The History of Factor XIII Deficiency.

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.

Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

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.

[A Case of Autoimmune Acquired Factor XIII Deficiency Diagnosed from Recurrent Postoperative Bleeding].

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.

[Autoimmune acquired coagulation factor XIII/13 deficiency caused by type Ab anti-FXIII-A autoantibody].

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 α2-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.

The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

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.

Transient Platelet Dysfunction in Congenital Factor XIII Deficiency with Enhanced Thrombin Generation Potential.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with defects in the F13A1 or F13B genes. Here, we report a case of congenital FXIII deficiency patient who presented with trauma-induced intramuscular hemorrhage accompanied with transient platelet dysfunction with increased endogenous thrombin potential (ETP). METHODS: FXIII antigen and activity, F13A1 gene sequencing, and thrombin generation assay were measured. RESULTS: The diagnosis of FXIII deficiency was confirmed by a double heterozygous mutation of the F13A1 gene and decreased levels of FXIII antigen and activity. Platelet dysfunction caused by an antiplatelet drug was revealed in both platelet aggregation test and PFA-100. After a bleeding event, the PFA-100 results returned to normal and the thrombin generation assay in patient's plasma showed a higher ETP than normal. CONCLUSIONS: This increase in ETP may protect against bleeding and may explain why some patients show only a mild bleeding tendency despite undetectable FXIII activity.

Pathological coagulation parameters in as many as 54 patients with autoimmune acquired factor XIII deficiency due to anti-factor XIII autoantibodies.

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 α2 -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.

Acquired FXIII inhibitor: Patient characteristics and treatment outcome, a case series in Taiwan.

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.

Clinical Validation of an Automated Fluorogenic Factor XIII Activity Assay Based on Isopeptidase Activity.

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.

A novel Cys328-terminator mutant implicated in severe coagulation factor XIII deficiency: a case report.

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.

Premarital Screening Program for Congenital Factor XIII Deficiency in Iran.

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.

Acquired factor XIII deficiency in two patients with bleeding events during veno-venous extracorporeal membrane oxygenation treatment.

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.

A retrospective study on clinical manifestations of neonates with FXIII-A deficiency.

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 ±â€¯0.9 days) and without CNS bleeding (2.9 ±â€¯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 ±â€¯0.5 and 0.7 ±â€¯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.

A Unique Factor XIII Mutation in Southeastern Iran with an Unexpectedly High Prevalence: Khash Factor XIII.

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.

Acquired Factor Xiii Deficiency: An Uncommon But Easily Missed Cause Of Severe Bleeding

Factor XIII (FXIII) is a plasma clotting protein involved in clot stabilization. Severe FXIII deficiency may present with severe, even fatal bleeding. Critically however, routine coagulation assays may be normal and only specific FXIII assays will detect the abnormality. Herein we discuss a case report of a patient with acquired FXIII deficiency in order to highlight the clinical challenges associated with establishing the diagnosis and discuss the treatment approach. A 70-year-old man presented with a gluteal haematoma despite no preceding personal history of bleeding. Extensive initial haemostatic investigations were normal until a specific FXIII assay showed a marked reduction in FXIII levels. With directed treatment, bleeding episodes ceased and remission was achieved. Clinical awareness of FXIII deficiency is important, so appropriate testing can be implemented in patients with unexplained bleeding diatheses, particularly those in whom bleeding responds poorly to standard replacement therapy.

Rotational thromboelastometry can detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis.

BACKGROUND & AIMS: Patients with progressive liver disease exhibit complex coagulation disorders. Factor XIII plays a crucial role in the last steps of haemostasis, and its deficiency is associated with an increased incidence of bleeding diathesis. However, current conventional coagulation tests cannot detect factor XIII deficiency. In this study, we examined factor XIII activity and the ability of rotational thromboelastometry to detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis. METHODS: We retrospectively studied 74 patients with cirrhosis, comparing the results of conventional coagulation tests (international normalized ratio, activated partial thromboplastin time, platelet count, fibrinogen level), rotational thromboelastometry, factor XIII activity and clinical scores. RESULTS: Patients with cirrhosis exhibited reduced factor XIII activity. Factor XIII activity was positively correlated with conventional coagulation parameters and rotational thromboelastometry values, such as maximum clot formation (MCF)extem (r=.48, P<.0001) and MCFfibtem (r=.60, P<.0001). However, maximum lysis (ML)extem and MLaptem were not correlated with factor XIII activity. Three-month mortality rates (P=.0469) and bleeding complications (P<.0001) were significantly associated with lower factor XIII activity. Patients with haemorrhage exhibited significantly altered rotational thromboelastometry values. CONCLUSIONS: Reduced levels of MCFextem and MCFfibtem but not high levels of MLextem and MLaptem are associated with factor XIII deficiency in patients with liver disease. Therefore, substituting factor XIII should be considered for such patients to strengthen clot formation in patients experiencing haemorrhage or those who have undergone interventions.

Lobar Hemorrhage Induced by Acquired Factor XIII Deficiency in a Patient with Cerebral Amyloid Angiopathy.

A 68-year-old man presented with intracranial hemorrhage in the right frontal lobe, which rapidly increased the day after admission. We performed hematoma removal with a biopsy of the cortex around the hematoma. The day after the operation, a subcutaneous hematoma over the craniotomy appeared, and the computed tomography showed a recurrent hemorrhage with an acute subdural hematoma. We were aware of a bleeding tendency, and a detailed hematologic examination by hematologists revealed autoimmune acquired factor XIII deficiency due to an antifactor XIII antibody. Specimens taken around the hematomas were pathologically diagnosed as cerebral amyloid angiopathy (CAA) on immunohistochemical examination. We considered that acquired factor XIII deficiency had induced lobar hemorrhage in the frontal lobe affected with CAA, and the coagulation disorder induced postoperative rebleeding. The patient died from repeated lobar hemorrhage 3 years after the surgery. There is no routine screening coagulation test including the active partial thromboplastin time and the prothrombin time for factor XIII deficiency. It is important for neurologists and neurosurgeons to be aware of this rare disease in patients with a bleeding tendency.

Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy.

BACKGROUND: The influence of decreased factor XIII (FXIII) activity on perioperative bleeding has been reported in some surgical procedures. The purposes of this study were to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify the effects of low preoperative FXIII activity on intraoperative bleeding and postoperative complications. METHODS: Total of 43 patients who underwent a pancreatoduodenectomy were enrolled. The perioperative FXIII activities were measured, and their associations with intraoperative bleeding and postoperative outcomes were analyzed. RESULTS: Fifteen patients (35%) had low FXIII activities (<70%, lower than the institutional normal range). The patients with preoperative FXIII activities <70% experienced significantly greater blood loss (median, 1309 mL) during surgery compared to those with FXIII levels of ≥70% (median, 710 mL) (p = 0.001). The postoperative morbidity rates, including pancreatic fistula, were comparable between the patients with FXIII activities <70% and those with FXIII activities ≥70%. The FXIII levels substantially decreased on postoperative day 1 and remained at low levels until postoperative day 7. CONCLUSION: Unexpectedly high proportions of patients undergoing pancreatoduodenectomy had low preoperative FXIII activities. Preoperative FXIII deficiency may increase intraoperative bleeding but had no influence on the postoperative outcomes.

Genetic basis of severe factor XIII deficiency in a large cohort of Indian patients: Identification of fourteen novel mutations.

Congenital factor XIII (FXIII) deficiency, the most under diagnosed disorder is caused mainly due to underlying defects in the catalytic A subunit of FXIII. More than 100 mutations throughout the factor XIII A gene (F13A1) have been identified so far. Present study aims to characterize the molecular basis of severe congenital FXIII deficiency in a large series of patients from different parts of India. F13A1 defects were identified in 37 severe FXIII deficient unrelated Indian patients by direct DNA sequencing. 25 mutations were detected, of which 10 were missense, 9 nonsense, 3 splice site and 3 deletions; 14 were novel. This is the largest series of FXIII deficient cases reported from India in which mutations were analysed with high heterogeneity in the nature of mutations along with several common mutations.