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Introduction: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency., Aim: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC)., Methods: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured., Results: We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores., Conclusion: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Objectives: Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5 million. The clinical symptomatology, diagnosis, and management of FXIIID are described., Methods: A retrospective chart review of children with FXIIID was performed from January 2000 through October 2021 at a tertiary care center in Southern India. The diagnosis was performed by the Urea clot solubility test (UCST) and Factor XIII antigen assay., Results: Twenty children (representing 16 families) were included. Male: Female ratio was 1.5:1. The median age of symptom onset was 6 mo, and the median age of diagnosis was 1 y, demonstrating a delay in diagnosis. Consanguinity was present in 15 (75%) with 4 children having affected siblings. Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period. Fourteen children were on cryoprecipitate prophylaxis. Four children had breakthrough bleeds due to irregular prophylaxis, including one intracranial bleed due to a delay in cryoprecipitate prophylaxis during the covid pandemic., Conclusions: Congenital FXIIID presents with a wide range of bleeding manifestations. The high prevalence of consanguinity in Southern India can be a cause of FXIIID's high prevalence in this region. There is a propensity for intracranial bleeding with a significant number having this at first presentation. Regular prophylaxis is required and feasible to prevent potentially fatal bleeds., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

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: The characterization of inherited mild factor XIII deficiency is more imprecise than its rare, inherited severe forms. It is known that heterozygosity at FXIII genetic loci results in mild FXIII deficiency, characterized by circulating FXIII activity levels ranging from 20% to 60%. There exists a gap in information on 1) how genetic heterozygosity renders clinical bleeding manifestations among these individuals and 2) the reversal of unexplained bleeding upon FXIII administration in mild FXIII-deficient individuals., Objectives: To assess the prevalence and burden of mild FXIII deficiency among the apparently healthy German-Caucasian population and correlate it with genetic heterozygosity at FXIII and fibrinogen gene loci., Methods: Peripheral blood was collected from 752 donors selected from the general population with essentially no bleeding complications to ensure asymptomatic predisposition. These were assessed for FXIII and fibrinogen activity, and FXIII and fibrinogen genes were resequenced using next-generation sequencing. For comparison, a retrospective analysis was performed on a cohort of mild inherited FXIII deficiency patients referred to us., Results: The prevalence of mild FXIII deficiency was high (∼0.8%) among the screened German-Caucasian population compared with its rare-severe forms. Although no new heterozygous missense variants were found, certain combinations were relatively dominant/prevalent among the mild FXIII-deficient individuals., Conclusion: This extensive, population-based quasi-experimental approach revealed that the burden of heterozygosity in FXIII and fibrinogen gene loci causes the clinical manifestation of inherited mild FXIII deficiency, resulting in ''unexplained bleeding'' upon provocation., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Despite the early discovery of factor XIII (FXIII) in 1944, the diagnosis of FXIII deficiency was not made until 1960, after all the other coagulation factor deficiencies, most likely due to the normality of routine coagulation testing in FXIII deficiency. Although the first case was detected by the clot solubility test and this test has long since been used to detect FXIII deficiency, the test is no longer recommended by experts. Over the past 60 years, knowledge about FXIII deficiency has expanded considerably, between 1992, when the first variant was identified, and 2022, 197 mutations have been reported. Almost all missense mutations have a similar effect on FXIII, leading to instability and faster degradation of mutant FXIII protein. Therapeutic options have evolved from historical fresh frozen plasma (FFP), old plasma, whole blood, and cryoprecipitate, to plasma-derived and recombinant FXIII concentrates, respectively available since 1993 and 2012. These concentrate products were respectively approved by the Food and Drug Administration in 2011 and 2013. This historical review covers various aspects of FXIII related disorders, including the discovery of the FXIII, associated disorders, molecular basis, diagnosis, and treatment of FXIII deficiency., Competing Interests: None declared., (Thieme. All rights reserved.)

Autoimmune diseases, including dermatomyositis, can be complicated by an acquired autoimmune coagulation factor XIII deficiency, which sometimes results in fatal bleeding. Here, we report the case of a young woman with anti-NPX-2 antibody-positive dermatomyositis who developed massive haemothorax with acquired factor XIII deficiency during treatment, including plasma exchange therapy. Emergency transcatheter arterial embolisation was performed and coagulation factor XIII concentrates (Fibrogammin P® 240 U/day for 5 days) were supplemented. Subsequently, the patient was discharged and managed with oral prednisolone and tacrolimus. Coagulation system test results were followed up regularly and remained within normal limits and the patient progressed without recurrence of bleeding symptoms. Coagulation factor XIII deficiency cannot be assessed without measuring coagulation factor XIII activity because common coagulation-fibrinolytic system test results are not abnormal. The measurement of factor XIII activity should be performed when autoimmune diseases are complicated by unexplained bleeding., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Severe traumatic bleeding depletes coagulation factor XIII (FXIII) and fibrinogen. However, the role of FXIII level in bleeding-related outcomes is unknown., Objectives: To evaluate the association between FXIII levels at hospital arrival and critical administration threshold (≥3 red blood cell units in 1 hour within the first 24 hours), bleeding-related outcomes, death, and baseline characteristics., Methods: A retrospective cohort study was conducted in severely injured adult patients (Injury Severity Score of ≥22 or ≥2 red blood cell units transfused in 24 hours) admitted to a level 1 trauma center. Clinical and laboratory data were collected. Baseline FXIII antigen levels were measured in banked patient plasma. Multivariable logistic and linear regression models were used to estimate the association between FXIII levels, outcomes, and baseline characteristics., Results: Three hundred sixty-four of 1730 subjects admitted during a 2-year period were analyzed. Median age was 44 years (IQR, 27-62 years), and median Injury Severity Score was 29 (IQR, 22-34). FXIII levels were not associated with critical administration threshold (odds ratio [OR], 1.06; 95% CI, 0.97-1.17) or death (OR, 0.98; 95% CI, 0.90-1.07). FXIII was associated with major bleeding (OR, 1.10; 95% CI, 1.02-1.2) and massive transfusion (OR, 1.25; 95% CI, 1.08-1.44). Lower baseline FXIII levels were associated with arrival from a referring hospital (FXIII level, -0.07 U/mL; 95% CI, -0.11 to -0.03), hemoglobin (FXIII level, -0.05 U/mL; 95% CI, -0.07 to -0.03), fibrinogen level (FXIII level, -0.05 U/mL; 95% CI, -0.08 to -0.02), and platelet count (FXIII level, -0.02 U/mL; 95% CI, -0.04 to -0.008)., Conclusions: Baseline FXIII levels in severely injured patients were inconsistently associated with bleeding-related outcomes and mortality. However, their association with major bleeding warrants further investigation of the role of FXIII in massively transfused patients with trauma., Competing Interests: Declaration of competing interests J.C.G.B. reports salary support from the Ministry of Health, Long-Term Care-Clinician Investigator Program, and the Department of Anesthesia and Pain Medicine at the University of Toronto during the completion of this study. J.C. reports research support from the Canadian Blood Services and Octapharma. K.K. reports research support from Octapharma; consultancy fees from Octapharma and Instrumentation Laboratory; and funding in part by merit awarded by the Department of Anesthesia and Pain Medicine, University of Toronto. M.S. is a consultant for Band Therapeutics; receives unrestricted research funding from Pfizer and Octapharma; and receives honoraria from Pfizer, Octapharma, Novartis, and Amgen., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Inherited factor XIII (FXIII) deficiency is an extremely rare and under-diagnosed autosomal recessive inherited coagulopathy, which is caused by genetic defects in the F13A1 or F13B gene. More than 200 genetic mutations have been identified since the first case of inherited FXIII deficiency was reported. This study aimed to identify underlying gene mutations in a patient with inherited FXIII deficiency who presented with recurrent intracerebral hemorrhage. Levels of plasma FXIII-A antigen were measured, F13A1 and F13B genes were sequenced, mutation information was analyzed, and the mutated protein structure was predicted using bioinformatics methods. Molecular genetic analysis identified four mutations of FXIII-related genes in the proband, including three previously reported mutations inherited from his parents (c.631G>A, p.Gly210Arg and c.1687G>A, p.Gly562Arg of F13A1 gene and c.344G>A, p.Arg115His of F13B gene) and a novel spontaneous mutation of F13A1 gene (c.2063C>G, p.Ser687Cys). Molecular structural modeling demonstrated that the novel Ser687Cys mutation may cause changes in the spatial structure of FXIII-A and increase its instability. In conclusion, we identified a novel and likely pathogenic mutation of the F13A1 gene, which enriched the gene mutation spectrum of inherited FXIII deficiency. The findings may provide promising targets for diagnosis and treatment of inherited FXIII deficiency., (© 2023. Japanese Society of Hematology.)

Abstract: Factor XIII deficiency (FXIIID) is a rare hereditary bleeding disorder arising from heterogeneous mutations, which can lead to life‐threatening hemorrhage. The diagnosis of FXIIID is challenging due to normal standard coagulation assays requiring specific FXIII assays for diagnosis, which is especially difficult in developing countries. This report presents an overview of FXIIID diagnosis and laboratory methods and suggests an algorithm to improve diagnostic efficiency and prevent missed or delayed FXIIID diagnosis. Assays measuring FXIII activity: The currently available assays utilized to diagnose FXIIID, including an overview of their complexity, reliability, sensitivity, and specificity, as well as mutational analysis are reviewed. The use of a FXIII inhibitor assay is described. Diagnostic tools in FXIIID: Many laboratories are not equipped with quantitative FXIII activity assays, and if available, limitations in lower activity ranges are important to consider. Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries. To minimize the number of patients with undiagnosed FXIIID, test quality should be improved in less well‐equipped laboratories. Common country‐specific mutations may facilitate diagnosis through targeted genetic analysis in reference laboratories in suspected cases. However, genetic analysis may not be feasible in every country and may miss spontaneous mutations. Centralized FXIII activity measurements should also be considered. An algorithm for diagnosis of FXIIID including different approaches dependent upon laboratory capability is proposed. [ABSTRACT FROM AUTHOR]

The patient was a 79-year-old man with ureteroileal anastomotic stricture after a Bricker ileal conduit. Endourological treatment of stenosis was performed via percutaneous nephrostomy and ileal conduit. The patient experienced lower abdominal pain on the following day, and computed tomographic (CT) scan showed hematoma retention around the kidney and active bleeding from the renal artery branches. Transarterial embolisation (TAE) was performed and the bleeding was controlled. Two days later, there was a sudden progression of anemia and CT showed an increase in hematoma around the kidney. We subsequently performed nephrectomy for hemostasis. Five days later, the anemia progressed further. There was hematoma retention in the retroperitoneal cavity, and emergency laparotomy hemostasis was performed. Routine coagulation test results were normal. Heavy bleeding was observed several days after TAE and the possibility of coagulation factor XIII deficiency was considered. Factor XIII deficiency was confirmed by a low factor XIII activity level. The patient was given plasma-derived factor XIII. After receiving factor XIII replacement, factor XIII activity remained unchanged and the patient continued to bleed. Thereafter, a cross-mixing test was performed and the patient was diagnosed with autoimmune acquired factor XIII deficiency. Cortical steroids were administered to remove the factor XIII inhibitor. Steroid administration showed a rapid increase in factor XIII activity, and bleeding symptoms were no longer observed. In cases of serious bleeding of unknown cause with a normal coagulation profile, acquired factor XIII deficiency should be suspected and factor XIII activity measured.

Factor XIII (FXIII) cross-links fibrin monomers to strengthen clots. The congenital severe autosomal type of FXIII deficiency with <5 percent of normal FXIII activity is an extremely rare bleeding disorder with <10 cases in Sweden. It often debuts at birth with prolonged umbilical cord bleedings and an increased risk for bleeding throughout life. Patients with severe congenital FXIII deficit have an established FXIII concentrate treatment, both for prophylaxis and at bleeding episodes. Acquired autoantibodies against FXIII are also rare, with high bleeding risks. Quantitative FXIII analyses are only available in few laboratories in Sweden. Sometimes more complex antigen/antibody/gene mutation tests are needed for diagnosis, but these are not available in Sweden. Other acquired FXIII deficiencies can occur in patients with several diseases and during surgery/trauma. Their treatment and diagnostic logistics are less defined. Recent European guidelines on perioperative bleeding have suggested FXIII concentrate treatment.

Background: Coagulation factor XIII (FXIII) consists of 2 A (FXIII-A) and 2 B (FXIII-B) subunits that cross-link and strengthen the hemostatic fibrin thrombus; thus, abnormal bleeding occurs when FXIII is significantly reduced. Autoimmune-acquired FXIII deficiency (AiF13D) is characterized by lethal bleeding secondary to the development of autoantibodies against FXIII. However, since anti-FXIII autoantibodies are polyclonal, the mechanism underlying FXIII dysfunction is unclear., Objectives: The objective of this study was to dissect the inhibitory mechanisms of polyclonal anti-FXIII autoantibodies., Methods: In this study, we prepared the human monoclonal antibodies (hmAbs) from the peripheral blood of an 86-year-old man with AiF13D by using a new complementary DNA cloning method and analyzed the properties of each autoantibody., Results: Seventeen clones obtained from hmAbs were divided into the following 3 groups: dissociation inhibitors of FXIII-A 2 B 2 (6 clones), assembly inhibitors of FXIII-A 2 B 2 (3 clones), and nonneutralizing/inhibitory hmAbs (8 clones). Dissociation inhibitors strongly inhibited fibrin cross-linking and amine incorporation. Assembly inhibitors extracted FXIII-A from FXIII-A 2 B 2 , strongly inhibited binding of FXIII-A to FXIII-B, and activation peptide cleavage. However, the patient's plasma presented a strong inhibition of A 2 B 2 heterodimer assembly but only a slight inhibition of thrombin-Ca 2+ -dependent dissociation, suggesting that the assembly inhibitors concealed the effect of dissociation inhibitors in plasma. By contrast, nonneutralizing antibodies had little effect on the function of FXIII, suggesting that nonneutralizing hmAbs (and/or dissociation inhibitors and/or assembly inhibitors) promoted the clearance of FXIII-A from the blood., Conclusion: Cloning of anti-FXIII autoantibodies enabled us to not only elucidate the mechanism and pathophysiology of AiF13D but also develop a completely new type of anticoagulant., (Copyright © 2022. Published by Elsevier Inc.)

An 88-year-old man became unconscious and was admitted to our hospital due to severe anemia. Extensive subcutaneous hemorrhage around the chest and back and pectoralis major muscle hematoma were observed. Coagulation screening tests showed moderately reduced factor XIII/13 (FXIII) activity. During hospitalization, the patient had repeated bleeding events in the gastrointestinal tract and muscles, leading to hemorrhagic shock. We suspected the presence of FXIII inhibitors from FXIII infusion test results. The cross-mixing test for cross-linking of fibrin revealed inhibition of polymerization of α-chain and α 2 -plasmin inhibitor incorporation into fibrin. In addition, by detecting IgG autoantibody to thrombin-activated FXIII, we confirmed the presence of type Ab anti-FXIII-A subunit autoantibody, which represses the catalytic subunit activity of activated FXIII. Autoimmune FXIII deficiency should be considered when a patient presents with severe hemorrhagic diathesis with no other cause than moderately reduced of FXIII activity, as reported in this case.

A term Caucasian neonate with an uncomplicated birth history presented with persistent umbilical stump bleeding unresponsive to extensive topical haemostatic measures initially. He subsequently developed hypovolaemic shock. Routine full blood count and basic coagulation screen were unremarkable. He received packed red cell and cryoprecipitate transfusions. Further specialist coagulation studies performed revealed factor XIII deficiency. Genetic investigations demonstrated a compound heterozygosity for the disorder. He was later started on monthly prophylactic treatment of plasma-derived factor XIII. Clinicians should have a high index of suspicion for factor XIII deficiency for newborns with abnormal umbilical stump bleeding in the presence of no bleeding risk factors and normal routine blood investigations., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The objective of the study was to analyse a novel F13A1 gene mutation in a Chinese patient with factor XIII (FXIII) deficiency and explore the molecular mechanism. Pedigree investigation, clinical diagnosis, phenotypic and genetic analysis were conducted. The F13A1 gene was amplified by PCR and directly sequenced. Online bioinformatics software was needed to analyse the mutation. A novel mutation c.515G>C (p.Arg208Pro) in exon 4 was found in the proband. Protein Arg208 is conserved highly among homologous species. Bioinformatics software showed that Arg208Pro mutation might affect the protein function. We preliminarily believed the mutation Arg208Pro was responsible for the decrease FXIII level. We reported a novel mutation in the F13A1 gene, which can flesh out the mutant library., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Factor XIII deficiency is a rare cause of post-operative bleeding. It poses a diagnostic challenge as standard coagulation tests including prothrombin time, international normalized ratio, and activated partial thromboplastin time are usually normal in factor XIII deficiency. We present the case of our patient, a 19-year-old male with acquired factor XIII deficiency diagnosed after ballistic injury with a post-operative course complicated by hemorrhage. This case demonstrates an uncommon cause of coagulopathy, acquired factor XIII deficiency, and the challenges it poses to post-operative management. The diagnosis of acquired factor XIII deficiency may be challenging, but a high clinical suspicion is imperative to avoid a missed diagnosis and delayed treatment.

Introduction: Hyperfibrinolysis induced by factor XIII deficiency (FXIIID) is extremely rare, and patients with no manifestations of active bleeding can easily and frequently be neglected in clinical practice, leading to a missed diagnosis. Herein, we report a rare case of idiopathic FXIIID with secondary hyperfibrinolysis., Patient Concerns: A 69-year-old man presented with ecchymosis of the right arm and chest wall., Diagnosis: Considering the clinical picture, coagulation function test results, and FXIII activity, the patient was finally diagnosed with hyperfibrinolysis secondary to acquired factor XIII deficiency., Interventions: The patient was treated with fresh frozen plasma, aminomethylbenzoic acid, a prothrombin complex, etamsylate, dexamethasone, and cryoprecipitate., Outcomes: The patient improved and was discharged after factor replacement therapy, and no further bleeding was reported 1 month after discharge., Conclusion: This case report illustrates that the complications of Factor XIII deficiency may include hyperfibrinolysis. Since timely diagnosis of FXIIID is challenging, detailed coagulation factor examinations are needed for definitive diagnosis. It has been suggested that gene testing and antibody testing can help in diagnosis. If ideal treatment is not available, alternative treatment should be provided to reduce bleeding., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Congenital factor (F) XIII deficiency is a rare coagulation factor deficiency that is inherited in an autosomal recessive manner. FXIII deficiency presents various clinical manifestations, such as intracranial hemorrhage (ICH), which is the most common cause of morbidity and mortality. As ICH can occur in the neonatal period, prenatal diagnosis (PND) is an effective way to reduce neonatal ICH and its associated fatal consequences. In this study, we investigated a noninvasive prenatal diagnosis (NIPD) method, cell-free fetal DNA (cffDNA), for PND in FXIII deficiency. This study was conducted on seven pregnant women in the first trimester. After extraction of cffDNA from maternal plasma, PCR-restriction fragment length polymorphism (PCR-RFLP) was performed to find the underlying F13A gene mutations previously identified in the family members. PCR-RFLP was also performed on postnatal DNA samples. Sanger sequencing was performed to confirm the results. Four cases were heterozygous for F13A gene mutations, whereas three were unaffected. PCR- RFLP results for cffDNA and postnatal DNA samples were identical, and Sanger sequencing confirmed the results. cffDNA is a noninvasive and effective method for PND in congenital FXIII deficiency., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency., (© 2022. The Author(s).)

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

Background: Factor XIII (FXIII)-B subunit measurements are required for the diagnosis and characterization of the type of FXIII deficiency. Furthermore, therapy for FXIII-A deficiency with recombinant FXIII (rFXIII-A) relies on available FXIII-B., Objective: To carry out a collaborative study to calibrate and assign value to the current WHO 1st International Standard (IS) FXIII Plasma for Total FXIII-B subunit, relative to locally collected normal plasma pools., Methods: Laboratories were instructed to use a validated method (specific ELISA antibodies provided) for assessment of Total FXIII-B subunit antigen potency. All laboratories used this method with one laboratory using an additional in-house method. Nine data sets were received from seven laboratories (37 assays in total), which provided a total of 35 valid estimates for this new assignment. Total FXIII-B subunit estimates were calculated relative to locally collected normal plasma pools, using an arbitrary value of 1.00 unit of Total FXIII-B subunit per ml, for each pool., Results: Combination of results produced an overall mean of 0.98 units/mL with an inter-laboratory variability (geometric coefficients of variation - GCV%) of 18.3% [95% confidence interval: 0.86-1.11]. Real-time and bench stability studies indicated good stability and preservation of the FXIII-B subunit analyte in the WHO 1st IS FXIII Plasma (02/206)., Conclusion: Following agreement by study participants, ISTH/SSC Experts, WHO-ISTH Liaison Group and the SSC Board, the WHO/ECBS established the current WHO 1st IS Factor XIII plasma (NIBSC code 02/206) by additionally assigning it with a Total FXIII-B subunit antigen value of 0.98 IU/ampoule, in October 2019., (© 2021 International Society on Thrombosis and Haemostasis.)

Case: An 18-year-old man developed ecchymosis after arthroscopic anterior cruciate ligament reconstruction with semitendinosus graft and meniscal repair. The results of routine coagulation studies were normal, but factor assays showed a reduction in factor XIII levels. The bleeding symptoms were dramatically improved after administration of cryoprecipitate., Conclusion: Factor XIII deficiency is one of the rare clotting factor deficiencies that can be present at birth or be manifested later in life. Clinical awareness of factor XIII deficiency is essential so that appropriate testing and treatment can be achieved., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B733)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Factor XIII (FXIII) deficiency is a rare autosomal recessive disorder that can result in life-threatening bleeding and early fetal loss. FXIII not only is responsible for cross-linking fibrinogen to stabilize and strengthen clot formation but also facilitates wound healing and angiogenesis and plays an important role in fetal vitality. Modern therapeutics allow for prophylactic treatment that can prevent most major bleeding and increasing fetal viability. Early diagnosis is paramount due to the high risk of intracranial bleeding., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: None declared.

Factor XIII (FXIII) is a thrombin-activated protransglutaminase that plays a key role in blood clot formation. Congenital FXIII A-subunit deficiency represents a rare bleeding disorder that affects one in 2-3 million individuals worldwide and is treated with recombinant FXIII (rFXIII). However, due to the rarity of the disease, clinicians are often left to weigh individual variation in FXIII activity and/or symptoms to optimally guide dosing. Cases often become further complicated when patients experience refractory bleeding, which can be difficult to treat. This report describes an approach to rFXIII dosing in two patients who required deviation from standard protocols to maintain therapeutic FXIII troughs. We highlight limitations in our understanding of FXIII deficiency management, while also providing an example of the application of pharmacokinetic data to individualise therapy for improved outcomes. Finally, the case reminds us of the importance of patient-centered, cost-conscious care and multidisplinary teamwork in complex cases., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Autoimmune factor XIII (FXIII) deficiency (AiF13D) due to anti-FXIII autoantibodies is an extremely rare, life-threatening bleeding disorder that mostly occurs in the elderly. The number of patients diagnosed with AiF13D has been increasing in Japan, probably because of the nationwide survey on AiF13D supported by the Japanese Ministry of Health, Labour and Welfare., Aim: To explore the pathologic characteristics of coagulation parameters in AiF13D., Methods: AiF13D-suspected cases were consulted, and underwent unified/integrated coagulation screening and were definitively diagnosed as AiF13D separately., Results: AiF13D patients had lower FXIII antigen levels than non-AiF13D patients, but their values overlapped. Among a series of 22-item screening tests and their resulting parameters, the 'FXIII inhibitory potential' yielded by a 1:1 mixing test of the patient's and healthy control's plasma and its 'residual FXIII activity' in 54 AiF13D cases were most distinguishable from 139 non-AiF13D cases, followed by FXIII activity per se and FXIII-specific activity. While the cross-linked α 2 -plasmin inhibitor level reduced, the levels of D-dimer, fibrin/fibrinogen degradation products and plasmin-plasmin inhibitor complex increased, probably because the patients' haematoma nonspecifically induced secondary fibrinolysis in both AiF13D and non-AiF13D patients., Conclusion: AiF13D appears to induce a hypocoagulopathy combined with a hyper-fibrinolytic state secondary to severe FXIII deficiency caused by anti-FXIII autoantibodies, and the consequent bleeding further modifies its pathological conditions. In addition, the 1:1 mixing test of FXIII activity was confirmed to be a reliable screening method for AiF13D, especially when its derivative parameter, such as the 'FXIII inhibitory potential' or 'FXIII inhibitory potential ratio', is employed., (© 2021 John Wiley & Sons Ltd.)

Hereditary factor XIII (FXIII) deficiency is a rare autosomal bleeding disorder which can cause life-threatening bleeding. Acquired deficiency can be immune-mediated or due to increased consumption or reduced synthesis. The most commonly used screening test is insensitive, and widely used quantitative assays have analytical limitations. The present study sought to validate Technofluor FXIII Activity, the first isopeptidase-based assay available on a routine coagulation analyser, the Ceveron s100. Linearity was evidenced throughout the measuring range, with correlation coefficients of >0.99, and coefficients of variation for repeatability and reproducibility were <5% and <10%, respectively. A normally distributed reference range of 47.0-135.5 IU/dL was derived from 154 normal donors. Clinical samples with Technofluor FXIII Activity results between 0 and 167.0 IU/dL were assayed with Berichrom ® FXIII Activity, a functional ammonia release assay, and the HemosIL ™ FXIII antigen assay, generating correlations of 0.950 and 0.980, respectively. Experiments with a transglutaminase inhibitor showed that Technofluor FXIII Activity can detect inhibition of enzymatic activity. No interference was exhibited by high levels of haemolysis and lipaemia, and interference by bilirubin was evident at 18 mg/dL, a level commensurate with severe liver disease. Technofluor FXIII Activity is a rapid, accurate and precise assay suitable for routine diagnostic use with fewer interferents than ammonia release FXIII activity assays.

Introduction: Acquired factor XIII (FXIII) inhibitor is a rare but possibly underdiagnosed bleeding disorder. To date, less than one hundred cases have been reported, but the number has increased rapidly in recent years, especially in Japan. Because of the rarity of this disorder, no treatment guidelines are available. In some reports, physicians treated the bleeding with cryoprecipitate or factor XIII concentrate and eradicated the inhibitor with various immune suppressants., Methods: From January 2015 to December 2018, we collected consecutive patients diagnosed as having acquired FXIII inhibitor. FXIII activity and inhibitor were measured by a fluorescent factor XIII assay using isopeptidase reaction catalyzed by activated factor XIII and the Bethesda method, respectively. Factor XIII antigen was measured by latex-enhanced immunoassay., Results: We found five adult patients with detectable FXIII inhibitor. Four of them were older than 70. Two had systemic lupus erythematosus. All the patients presented with ecchymosis and intramuscular hematoma. No life-threatening bleeding was observed. Delayed diagnosis was common with varied time periods needed to achieve a correct diagnosis. All bleedings were treated and improved by cryoprecipitate. Steroids were given to all patients and cyclophosphamide, rituximab, and other immune suppressants were also used. FXIII inhibitor was totally resolved in three, partially resolved in one, and persisted in one patient., Conclusion: We documented five patients with acquired FXIII inhibitor, found over 4 years. The most common presentations were ecchymosis and intramuscular hematomas. Cryoprecipitate was effective in controlling most bleeds. Steroid, cyclophosphamide and rituximab were effective in eradicating inhibitor in some patients., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

A young third gravida was referred with prenatal diagnosis of factor XIII deficiency at 20 weeks of pregnancy for Medical Termination of Pregnancy (MTP). Her first baby, who was born by emergency Lower Segment Caesarean Section (LSCS) for fetal distress, had intracranial haemorrhage in the early neonatal period and was investigated elsewhere and diagnosed to have factor XIII deficiency. The child currently has global developmental delay and cerebral palsy. The mother had a second-degree consanguineous marriage and the couple were diagnosed to be carriers of factor XIII deficiency. She had lot of barriers to get prenatal diagnosis during the second pregnancy and it ended up in Intra Uterine Fetal Death (IUFD) at 27 weeks. During the current pregnancy, prenatal diagnosis (PND) was done only after the second trimester amniocentesis and the genetic mutation was F13 A1, Ex12, C.1687 G>A. Second trimester MTP in a previous scarred uterus was difficult as it is essential to avoid scar rupture. PND during the first trimester is ideal., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Factor XIII (FXIII) deficiency is an extremely rare bleeding disorder that is commonly due to mutations in the FXIIIA subunit gene (F13A1), and it has been reported to have a prevalence of one per 2 million. We describe a new genetic variant in the F13A1 gene that caused a patient to suffer from lifelong hemorrhagic diathesis., Case Presentation: We evaluated a 20-year-old female with umbilical cord bleeding after birth, an intracerebral hemorrhage at age 6, and other bleeding episodes, including hematuria and cephalohematoma, who suffered from a lifelong hemorrhagic diathesis. The clot solubility test showed that the clot of the patient was dissolved in urea solution at 10 h. Genetic testing identified a novel homozygous mutation, c.984C > A(p. Cys328stop), resulting in a premature stop codon in exon 8 of the F13A1 gene. The results obtained with ClusterX software showed that Cys328 of exon 8 in the F13A1 gene is highly conserved among species., Conclusion: We reported a novel homozygous mutation in the F13A1 gene in a factor XIII (FXIII)-deficient patient, which adds a new point mutation to the mutant library. In this paper, we discuss other aspects of the disease, including laboratory examination, homogeneous sequence alignment and molecular modeling.

We report two cases of acquired factor XIII deficiency with bleeding events during veno-venous extracorporeal membrane oxygenation (ECMO). Case 1: A 76-year-old man diagnosed with aspiration pneumonia after near-drowning was started on ECMO. Later, the patient presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 29%. Although the patient recovered after receiving 1200 International Units of factor XIII concentrate, the patient had another episode of decreased factor XIII activity and bloody stool and was treated again with factor XIII concentrate. Case 2: A 48-year-old female diagnosed with pneumonia was started on ECMO. Soon after, she presented with hemoptysis and anemia. Blood tests showed a decreased factor XIII activity of 39%. The patient was treated with 720 IU of factor XIII concentrate with good recovery. Acquired factor XIII deficiency cannot be detected by routine coagulation tests, therefore it may be under-diagnosed in the ICU. Detection of acquired factor XIII deficiency is essential when treating a bleeding ECMO patient.

Background: Factor XIII deficiency is one of the most severe congenital bleeding disorders with high rate of life-threatening bleeding including central nervous system bleeding, umbilical cord bleeding, and recurrent miscarriages. Due to the highest global incidence of the disorder in Iran, this study aimed to design a premarital screening program in Iran., Methods: This descriptive study was performed on 30 couples with a positive family history of factor XIII deficiency. Underling F13A gene mutation was determined in the family members, and all the selected couples underwent molecular testing mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), tetra primer-amplification refractory mutation system-PCR (T-ARMS-PCR), and sequencing., Results: The probability of affected childbirth existed for ten couples. Three couples decided not to marry, while seven got married and three of them decided to have a baby. The genotypes of the fetuses were determined and revealed that none of them was a homozygote for the F13A gene mutation., Conclusions: Because of the importance of factor XIII deficiency diagnosis, it can be helpful to control the incidence of factor XIII deficiency by implementing preventive programs such as premarital screening.

Background/aims: The coagulation system is known to be rebalanced but fragile in stable cirrhosis. Acute kidney injury (AKI) is common in these patients and associated with an increased bleeding risk. We aimed to assess coagulation parameters in this population., Methods: We prospectively enrolled 43 hospitalized patients with decompensated cirrhosis with (n = 22) or without (n = 21) AKI. Coagulation factor levels, viscoelastic coagulation assay, and thrombin generation assay were performed and compared between these groups and a healthy reference group., Results: Conventional markers of coagulation were not statistically different between patients with and without AKI. Factor XIII was significantly reduced in all patients with cirrhosis compared to healthy controls (p = <0.0001). In patients with AKI, factor XIII was significantly lower compared to patients without AKI (AKI 38% vs. non-AKI 60% p = 0.002). In patients with cirrhosis, factor XIII had a significantly positive correlation with EXTEM maximal clot firmness (r = 0.5440, p = 0.0002) and FIBTEM maximal clot firmness (r = 0.7397, p = <0.0001) and a negative correlation with EXTEM clot formation time (-0.413, p = 0.0065)., Conclusions: Factor XIII was significantly reduced in decompensated cirrhosis patients with AKI compared to decompensated patients without AKI. These findings suggest that exacerbation of factor XIII deficiency in AKI in decompensated cirrhosis may affect bleeding risk and warrants further study., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

A 5-year-old girl presented to paediatric emergency with fever and seizures for a short duration. At first, meningitis was suspected and management was started empirically. There was no improvement in the clinical condition of the patient and investigations revealed spontaneous intracranial haemorrhage (ICH) secondary to factor XIII deficiency. The child was transfused cryoprecipitate and managed conservatively for ICH. She became asymptomatic and was kept on monthly cryoprecipitate transfusions. This case report summarises factor XIII deficiency in ICH which was not suspected initially, but diagnosed later on after CT scan head and factor XIII assay. This report also highlights events occurring during its management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

We assessed clinical presentations and the rate of central nervous system (CNS) bleeding in neonates with FXIIID who exhibited bleeding diathesis in the early days of their lives. A total of 27 neonates presented bleeding or abnormal clinical symptoms, diagnosed with FXIII deficiency were evaluated. Factor XIII concentrate was initiated as the first-line of treatment, and prophylactic therapy was given to all patients. Umbilical cord bleeding, delayed detachment of umbilical stunt, seizure, hematoma, and ecchymosis were concurrent complications in 27 (100%), 5 (18.5%), 5 (18.5%), 3 (11.1%), and 1 (3.7%) of the patients, respectively. History of having CNS bleeding was detected in 13 (48.1%) patients. There was no significant association between CNS bleeding and gender, familial history of FXIIID, or other clinical presentations. Also, there was no significant difference in the mean age of the patients who had CNS bleeding (3.4 ± 0.9 days) and without CNS bleeding (2.9 ± 0.7 days). However, a near significant threshold difference between the patients with and without CNS bleeding was found regarding the mean number of suspicious FXIIID death in their family (1.8 ± 0.5 and 0.7 ± 0.1, respectively, P = 0.05). Therefore, a suggested diagnostic algorithm based on prenatal diagnosis could be useful for timely detection of FXIII deficiency in neonates., (Copyright © 2019 Elsevier 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.)

Congenital factor XIII (FXIII) deficiency is an extremely rare hemorrhagic disorder characterized by a deficiency of FXIII and associated with a high rate of morbidity and mortality. The disorder is more frequent in Iran, especially in Khash, a city in the southeast of the country. As identified in the current report, the prevalence of FXIII deficiency in this city is 1 homozygote per approximately 500 population (which is ∼4,000 times higher than the worldwide prevalence) with 3.5% heterozygotes. The disorder is accompanied by a high rate of mortality in rural areas of Khash, given an averaged observed rate of approximately three deaths per each family with FXIII deficiency, mostly due to late-diagnosis and/or misdiagnosis, and fetal consequences of both umbilical cord and central nervous system bleeding. Almost all patients with FXIII deficiency in the southeast Iran have a unique mutation in F13A gene (Trp187Arg), which leads to a severe FXIII deficiency. This mutation is used for pre-marriage and prenatal diagnosis, as well as for carrier detection and diagnostic confirmation. Fibrogammin P has been used worldwide for about one decade, along with different therapeutic regimens for prophylaxis treatment, major and minor surgeries, and successful delivery. Due to the rapid increase in the number of patients identified to have congenital FXIII deficiency, and the high rate of related morbidity and mortality, a comprehensive regional preventive program is necessary to prevent further expansion of this condition and decrease the burden on the health care system. The area of Khash city provides novel insights into severe FXIII deficiency due to its high prevalence in this region. This report also provides a review of FXIII deficiency, its diagnosis, prevalence, molecular basis, clinical manifestations, management, and treatment, with a particular focus on Iran, representing a hotspot for this disorder., Competing Interests: The authors state that they have no conflict of interest., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: Prenatal diagnosis (PND) procedure is urgent to be established for timely management and fatal consequence prevention of factor XIII deficiency (FXIIID), and variations data among Chinese are very scanty. We aimed to find a novel mutation among Chinese and establish a rapid and precise PND procedure with pathogenicity analysis to contribute to the prevention of postpartum hemorrhage in pregnant women and central nervous system bleeding in newborns., Methods: FXIIID was diagnosed by qualitative and quantitative tests of clot solubility test and enzyme-linked immunosorbent assay, respectively. Variations were detected by direct sequencing of F13A and F13B genes in the pedigree and the unborn fetus. Pathogenicity assessment of variations was based on American College of Medical Genetics and Genomics Guidelines., Results: Ten variants in the F13A gene including a novel missense mutation in exon 10, a nonsense mutation in exon 4, a missense mutation in exon 12, 2 missense mutations in exon 14, 3 polymorphisms in intron 10, 2 polymorphisms in intron 14 were detected. Two variants in the F13B gene including a polymorphism in 3'UTR and a synonymous mutation were detected. The compound heterozygous mutations of the nonsense mutation and a novel missense mutation of the F13A gene caused the deficiency in proband, and the fetus which was evaluated to be unaffected by PND was born successfully and the results were verified by follow-up visits., Discussion: We first established the PND procedure with pathogenicity assessment in FXIIID patients. The F13A gene mutations' spectrum of the Chinese Han population was enriched.