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For infants that present with intracranial hemorrhage in the setting of suspected abusive head trauma (AHT), the standard recommendation is to perform an evaluation for a bleeding disorder. Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder associated with intracranial hemorrhages in infancy, though testing for FXIII is not commonly included in the initial hemostatic evaluation. The current pediatric literature recognizes that trauma, especially traumatic brain injury, may induce coagulopathy in children, though FXIII is often overlooked as having a role in pediatric trauma-induced coagulopathy. We report an infant that presented with suspected AHT in whom laboratory workup revealed a decreased FXIII level, which was later determined to be caused by consumption in the setting of trauma induced coagulopathy, rather than a congenital disorder. Within the Child Abuse Pediatrics Research Network (CAPNET) database, 85 out of 569 (15 %) children had FXIII testing, 3 of those tested (3.5 %) had absent FXIII activity on qualitative testing, and 2 (2.4 %) children had activity levels below 30 % on quantitative testing. In this article we review the literature on the pathophysiology and treatment of low FXIII in the setting of trauma. This case and literature review demonstrate that FXIII consumption should be considered in the setting of pediatric AHT., Competing Interests: Declaration of competing interest AAL has no conflicts of interest. CTC declares conflicts of interest of participation on an advisory board for Bayer Pharmaceuticals and as a consultant for Oliver Wyman. AS has no conflicts of interest. FWL has no conflicts of interest. ANB has no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen ® ) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen., Materials and Methods: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020., Results: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported., Discussion: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

Congenital factor XIII (FXIII) deficiency is one of the rarest bleeding disorders, with an incidence of one per 2 million persons. Intracranial hemorrhage (ICH), a major cause of mortality in FXIII deficiency, is reported to be associated with vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1). Therefore, we investigated the association of VEGF and TSP-1 expression and methylation patterns with ICH in congenital FXIII deficiency patients. This study was conducted on 40 participants with FXIII, 20 of whom experienced ICH (cases), and 20 who did not (controls). Methylation pattern, gene expression, and plasma protein level were assessed using bisulfite sequencing PCR, quantitative real-time PCR, and ELISA. We found a partially methylated pattern for both VEGF and TSP-1 (P > 0.05). VEGF mRNA levels of the case group were significantly higher than those of the control group (P < 0.05), whereas TSP-1 mRNA levels did not show significant upregulation (P > 0.05). Plasma VEGF and TSP-1 concentrations in the case group were higher, but not statistically significant (P > 0.05). Our findings showed no obvious correlation between VEGF or TSP-1 methylation patterns and expression, suggesting that their expression in FXIII deficiency may not solely be controlled by gene methylation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The genetic defects of a 12-year-old patient with factor XIII deficiency (FXIIID) and eight pedigree members suspected with FXIIID were studied. Clinical diagnosis, pedigree investigation, phenotypic study and genetic analysis were performed. DNA sequence analysis revealed that the proband had a novel deletion mutation of F13A1 gene (NM&#95;000129: exon 12: c.1652delC: p.Thr551LysfsTer26) which he inherited from both the parents who were heterozygous for the same 1652delC deletion. This frameshift (p.Thr551LysfsTer26) led in homozygous form to severe FXIIID. Additionally, a homozygous missense mutation of NBEAL2 gene (NM&#95;015175: exon 13: c.1367C > T: p.Ala456Val) was identified in the proband. Again, the mutation was inherited from both the parents who were heterozygous for the same c.1367C > T novel mutation. Other members of the pedigree were also revealed to be heterozygous for the same proband's F13A1 and NBEAL2 genes mutations. We first report a pedigree with pathogenic F13A1 gene mutation and a novel mutant NBEAL2 gene., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recombinant factor XIII-A 2 (rFXIII-A 2 ) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A 2 prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A 2 (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A 2 dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A 2 efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A 2 ; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A 2 was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A 2 prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A 2 dose, and four were performed 10 to 21 days after the last dose., Competing Interests: M. Carcao has received research funding from Baxalta (now a part of Shire), Bayer HealthCare, Biogen, Novo Nordisk and Pfizer; additionally, he has received honoraria for advisory board participation and for speaking from Baxalta (now a part of Shire), Bayer HealthCare, Biogen, Biotest, CSL Behring, Novo Nordisk, Octapharma and Pfizer. C. Altisent has received honoraria or consultation fees from Baxalta (now a part of Shire), Bayer HealthCare, CSL Behring, Grifols, NovoNordisk, Octapharma, Pfizer and Sobi. G. Castaman has received honoraria for advisory board participation and for speaking from Baxalta (now a part of Shire), Bayer HealthCare, Biogen, CSL Behring, Novo Nordisk, Pfizer and Sobi, and has received research support from CSL Behring and Pfizer. K. Fukutake has received research grants from Baxalta (now a part of Shire), Bayer HealthCare, Biogen, CSL Behring, Japan Blood Products Organization, Kaketsuken, Novo Nordisk, Ortho Clinical Diagnostics and Pfizer, as well as honoraria and personal fees for participating in educational events, advisory board and publications from Abbott, Baxalta (now a part of Shire), Bayer HealthCare, Biogen, CSL Behring, Fujirebio Inc., Kaketsuken, LSI Medience, Novo Nordisk, Pfizer, Roche Diagnostics, Sekisui Medical, Siemens, SRL Inc. and Torii Pharmaceuticals outside the submitted work. B. Kerlin has served as an advisory board member for Bayer Healthcare US and Baxalta (now part of Shire), and has received research support from Novo Nordisk A/S and the CSL Behring foundation. C. Kessler has received grants from Baxalta (now a part of Shire), Bayer HealthCare, Biogen, Novo Nordisk, Octapharma, Pfizer and Roche. In addition, he has received honoraria and personal fees for participating in educational events and advisory boards from Baxalta (now a part of Shire), Bayer Healthcare, Biogen, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer and Roche. R. Lassila has received honoraria for advisory board participation from Baxalta (now a part of Shire), CSL Behring, Novo Nordisk, Octapharma and Pfizer. D. Nugent has no conflicts of interest to declare. J. Oldenburg has received reimbursement for attending symposia/congresses, and/or honoraria for speaking, and/or honoraria for consulting, and/or funds for research from Baxalta (now a part of Shire), Bayer HealthCare, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche and Swedish Orphan Biovitrum. M.-L. Garly is an employee of Novo Nordisk. A. Rosholm is an employee of Novo Nordisk and holds shares in Novo Nordisk. A. Inbal has no conflicts of interest to declare., (Schattauer GmbH Stuttgart.)

Essentials Data on surgery in factor XIII (FXIII) deficiency patients are scarce and lack standardized guidelines. Variable dosage of 10-50 U kg -1 was given to FXIII deficiency patients undergoing surgery. Surgical outcomes showed excellent hemostasis with a minimal risk of post-operative complications. Surgery can be performed safely in FXIII deficiency patients following FXIII administration., Summary: Background The lack of accepted standardized surgical guidelines leads to dependence on the treating physicians' and centers' experiences. Aim Our aim is to evaluate the surgical outcomes of a large group of congenital factor XIII deficiency (FXIIID) patients. Methods A case series study was conducted prior to surgery on congenital FXIIID patients in two major referral centers located in Iran from 2010 to 2016. All patients were on prophylaxis using plasma factor XIII concentrate (10 U kg -1 , every 28 days) except for three patients. Single doses of 10 U kg -1 or 30 U kg -1 plasma factor XIII concentrate were given before a minor procedure and circumcision, respectively. Two doses of plasma factor XIII concentrate, one 30 U kg -1 prior to the procedure and the second dose of 30 U kg -1 on postoperative day 3, were given for major surgery. The dose was 50 U kg -1 both before and after neurosurgical procedures. Results One hundred and sixty-two FXIIID patients underwent minor, major and obstetrical/gynecological surgeries. Median age of the patients was 14 years (ages ranged 15 days to 47 years). The male-to-female ratio was 89/73. Five postoperative complications, two bleeding and three thrombosis, were recorded. Conclusion Our study showed excellent hemostasis in FXIIID patients undergoing surgeries. During the period of these surgeries, we observed only 1.8% postoperative complications. Surgery can be performed safely in FXIIID patients, and our proposed treatment regimens lead to adequate hemostatic coverage with minimal risk, for both minor and major surgeries., (© 2017 International Society on Thrombosis and Haemostasis.)

: Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder accompanied by a variety of bleeding events. Severely deficient patients require regular replacement therapy. With development of FXIII concentrate, the risk of viral infections transmitted by fresh frozen plasma and cryoprecipitate is diminished, but the possibility of inhibitor development remains a challenging issue in the management of these patients. The aim of this study was to assess FXIII inhibitor development in Iranian patients with FXIII deficiency (FXIIID). This study enrolled 50 (30 women and 20 men) patients with severe congenital FXIIID from southeast Iran who underwent long-term (more than 4 years or more than 50 injections) prophylaxis with FXIII concentrate (Fibrogammin P, Dade Behring, Marburg, Germany). We evaluated plasma FXIII activity and FXIII inhibitor on day 28 after the last prophylaxis administration. The method for investigation of FXIII inhibitor was based on Bethesda assay. The mean age of the study population was 13.8 ± 8.3 years. The minimum and maximum FXIII activity levels were less than 1-4.5% (mean ± SD, 2.6 ± 0.7%). Our investigations showed that all patients with severe form of FXIIID were treated without inciting inhibitor development. Despite long-term prophylaxis in the studied patients, none was found to have developed FXIII inhibitors.

Unlabelled: Inherited mild factor XIII deficiency belongs to one of the most underdiagnosed bleeding disorders so far. This is, because most patients do not develop bleeding complications in daily life. Patient, methods: A man (age: 64 years) without a history of bleeding presented with painful swelling of neck, weight loss, anemia and episodic bleeding from the right tonsil necessitating tonsillectomy. Histologic and immunohistochemical evaluation revealed cytokeratin-positive epitheloid angiosarcoma. Blood coagulation status showed significantly elevated D-dimer and decreased FXIII levels (FXIII-activity 35%, FXIIIA-Ag 16-26%). Plasma mixing studies excluded neutralizing antibodies against FXIII., Results: A novel heterozygous F13A1 gene nonsense mutation (p.Glu103Ter, c.307G>T) was found confirming heterozygous FXIII-A deficiency. The same mutation was detected in two further asymptomatic relatives. For further clinical management the patient was transfused with FXIII-concentrate and showed an adequate increase of FXIII ruling out FXIII deficiency to be induced by increased turnover. Despite this haemostatic management and antifibrinolytic treatment the patient had to undergo several revisions due to delayed, Hb relevant bleeding after cervical lymph nodes extirpation and resection of tonsil. Two chemotherapy cycles with paclitaxel and palliative radiotherapy of the neck area were performed, but the patient died unfortunately two months after diagnosis., Conclusions: It is a unique case showing the combination of a highly aggressive angiosarcoma and presence of inherited FXIII deficiency. It is also a rare example demonstrating the benefit of FXIII genotyping besides the expected acquired FXIII deficiency possibly due to neoplasm induced increased consumption by elevated crosslinking of fibrin fibers.

Unlabelled: Congenital factor XIII (FXIII) deficiency is a rare condition with substantial risk for life-threatening bleeding. Replacement of deficient FXIII with plasma-derived FXIII concentrate is a treatment option. The current 12-week study evaluated the steady-state pharmacokinetic (PK) and safety profile of prophylactic infusions of FXIII concentrate (human) in patients with congenital FXIII deficiency. Patients received FXIII concentrate (human) 40 IU kg(-1) on Days 0, 28, and 56. FXIII levels were assessed before and after each infusion; steady-state PK parameters were assessed up to 28 days after the infusion on Day 56. Treatment effectiveness in maintaining trough FXIII activity levels ≥ 5% over 28 days and safety parameters were also assessed. Fourteen patients received FXIII concentrate (human) and 13 completed the study. Post-infusion, FXIII activity levels increased to within the range found in patients without congenital FXIII deficiency without reaching supra-therapeutic levels. Non-baseline-adjusted trough FXIII activity levels were maintained at or above 10% at all post-baseline visits in all patients. Steady-state PK parameters were baseline-adjusted; maximum FXIII activity was 87.7% at 1.72 h post-infusion, subsequently declining to a minimum of 5.0%. The half-life was 6.6 days. FXIII concentrate (human) was generally well tolerated. Two patients had possibly treatment-related adverse events. There were no reports of thromboembolism, viral transmission, bleeding events or treatment-related hypersensitivity. These findings support use of FXIII concentrate (human) 40 IU kg(-1) every 28 days as an appropriate regimen for routine, long-term prophylaxis in children and adults with congenital FXIII deficiency., Clinical Trial Registration: www.clinicaltrials.gov/ct2/show/NCT00883090., (© 2014 John Wiley & Sons Ltd.)

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive bleeding disorder mainly caused by mutations in the F13A1 gene on 6p25.1, which lead to defective A subunit of FXIII. We herein describe two unrelated Korean patients with congenital FXIII deficiency. Proband 1 (a 30-year-old man) and Proband 2 (a 10-year-old girl) presented with severe bleeding episodes (huge intramuscular hematoma and acute intracerebral hemorrhage). Coagulation screening tests for bleeding diathesis were normal, but the FXIII activity was undetectable on urea clot lysis assay. The molecular genetic analysis of F13A1 revealed two mutations in the patients: Proband 1 was homozygous for a previously reported mutation c.1984C>T (p.Arg662) and Proband 2 was compound heterozygous for c.1029T>A (p.His343Gln) and c.1984C>T (p.Arg662). His343Gln was a novel missense mutation occurring in the core domain of the FXIII A subunit. This is the first report of genetically confirmed FXIII deficiency in Korea, with novel and recurrent F13A1 mutations.

Unlabelled: Congenital factor XIII (FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, open-label study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg(-1) in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥ 85%) had trough FXIII activity levels ≥ 10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product., Clinical Trial Registration: www.clinicaltrials.gov/ct2/show/NCT00885742., (© 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Case Description: A 5-year-old castrated male Toy Poodle cross was evaluated because of lethargy, inappetence, and suspected abdominal hemorrhage. The dog had been evaluated on 4 other occasions for episodes of excessive bleeding associated with trauma or surgical procedures., Clinical Findings: At previous evaluations, results of repeated measurements of prothrombin time, partial thromboplastin time, and buccal mucosal bleeding time were unremarkable; activated clotting time, plasma von Willebrand factor concentration, results of platelet function testing, and plasma factor VII, VIII, IX, X, XI, and XII concentrations were considered normal. At this evaluation, clinicopathologic analyses revealed mild regenerative anemia that progressed over a 4-day period to moderate regenerative anemia and acute inflammation with panhypoproteinemia. Abdominal ultrasonography revealed a large mass (suspected to be a hematoma) near the urinary bladder. Rotational thromboelastometry revealed that clotting times were within reference limits, with abnormal clot formation times and clot firmness. The result of a factor XIII (FXIII) clot solubility assay confirmed FXIII deficiency., Treatment and Outcome: The dog's bleeding diathesis resolved with inpatient care and IV fluid therapy, although plasma transfusions had been required at previous evaluations. Seven months after discharge from the hospital, the dog continued to do well clinically, although it had several additional episodes of excessive bleeding., Clinical Relevance: To the authors' knowledge, this is the first reported case of congenital FXIII deficiency in a dog. In addition to more common inherited coagulopathies, FXIII deficiency should be a differential diagnosis for dogs with episodes of excessive bleeding and apparently normal results of standard coagulation tests.

We describe an unusual presentation of factor XIII (FXIII) deficiency in a 17-year-old boy who was diagnosed with this congenital deficiency at the age of 18 months. He had a history of spontaneous splenic rupture 8 years ago, which was managed conservatively. He now presented with sudden severe abdominal and left shoulder pain for 1 day, with no history of antecedent trauma. He was in shock, and examination revealed diffuse peritonitis. A computed tomography scan showed a grade IV splenic laceration. He was taken as an emergency to the operating room where he was found to have a shattered spleen, and a splenectomy was performed. He received cryoprecipitate transfusions perioperatively. After an uneventful recovery, the patient was discharged. To the best of our knowledge, this is the first described case of a recurrent splenic rupture in a patient with FXIII deficiency.

Factor XIII (FXIII) is a transglutaminase consisting of 2 catalytic A subunits and 2 noncatalytic B subunits in plasma. The noncatalytic B subunits protect the catalytic A subunits from clearance. Congenital FXIII deficiency may manifest as a lifelong bleeding tendency, abnormal wound healing, and recurrent miscarriage. Acquired FXIII deficiency, with significant reductions in FXIII levels, has been reported in several medical conditions. The routine screening tests for coagulopathies-prothrombin time, activated partial thromboplastin time, and thrombin time-do not show abnormalities in cases of FXIII deficiency. A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test. Treatment consists of recombinant FXIII or FXIII concentrate. If these are unavailable, then fresh-frozen plasma and cryoprecipitates may be used. Factor XIII has a long half-life; therefore, the patients can lead near-normal lives with regular replacements. Patients with acquired FXIII deficiency with inhibitors need immunosuppressive therapy in addition to factor replacements.

Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder. There is a paucity of data in the literature about obstetrics and gynaecological problems in women affected by FXIII deficiency. The aim of this study was to examine gynaecological problems and obstetric complications and outcome in women with congenital FXIII deficiency. An electronic search was performed to identify the published literature on PUBMED, MEDLINE, EMBASE, Journals @OVID and CINAHL Plus databases using the following keywords: 'congenital factor XIII deficiency' AND 'women OR Pregnancy'. A total of 39 relevant articles were found and included in this systematic review; 27 case reports and 12 case series dating from 1964 to 2012. A total of 121 women were identified. Menorrhagia (26%) was the second most common bleeding reported after umbilical bleeding. Ovulation bleeding reported in 8% of women. Among 63 women, 192 pregnancies were reported; of these, 127 (66%) resulted in a miscarriage and 65 (34%) reached viability stage. In 136 pregnancies without prophylactic therapy, 124 (91%) resulted in a miscarriage and 12(9%) progressed to viability stage. Antepartum haemorrhage occurred in 5/65 (8%) pregnancies reaching viability stage while postpartum haemorrhage (PPH) seen in 16 (25%) cases. Women with congenital FXIII deficiency suffer significant bleeding complications. Menorrhagia and ovulation bleeding are common gynaecological problems and more prevalent than reported. Pregnancies in women with FXIII deficiency have a significant risk of miscarriage, placental abruption and PPH if not on prophylaxis treatment., (© 2013 John Wiley & Sons Ltd.)

Factor XIII (FXIII) is a fibrin-stabilising factor consisting of catalytic A subunits (FXIII-A) and carrier B subunits (FXIII-B). FXIII-B prevents the fast clearance of FXIII-A from the circulation. Congenital FXIII-A deficiency is a rare bleeding disorder, and congenital FXIII-B deficiency is even rarer. Through our recent nationwide survey on "acquired haemophilia-like disease due to anti-FXIII autoantibodies," we newly diagnosed severe congenital FXIII-B deficiency in a Japanese man. He developed thrombocytopenia and gingival bleedings at the age of 73, and his FXIII activity was as low as 10% of the normal. When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates. However, his FXIII activity remained around 10% of the normal. At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma. A dot blot assay detected anti-FXIII-B alloantibodies for the first time in this disease, which could be attributed to the infusion of exogenous FXIII. He was found to be homozygous for a Japanese founder-effect mutation of F13B. Repeated infusions of exogenous FXIII for hemostasis increased anti-FXIII-B alloantibodies that resisted FXIII substitution. To the best knowledge of the authors, none of the remaining 10 reported cases of congenital FXIII-B deficiency developed alloantibodies to exogenous FXIII-B of plasma FXIII. An originally mild bleeding phenotype of severe congenital FXIII-B deficiency can be exaggerated by additional acquired conditions. Physicians should consider congenital FXIII-B deficiency when they encounter cases of unexplained bleeding disorders.

Introduction: Coagulation factor XIII (FXIII) is a fibrin-stabilizing factor, which contributes to hemostasis, wound healing, and maintenance of pregnancy. Accordingly, patients with congenital FXIII deficiency manifest a life-long bleeding tendency, abnormal wound healing and recurrent miscarriage. In order to understand the molecular mechanisms of congenital FXIII deficiency, genetic analysis and molecular modeling were carried out in a Japanese male neonate with severe FXIII deficiency., Methods and Results: Two novel mutations, Y204Stop (or Y204X, TAT to TAA) and S708R (AGC to AGG), were heterozygously identified by nucleotide sequencing analysis in exons V and XV of the gene for the A subunit of FXIII (FXIII-A). Y204X and S708R would lead to nonsense mediated mRNA decay and misfolding of the FXIII-A molecule, respectively. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, the presence of these mutations was confirmed both together in the proband and one each separately in either the maternal or paternal sides of his family. In addition, moderately decreased FXIII activity was associated with the presence of either mutation. Molecular modeling predicted that the mutant molecule of S708R would be structurally compromised by the substitution of the Ser with the larger extended bulky and positively charged Arg side-chain., Conclusion: It is probable that the impaired tertiary structure of the mutant S708R molecule leads to its instability, which is at least in part responsible for the FXIII deficiency of this patient. This is consistent with the fact that the mutations and the reduced FXIII activities co-segregate among the patient's family members., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Coagulation factor XIII (FXIII) has a major role in the final stage of blood coagulation, is important for wound healing and maintaining pregnancy. Severe congenital FXIII deficiency is a rare disorder with 1 patient in 1-3 million. Untreated, it causes bleeding events, with intracranial haemorrhage being the major cause of death, impaired wound healing, and abortion. FXIII deficiency was traditionally diagnosed using the clot solubility test, but quantitative FXIII activity and antigen assays are preferred today. Treatment consists of replacement therapy with FXIII concentrates administered every 4-6 weeks. The molecular-genetic causes of FXIII deficiency are mutations in the genes coding for the FXIII A- and B-subunits. More than 60 mutations distributed throughout the FXIII A-subunit gene have been identified so far and 4 mutations in the FXIII B-subunit gene. The first case of congenital FXIII deficiency was reported in Switzerland in 1960. In Switzerland we observed a disproportionately high incidence, which can be explained in part by a founder effect. In this article, we summarise general facts on severe congenital FXIII deficiency, and we characterise all FXIII deficient patients living in Switzerland, including the first case described in 1960 who is a member of a large family originating from the canton of Uri.

Congenital factor XIII (FXIII) deficiency is a rare congenital hemorrhagic disorder. Since FXIII is an essential factor in pregnancy, pregnant patients with congenital FXIII deficiency should receive adequate replacement of FXIII concentrate. We report here on a 19-year-old pregnant woman with congenital FXIII deficiency. Despite regular replacement of FXIII concentrate, FXIII activity decreased rapidly after 32 weeks of gestation and she had to receive a high-dose of FXIII concentrate until delivery. Careful monitoring of FXIII activity is needed in patients with congenital FXIII deficiency, because FXIII activity may decrease rapidly in late pregnancy.

Congenital deficiency of blood coagulation factor XIII is an uncommon, inherited disorder characterized by hemorrhagic diathesis, habitual abortions and defective wound healing. We analyzed 8 reported successful pregnancies in women with a congenital deficiency of A-subunit of factor XIII (XIIIA), in which the plasma level of maternal factor XIIIA and/or the precise replacement therapies are described. Because decidual bleeding usually begins from 5 to 6 weeks' gestation and, without replacement therapy, spontaneous abortion always occurs, we herein offer the following prenatal and peripartum management guidelines and observations: i) the level of plasma A-subunit of factor XIII antigen (XIIIA-Ag) or factor XIII activity (XIII-act) must be at least 2%-3%, and, if possible, higher than 10% to prevent decidual bleeding and miscarriage during the pregnancy; ii) factor XIIIA concentrate is better than fresh frozen plasma or cryoprecipitate for replacement therapy; iii) the administration of 250 international units (IU) every 7 days is sufficient to maintain the level of plasma XIIIA-Ag or XIII-act more than 10% in the early period of gestation (through 22 weeks' gestation); however, 500 IU every 7 days is indicated in the later period (from 23 weeks' gestation) to maintain that level; iv) during labor, the desired level of plasma XIIIA-Ag or XIII-act should be higher than 20%, and, if possible, higher than 30% in order to make ready for any risk of severe obstetrical hemorrhagic complications; thus a booster dose of 1000 IU is indicated before labor; v) no replacement therapy is necessary in the puerperium because it is usually uneventful without it.

Factor XIII deficiency is a rare autosomal recessive congenital disorder of haemostasis characterised by a plasmatic factor XIII level less than 1% in homozygote and bleeding as of the youth. We report a study about ten patients with congenital factor XIII deficiency from seven south-Tunisian families, there are seven females. Umbilical bleeding was common and only two patients had intracranial bleeding. The standard screening tests are normal. Factor XIII activity was less than 1% in all patients. A sub-unit A deficit was detected for the ten patients. Out hemorrhagic context, five patients receive regular prophylactic transfusion with fresh frozen plasma.

Congenital factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency.

We present the clinical, biochemical and genomic findings of a family with congenital factor XIII (FXIII) deficiency. Congenital FXIII deficiency is a very rare autosomal recessive bleeding disorder, characterized by umbilical cord bleeding at birth and spontaneous intracranial haemorrhage. Routine clotting tests are normal, which may delay the diagnosis, leading to an increased chance of severe sequelae. The propositus and her brother, known with haemorrhagic diathesis, were found to be compound heterozygous with a known missense mutation (1050 G --> T transversion in exon 7, Val316Phe substitution) and a novel mutation 889 G --> A in exon 6, which predicts a Gly262Glu substitution. As these mutations were known in the family, DNA obtained from cord blood of the youngest sister was analysed for mutations in exons 6 and 7 only. We postulate that the diagnosis was facilitated by determining the two different mutations in the genotype of this family. The analysis showed that she was heterozygous for the exon 7 mutation. Hence, she was not at risk of experiencing haemorrhagic diathesis. This diagnosis avoided the administration of FXIII concentrate to the newborn.

Transglutaminases are at least 9 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII (FXIII) is a plasma transglutaminase circulating in blood as a heterotetramer and consisting of two catalytic A subunits and two non-catalytic B subunits. It is a proenzyme activated by thrombin in the blood coagulation cascade. It plays an important role(s) in hemostasis, wound healing, and maintenance of pregnancy. Accordingly, a lifelong bleeding tendency as well as abnormal wound healing and recurrent spontaneous miscarriage are common symptoms of FXIII deficiency. Genetic and molecular mechanisms of congenital deficiencies have been analyzed in vitro. The mechanisms of these defects have also been studied in detail by using FXIII gene knock-out mice in vivo. We analyzed eight successful outcomes of pregnancy in patients with congenital deficiency of FXIIIA, in which the plasmatic level of maternal FXIIIA and/or the precise substitute therapies were mentioned. Then we propose the following guidelines for the perinatal management: (i) decidual bleeding usually begins from 5 weeks of gestation and spontaneous abortion always occurs subsequently without substitute therapy; (ii) the plasma level of FXIIIA must be at least 2 approximately 3%, however, if possible, higher than 10% to prevent bleeding and miscarriage; (iii) the administration of 250 IU of FXIIIA concentrate each 7 days is enough to keep the level of plasma FXIIIA more than 10% in the early gestation, however 500 IU each 7 days is adequate in the later period to keep that level; (iv) during labor, the desired level is higher than 20%, if possible, higher than 30% to avoid any risk of strong obstetrical bleeding.

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.

Severe homozygous factor XIII deficiency was first described in Switzerland, in 1961. At present 14 patients are known here. Nine are of Swiss origin, the others are immigrants from eastern Europe. A 27-year-old woman with many haemorrhages during childhood immigrated to Switzerland and went through four episodes of haemorrhagic corpus luteum cyst rupture with life-threatening blood loss into the abdomen and three haemorrhages into the retroperitoneal muscles causing sensomotoric palsies, before the diagnosis was established. A monthly prophylactic replacement therapy of 500 IE factor XIII concentrate was started. Since then no signs of haemorrhage occurred. For the last trimester of pregnancy treatment intervals were shortened and dosage increased. Haemorrhage from the umbilical cord for weeks, subcutaneous haematomas, intracranial haemorrhage, muscle haemorrhage and wound bleeding with impaired wound healing as well as tendency to marked scar formation are characteristic for severe homozygous factor XIII deficiency. Without replacement therapy women suffer from obligate abortion. Diagnosis is made by the solubility of fibrin clots in urea (5 mol/l) or monochloroacetic acid (1-2%). For confirmation and monitoring of replacement therapy a quantitative incorporation assay is used. Replacement therapy is necessary in case of haemorrhage, injury, and surgery. Because of the high risk of intracranial haemorrhage prophylaxis is strongly recommended.

There is an increasing interest in the role of coagulation factor XIII (FXIII) in cardio- and cerebrovascular diseases. It has recently been reported that a common G-->T point mutation in the A-subunit gene of FXIII, which codes for a valine (val) to leucine (leu) change (FXIIIVal34Leu), is protective against thrombotic diseases but seems to increase the risk of intracerebral bleeding. We developed a colorimetric incorporation assay for detection of FXIII activity based on incorporation of 5-(biotinamido) pentylamine (BAPA) into fibrin or fibrinogen. With this new assay, we studied the effects of FXIIIVal34Leu mutation, plasma fibrinogen concentration and congenital FXIII deficiency on FXIII activity. There are no data available about the ability of different FXIII assays to detect altered activity in FXIIIVal34Leu genotypes. We therefore compared our results determined by the incorporation method with a commonly used photometric method based on ammonia release after cross-linking of glycine-ethylester to a specific glutamine containing peptide substrate. We also determined FXIII A-subunit antigen (Ag) levels using enzyme-linked immunosorbent assay (ELISA) technique. The FXIIIVal34Leu genotype could not be detected either by the photometric method nor by the FXIII A-subunit ELISA. The incorporation assay showed an increased specific FXIII activity in subjects possessing the leu allele. The photometric assay and ELISA gave similar results independent from genotype. In patients with congenital FXIII deficiency before and after substitution, however, ELISA and the incorporation assay gave similar results, whereas the photometric assay showed consistently higher values. Our results show that the incorporation assay, not the photometric assay based on ammonia release, can be used for detection of elevated activity in subjects with FXIIIVal34Leu. Because of specificity and over a wide range sensitivity, the assay can also be used for determination of FXIII deficiency and monitoring of FXIII substitution therapy.

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.

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., (Copyright 2000 Harcourt Publishers Ltd.)

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.

Unlabelled: It is well known that maternal fibrinogen (Fg) and factor X III are essential for maintaining early pregnancy. We studied their role by analysis of clinical reports and immunohistochemical investigation., Methods: (1) We analyzed the pregnancy cases of congenital afibrinogenemia and congenital factor X III deficiency. (2) Immunohistochemical staining of Fg, subunit A of factor X III (X IIIA) and fibronectin (Fn) were performed in the human implantation site, placenta, and endometrial cells cultured in serum-free medium., Results: (1) Afibrinogenemia needed to be administrated Fg from 4 weeks' gestation (4 wG), and factor X III deficiency needed factor X III concentrate from 5 wG, in order to prevent abortion. (2) Implantation tissues: Fg, cellular X IIIA and Fn were present at the decidual stroma around invasive cytotrophoblasts at 5 wG. X IIIA-positive cells coincided with LN-5-positive macrophages. Placenta: Fg, cellular X IIIA and Fn were present in the decidual layer. Endometrial culture cells: Fn was secreted by spindle-like shaped cells. X IIIA was secreted by round-shaped cells., Conclusion: Maternal Fg and factor X III are essential just after 4-5 wG, and in that period they and Fn are present abundantly in decidual stroma around invasive cytotrophoblasts. It is concluded that when cytotrophoblasts invade endometrium maternal Fg, factor X III and Fn are concerned with cytotrophoblasts' anchoring as adhesive proteins.

Congenital factor XIII deficiency is a rare disease, but has provided valuable information on the physiological role of factor XIII and the benefit of factor XIII replacement therapy. It could be shown that not only homozygous patients but also heterozygotes are at risk for bleeding complications. Acquired factor XIII deficiency, however, is much more common, and preliminary studies suggest a lack of factor XIII to be an important feature of various diseases. In acute states and severe hemorrhages, replacement therapy with factor XIII concentrates is recommended. Recent progress in assay methods and future clinical studies should help to evaluate the therapeutic potential of factor XIII.

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.

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.

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.

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.

Four sisters born to consanguineous muslim parents with a bleeding disorder since birth are presented. They also had prolonged umbilical cord bleeding and history of delayed wound healing. Since childhood, they have been developing spontaneous ecchymotic spots. Three out of four sisters had Factor XIII deficiency. Their mother's sisters, who have been developing ecchymotic spots were found to have normal clot stability and Factor XIII levels. Family study indicates autosomal recessive mode of inheritance of the congenital Factor XIII deficiency.

A 32-year-old woman with a bleeding tendency born of a consanguineous marriage, was found to have factor XIII subunit B deficiency. An abnormally low level of factor XIII activity was initially noticed and this finding led to further studies of the proband and her family. The notable features were: undetectable subunit B of factor XIII in the proband and her brother and reduced levels of subunit B, 34-52%, in her parents and children. The proband's brother had a markedly decreased level of subunit A protein. The level of factor XIII subunit A in platelets of the proband was normal. The half-life of subunit A determined from the disappearance curve of infused factor XIII subunit A concentrate was approximately 3 d and this is the shortest estimate of the half-life of factor XIII to date. From these results, it is suggested that subunit A is unstable in plasma deficient in subunit B and subunit B stabilizes the A protein. This is the first report of congenital deficiency of factor XIII subunit B and this disorder is thought to be inherited as an autosomal recessive trait.

The outcome of all pregnancies complicated by congenital factor XIII (F XIII) deficiency has resulted in abortion without replacement therapy. We experienced a case with this disease and succeeded in normal vaginal delivery after treatment with weekly F XIII concentrate (Fibrogammin P, Behringwerke AG) during pregnancy. This 20-year-old woman, gravida 1, para 0, was found to have an F XIII level of 0% at age 6 and was treated with F XIII concentrate occasionally when she suffered from massive bleeding. In 1986 she became pregnant and was hospitalized at 6 weeks' gestation because of genital bleeding. Subsequent to this episode, F XIII concentrate was administered every week. At 37 weeks' gestation a 2,646-gram girl with a 1-min Apgar score of 9 was delivered. Postpartum blood loss was 260 ml. One year after delivery neither the mother nor the infant were found to have hepatitis B, nonA, nonB hepatitis, ATL or HIV. F XIII concentrate proved effective in such cases without any risk of viral infection.

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.

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.