Factor XIII Deficiency Research Articles

Premarital Screening Program for Congenital Factor XIII Deficiency in Iran.

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. 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. 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. 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.

A dialysis patient who was successfully treated with recombinant thrombomodulin and tranexamic acid for various bleeding symptoms due to chronic DIC associated with an aortic aneurysm and secondary factor XIII deficiency

A dialysis patient who was successfully treated with recombinant thrombomodulin and tranexamic acid for various bleeding symptoms due to chronic DIC associated with an aortic aneurysm and secondary factor XIII deficiency

Acquired coagulation disorders

Acquired coagulation inhibitors have become a popular area of research because they cause severe bleeding tendency in many patients. The use of acquired coagulation inhibitors requires rapid and precise diagnosis. Some acquired coagulation inhibitors show prolongation in the activated partial thromboplastin time (APTT) and/or prothrombin time (PT). To diagnose these disorders, mixing test is very useful. However, lupus anticoagulant related disorders, such as lupus anticoagulant hypoprothrombinemia syndrome (LAHPS), are difficult to diagnose because they are sometimes associated with a reduction in factor VIII and are thus difficult to distinguish from acquired hemophilia. Acquired factor XIII deficiency and acquired von Willebrand syndrome (AvWS) are easily overlooked because they show normal value in several patients with APTT and PT. Here I describe the diagnostic method for these disorders. In particular, five acquired coagulation inhibitors that appear to be clinically significant are studied.

Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

Background and aimsTransglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. MethodsAtherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. ResultsNo difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. ConclusionsThese studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition.

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.

PP-119 - Congenital factor XIII deficiency with the presence of inhibitor: a case report

PP-119 - Congenital factor XIII deficiency with the presence of inhibitor: a case report

Potential of the Community Counts registry to characterize rare bleeding disorders.

Rare bleeding disorders (RBDs) comprise of heterogeneous coagulation factor deficiencies and platelet disorders that are underreported worldwide. First report on RBD data from United States haemophilia treatment center network (USHTCN). A national surveillance system for the federally recognized USHTCN developed in collaboration with the Centers for Disease Control and Prevention (CDC) and American Thrombosis and Haemostasis Network (ATHN) was queried for patients with RBDs. Patient counts were extracted from the HTC Population Profile (HTC PP) component including limited data on patients followed through the USHTCN, and from the Registry component, including patient authorized, detailed clinical data. The prevalence of RBDs in the United States was estimated based on the HTC PP data and compared to the expected national prevalence based on data extrapolated from Orphanet, an international registry. Based on the estimated prevalence of RBD in the overall 2017 US population, the cases in the HTC network were lower than expected for FI, FII, FX, and FV+FVIII deficiencies by 36%, 61%, 75% and 94%, respectively, and higher than expected for FXIII, FV, FVII, and FXI deficiencies by 7%, 14%, 33% and 185%, respectively. The proportion of RBD patients reported in the HTC PP, enrolled in the Registry, was 10.8%. There is a clear need to identify individuals with RBDs who could benefit from the comprehensive care provided in the USHTCN. In addition, increased enrolment of people with all RBDs in the Registry is needed to improve knowledge of treatment outcomes of patients with RBDs in the United States.

Clinical and laboratory diagnosis of rare coagulation disorders (RCDs)

Rare coagulation disorders (RCDs) are a group of diseases due to coagulation factors deficiency leading to life-long bleeding diathesis. The diagnosis of RCDs is challenging due to the limited knowledge of these disorders and the large heterogeneity of their bleeding patterns. The clinical symptoms of RCDs are extremely diverse in terms of bleeding type, site, severity, age at onset, and duration. The strength of the association between clotting factor activity level in plasma and clinical symptoms is also variable within each RCD.The clinical evaluation of RCDs starts with a detailed collection of clinical history and has been facilitated by bleeding assessment tools, however their effectiveness in diagnosing RCDs requires further investigation. The following laboratory diagnosis of RCDs involves coagulation screening tests, including activated partial thromboplastin time, prothrombin time, and thrombin time. After ruling out the presence of an inhibitor by mixing studies, in case of abnormal results, the specific deficiency is identified by performing one-stage clotting assays using the specific factor-depleted plasmas as substrate. In fibrinogen and FXIII deficiencies coagulation screening tests are not informative, therefore additional tests are needed. Global assays have been developed and are thought to aid in patient management, however, they are not well standardized yet.In addition to outlining the principles of clinical and laboratory diagnosis, this review explores molecular basis of RCDs and laboratory techniques for genetic analysis, and discusses the importance and effectiveness of quality control programs to ensure standardized laboratory results.

Rare clotting factor deficiency among Sudanese children.

: Rare clotting factor (F) deficiency is a deficiency of one or more of coagulation factors other than FVIII, FIX and vonWillebrand (FI, FII, FV, FV + FVIII, FVII, FIX, FX, FXI and FXIII) that cause bleeding disorders and are inherited as autosomal recessive. Descriptive study was conducted in Hemophilia Centre, Khartoum, Sudan. The medical files of pediatric patients presented to the center were reviewed retrospectively. Forty-seven patients (male : female ratio = 1.2 : 1) were included. The majority (93.6%) have parental history of consanguinity and around one third (31.9%) have family history of bleeding disorder. FV deficiency was the most common deficient factor (36.2%) followed by FI deficiency (23.4%) and FX111 deficiency (21.3%). Bruising (46.8%) and epistaxis (25.5%) were the most common presenting complains. FV deficiency mainly presented with cutaneous ecchymosis (47.1%). FI deficiency presented with umbilical bleeding (45.5%) and FXIII presented with cutaneous ecchymosis (50%). Rare clotting factor deficiency is an existing disease in Sudan with the male : female ratio was 1.2 : 1. FV deficiency, FI deficiency, FXIII deficiency were the common deficiency encountered.

Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort.

This FranceCoag network study assessed 33 patients with congenital factor XIII (FXIII) deficiency presenting FXIII levels <10iu/dl. Diagnosis was based on abnormal bleeding in 29 patients, a positive family history in 2, recurrent miscarriages in 1 and was fortuitous in 1. Eighteen patients (62·1%) presented life-threatening umbilical or intracranial haemorrhages (ICH). Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae. All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis. In patients exhibiting FXIII levels <10iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed.

Phenotype and genotype of FXIII deficiency in two unrelated probands: identification of a novel F13A1 large deletion mediated by complex rearrangement

BackgroundInherited Factor XIII deficiency (FXIIID) is one of the most severe and under-diagnosed rare bleeding disorders. Only 5 large deletions involving one or more exons in F13A1 have been reported, and lacking of multiplex ligation-dependent probe amplification (MLPA) assay might underestimate the copy number variations (CNVs) in F13A1 and F13B. We had characterized the clinical presentation of two unrelated severe FXIIID probands and explored the pathogenic mechanisms.ResultsBoth probands experienced several episodes of fatal bleeding and delayed wound healings prior to diagnosis. FXIII activity was measured by the ammonia release assay, and FXIII-A and FXIII-B antigens were determined by ELISA. All the exons including exon-intron boundaries and promoter regions of F13A1 and F13B were amplified and directly sequenced. Copy number variations (CNVs) of F13A1 and F13B were detected by the CNVplex® method. Breakpoints of the F13A1 large deletion were identified by quantitative primer walking combined long-range PCR (LR-PCR) strategies. Proband 1 was found to have compound heterozygous mutations of a novel small deletion (c.1147del) and a missense mutation p.Arg383Ser. Proband 2 was compound heterozygous for a novel large deletion (g.[77815_112815del;112837_116628del]) and a missense mutation p.Arg716Gly in F13A1. Bioinformatics analysis of the large deletion breakpoints predicted that two fork stalling and template switching and/or microhomology-mediated break-induced replication (FoSTeS/MMBIR) events with two homologies of TCT and C might be responsible for the complex rearrangement. Prophylactic replacement therapy was immediately administered for the two probands upon establishment of the diagnosis.ConclusionsWe detected two type I FXIIID pedigrees and adopted CNVplex® method to detect CNVs of F13A1 and F13B for the first time. A large heterozygous deletion of g.[77815_112815del;112837_116628del] in F13A1, mediated by two FoSTeS/MMBIR events, was identified.

A Case Presenting Massive Umbilical Hemorrhage with Previously Unrecognized Factor XIII Subunit A Mutation (Factor XIII A1 gene; NM_000129.3 c.1817_1817delA (p.H606Pfs*23) (p.His606Profs*23, homozygous)

ABSTRACT Congenital factor XIII deficiency is an autosomal recessive inheritance bleeding disorder. Usually, the cause of this disease is deficiency of factor XIII subunit A protein in plasma. Some symptoms of the disease support that the clinical suspicions related to FXIII deficiency. For example; prolonged umbilical cord bleeding which is started in the newborn period. Diagnose of Factor XIII deficiency is difficult, on the other hand it has important therapeutic implications. When cryoprecipitate or plasma-derived factor XIII concentrate is used prophylactically, the prognosis of the disease will be good. We report here a case related to factor XIII deficiency with presented a massive umbilical cord bleeding as the first manifestation of factor XIII deficiency. The patient was managed successfully with cryoprecipitate, fresh frozen plasma transfusion and supportive treatments.

Correlation of bleeding score with frequency and severity of bleeding symptoms in FXIII deficiency assessing by the ISTH Bleeding Assessment Tool

ObjectivesThe ISTH bleeding assessment tool (ISTH-BAT) is developed for standardization of bleeding symptoms in bleeding disorders. The aim of this study is to apply this bleeding score for FXIII deficient patients and its relation to the frequency and severity of symptoms. MethodsIn this cross-sectional study, 63 patients with severe FXIII deficiency were evaluated for the assessment of bleeding score according to the standard ISTH-BAT questionnaire. All patients were registered at two major thrombosis and hemostasis centers in Iran affiliated to Zahedan University of medical sciences (50 patients) and Shiraz University of medical sciences (13 patients). ResultsSignificant correlations between the bleeding score and number of symptoms (r = 0.668, P < 0.001) and with a number of severe symptoms (r = 0.938, P < 0.001) were detected. There was no significant relationship between the mean bleeding score and CNS bleeding (P = 0.390). ConclusionThe ISTH-BAT score is an acceptable bleeding assessment tool for standardization and evaluation of patients with FXIII deficiency.

Factor XII deficiency is common in domestic cats and associated with two high frequency F12 mutations

Factor XII (FXII) is a coagulation protein that initiates surface-activation of the coagulation cascade in vitro. The protein's in vivo role, however, remains poorly defined. Factor XII deficiency, or Hageman trait, is a rare hereditary disorder that is not associated with bleeding, and wide variations in FXII activity (FXII:C) exist among healthy people. While FXII-deficient knockout mice appear to be resistant to arterial thrombosis, human F12 polymorphisms that influence FXII:C have not been associated with thrombotic risk in population surveys. Factor XII deficiency is a naturally occurring hereditary trait in domestic cats. We undertook phenotypic and genotypic analyses of FXII-deficient cats for comparative studies with the human disease counterpart. A retrospective review of feline submissions to our laboratory revealed that FXII deficiency is common in domestic cats, and also present in many different breeds. The trait has a geographic bias toward the Midwestern United States. Clinical history, coagulation assays, and samples for F12 sequencing were obtained from 26 FXII deficient cats. None of the cats had experienced abnormal bleeding and their residual FXII:C was related to F12 mutation number and mutation-type. We found 2 high frequency F12 mutations: an exon 13 missense mutation (c.1631G > C) and an exon 11 deletion mutation (c.1321delC), and additional sequence variants throughout the gene. Factor XII deficiency in pet cat populations provides an animal model system to help clarify the biologic actions and clinical relevance of FXII protein.

Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder.

Congenital FXIII deficiency is a rare bleeding disorder in which mutations are detected in F13A1 and F13B genes that express the two subunits of coagulation FXIII, the catalytic FXIII-A, and protective FXIII-B. Mutations in FXIII-B subunit are considerably rarer compared to FXIII-A. Three mutations in the F13B gene have been reported on its structural disulfide bonds. In the present study, we investigate the structural and functional importance of all 20 structural disulfide bonds in FXIII-B subunit. All disulfide bonds were ablated by individually mutating one of its contributory cysteine’s, and these variants were transiently expressed in HEK293t cell lines. The expression products were studied for stability, secretion, the effect on oligomeric state, and on FXIII-A activation. The structural flexibility of these disulfide bonds was studied using classical MD simulation performed on a FXIII-B subunit monomer model. All 20 FXIII-B were found to be important for the secretion and stability of the protein since ablation of any of these led to a secretion deficit. However, the degree of effect that the disruption of disulfide bond had on the protein differed between individual disulfide bonds reflecting a functional hierarchy/diversity within these disulfide bonds.

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 ± 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.

Acute kidney injury is associated with low factor XIII in decompensated cirrhosis

Background/aimsThe 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. MethodsWe 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. ResultsConventional 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). ConclusionsFactor 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.

Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency

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_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_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.

Use of Catridecacog in a patient with severe Factor XIII deficiency undergoing surgery.

Despite many articles regarding the antihemorrhagic treatment and prophylaxis, there is a lack of experience about how to best conduct major surgical procedures in patients with congenital factor XIII (FXIII) deficiency.Here we report a case of surgery (right inguinal hernia, complicated by heaviness and pain) performed in a patient with FXIII deficiency, receiving recombinant FXIII prophylaxis (Catridecacog 35 UI/kg every 28±2 days). Our experience shows that Catridecacog can be used safely and effectively not only for continued prophylaxis but also in surgery and adds to the very limited body of evidence currently available on surgery in this bleeding disorder.

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.