because of the low pH of monochloroacetic acid the pepsinogen is activated and the clots are digested, simulating the dispersion of a fibrin clot which occurs in the absence of fibrin-stabilizing factor (factor XIII). Because of its higher pH, urea will not activate pepsinogen and is therefore a better agent to screen factor XIII deficiencies.

Antigenic material related to the fibrin stabilizing factor (Factor XIII-FSF) has been found in all the examined patients with congenital deficiency, albeit in reduced amount. Recently, Bohn et al. (1973) showed that plasma Factor-XIII is composed by two subunits, A (or a) and S (or b); the former active protein, the latter probably FSF-vinding protein. Using specific anti-S and anti-A antisera the Authors found, in a case of congenital deficiency of factor XIII, absence of subunit A. Subunit S presented abnormal behaviour as demonstrated by means of quantitative immunoelectrophoresis according to Laurell.

1. Activated factor XIII is the enzyme that covalently cross-links fibrin monomers into fibrin polymers and results in increased clot strength and resistance of the clot to fibrinolysis. 2. Small amounts (greater than 1% of normal) of factor XIII are necessary for normal in vitro and in vivo activity. 3. Factor XIII deficiency is a rare autosomal recessive illness in which a hemorrhagic diathesis is caused by the virtual absence of the active a subunit of factor XIII. Approximately 100 cases have been described. 4. The disease in homozygotes is characterized by umbilical stump bleeding, a high incidence of fetal wastage, delayed soft tissue hemorrhage, and a high incidence of intracranial bleeding. The heterozygote is asymptomatic. 5. This paper calls attention to the apparent high incidence of oligospermia and small testes seen in homozygote males. Otherwise secondary sex characterics are normal. 6. Because there is no abnormality in thrombin generation and conversion of fibrinogen to fibrin, route coagulation tests (prothrombin time, partial thromboplastin time, thrombin time, etc.) are normal. Platelet function tests are normal. 7. Clots made from recalcified plasma severely deficient in factor XIII are soluble in 5 M urea or 1% monochloroacetic acid. These screening tests are simple and nearly pathognomonic of the illness. 8. More sophisticated and quantitative tests (e.g., dansylcadaverine incorporation) are available for definitive diagnosis and heterozygote detection. 9. Replacement treatment of the illness is simple, effective, and relatively inexpensive. Due to the long half-life of infused factor XIII and the small amounts necessary for normal hemostasis, prophylaxis is feasible and encouraged.

Report on a 30-year old primigravida with a family history of bleeding and a personal history of nasopharyngeal bleeding since age four. Severe menorrhagia since her menarche. First seen at 20 weeks gestation with naso-pharyngeal bleeding and a twin pregnancy. The patient was found to have Glanzmann's disease (congenital thrombasthenia) with an excessive lack of factor XIII. Ambulatory treatment with packed cell transfusions until 35 weeks gestation. The thrombelastogram did not improve with transfusions of platelet concentrates. In-patient treatment from 35 to 37 weeks gestation, no vaginal bleeding throughout the pregnancy. Elective Caesarean hysterectomy at 37 weeks gestation with lo units fresh blood, 3 units platelet concentrate and 10 ampules factor XIII concentrate in readiness. Delivery of twin girls 3180 and 3050 g without signs of Glanzmann's disease. Treatment of the maternal bleeding by replacement. Factor XIII 80% of normal 8 weeks postpartum. This appears to be the first case of twin pregnancy in the presence of Glanzmann's disease and the fourth case in the world literature.