Congenital Factor XIII Deficiency Research Articles

A Rare Case of Congenital Factor XIII Deficiency Secondary to Hyperconsumption: A Case Report

A Rare Case of Congenital Factor XIII Deficiency Secondary to Hyperconsumption: A Case Report

PB0234 Comprehensive Evaluation of Coagulation and Fibrinolysis Parameters in Patients with Congenital Factor XIII Deficiency in Pakistan: Case Control Study

PB0234 Comprehensive Evaluation of Coagulation and Fibrinolysis Parameters in Patients with Congenital Factor XIII Deficiency in Pakistan: Case Control Study

Clinical Profile of Congenital Factor XIII Deficiency in Children.

Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5million. The clinical symptomatology, diagnosis, and management of FXIIID are described. 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. 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. 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.

A multicenter, real-world experience with recombinant FXIII for the treatment of patients with FXIII deficiency: from pharmacokinetics to clinical practice. The Italian FXIII Study.

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

The most common disease-causing mutation of factor XIII deficiency is corrected by CRISPR/CAS9 gene editing system.

Factor XIII (FXIII) deficiency is one of the most severe congenital bleeding disorders, with an estimated incidence of one person per one million. Patients with severe FXIII deficiency present a wide range of clinical manifestations, including umbilical cord bleeding, intracranial haemorrhage and recurrent miscarriages. Due to the high rate of life-threatening bleeding, primary prophylaxis is mandatory from the time of diagnosis. Although replacement therapy is the most common therapeutic choice, gene therapy remains the only curative option. In the present study, we assessed the efficacy of the clustered regularly interspaced short palindromic repeats - CRISPR-associated protein 9 (CRISPR/Cas9) system in the correction of the most common FXIII disease-causing mutation (c.562 T > C). A dermal fibroblast was harvested from the human skin biopsy of a young patient with FXIII deficiency. Sanger sequencing was used to confirm the presence of c.562 T>C mutation in the patient and in the harvested fibroblasts. PX459 vector was digested with BbsI restriction enzyme, and after annealing and ligation of two 20-bp guide-RNAs (g-RNAs) close to the PAM (NGG) sequence, the constructed vectors were amplified in Escherichia coli Top 10. Transfection was performed by a nucleofector device, and DNA extraction was performed after puromycin selection and serial dilution from potentially transfected colonies. A 50-bp template oligonucleotide was used to aid homologous repair for correction of the underlying mutation and synonymous mutation as an internal control. The synonymous mutation (AAT to ACT) near the mutation site was used as internal control. Sanger sequencing was done in order to check the gene correction. The c.562 T > C mutation was detected in homozygote state in the primary fibroblasts of the patient and wild-type alleles were confirmed in the normal individual. Colony PCR and sequencing revealed successful cloning of the designed gRNAs. The detected mutation was corrected from a homozygote mutant state (c.562 T > C) to a homozygote wild type in transfected dermal fibroblasts of the patient. The control mutation, as an internal control, was also corrected in the same fibroblasts in the heterozygote manner. The result of the study shows that the CRISPR/CAS9 gene editing system is an effective tool for correction of point mutations in transfected fibroblasts of patients with congenital FXIII deficiency and represents a new, potentially curative, option.

Safety and effectiveness of recombinant factor XIII‐A2 in congenital factor XIII deficiency: Real‐world evidence

BackgroundRegular factor XIII (FXIII) prophylaxis is standard treatment for congenital FXIII A‐subunit deficiency (FXIII‐A CD). Recombinant factor XIII‐A2 (rFXIII‐A2) was extensively evaluated in the mentor trials. ObjectiveTo assess real‐world safety and treatment effectiveness of rFXIII‐A2 prophylaxis from the mentor 6 trial. Patients/Methodsmentor 6 was a noninterventional, postauthorization safety study investigating rFXIII‐A2 prophylaxis in FXIII‐A CD. rFXIII‐A2 treatment was observed for 2 to 6 years per patient. The primary end point was documentation of adverse drug reactions (including anti‐FXIII antibody development). Secondary end points were serious adverse events (SAEs), medical events of special interest (MESIs), and annualized bleeding rate (ABR). ResultsAmong 30 patients (mean age, 25.5 years), there were 44 adverse events (AEs) (30 mild, 13 moderate, 1 severe). Eleven AEs were possibly/probably related to rFXIII‐A2. Of four MESIs, two were unlikely related to rFXIII‐A2 (accidental overdose, deep vein thrombosis), and two were possibly/probably related (nonneutralizing anti‐FXIII antibody, decreased therapeutic response). All 10 SAEs were unlikely related to rFXIII‐A2. Over a follow‐up of 75.4 patient‐years, there were six treatment‐requiring bleeds (all trauma‐related with no spontaneous bleeds), giving a treatment‐requiring ABR of 0.066; five bleeds were treated successfully with rFXIII‐A2. Eight of nine minor surgeries performed during rFXIII‐A2 prophylaxis reported successful hemostatic outcomes (one missing evaluation). ConclusionsThese data confirm that rFXIII‐A2 prophylaxis is well tolerated as long‐term care. There were no spontaneous bleeds, ABR was low, and rFXIII‐A2 successfully treated bleeds in patients receiving rFXIII‐A2 prophylaxis.

Noninvasive prenatal diagnosis of congenital factor XIII deficiency in Iran

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.

Factor XIII and surgical bleeding.

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.

Clinical profile of congenital factor XIII deficiency in children: Experience from a tertiary care centre in South India

Clinical profile of congenital factor XIII deficiency in children: Experience from a tertiary care centre in South India

A CASE REPORT WITH SEVERE CONGENITAL FACTOR XIII DEFICIENCY AND AN UNCOMPLICATED PREGNANCY AND BIRTH PROCESS

Factor XIII deficiency is an extremely rare type among bleeding diathesis. In factor XIII deficiency, normal results of coagulation screening tests are expected. It usually does not cause spontaneous bleeding. Apart from bleeding diathesis, it may cause delayed wound healing and recurrent spontaneous abortions in women. Here, we present a 32-year-old case with severe congenital factor XIII deficiency who had an uncomplicated pregnancy and birth with regular replacement therapies. A 32-year-old patient with severe congenital factor XIII deficiency, who had a history of spontaneous abortion at the 11th week of her first pregnancy, applied to our center with a request for childbirth. It was learned that the factor XIII levels of the patient could not be measured, that she was using plasma-derived FXIII concentrate at a dose of 25 units/kg every time once a month, and in cases where this could not be obtained, 5 units/kg cryoprecipitate was given instead. After the completion of the pre-pregnancy assessments, starting 3 months before the planned pregnancy and continuing for the whole pregnancy and for 3 months after birth, 25 units/kg plasma-derived concentrate at a dose of 25 units/kg was applied each time and every two weeks, and in cases where this could not be provided, the follow-up was continued by applying cryoprecipitate at a dose of 5 units / kg instead. During this whole process, FXIII levels ranged between 70% and 100%. The patient, who developed an abortion risk due to decidual bleeding in the first trimester, was hospitalized and an additional 25 units / kg plasma-derived FXIII concentrate was administered and a parenteral dose of 30 mg / kg tranexamic acid was applied until the signs of decidual bleeding disappeared. An additional 50 units/kg dose of plasma-derived FXIII concentrate was administered to the patient 30 minutes before birth who had a planned delivery by cesarean section at 38 weeks of gestation, and 30 mg/kg parenteral tranexamic acid was administered for 7 days following the delivery. FXIII level was detected 50% in the child of a healthy, 3500-g born boy. The patient and her baby, who are in the first year after birth, are followed up without any complications, and prophylactic plasma-derived FXIII concentrate or cryoprecipitate is administered to the patient once a month. Inherited bleeding diathesis lead to an increased risk of bleeding and abortion in obstetric patients. Factor XIII deficiency is an extremely rare type among them. FXIII has a role in angiogenesis as well as hemostasis. Therefore, wound healing and tissue repair are impaired in Factor XIII deficiency. The risk of premature separation of the placenta, miscarriage especially in the first trimester, and postpartum uterine bleeding are increased in FXIII deficiency. Tranexamic acid can be used safely in obstetric patients with bleeding diathesis. It may be possible to ensure that patients with factor XIII deficiency have an uncomplicated pregnancy and delivery with regular follow-ups, regular prophylactic factor preparations, plasma replacements if they are not found, and in cases of bleeding, with additional doses of factor preparations or plasma replacement applications with tranexamic acid.

Congenital Coagulation Factor XIII Deficiency Revealed by Convulsion: A Case Report

Factor XIII deficiency is a rare inherited disease, with a particularly high risk of intracerebral hemorrhage. We report the case of a newborn who was suspected to have a coagulation disorder at birth, due to an intracerebral hemorrhage. A quantitative dosage of factor XIII was requested but the usual coagulation tests (thromboplastin, thrombokinase, fibrinogen) were normal. Because of unavailability of specific treatment with factor XIII concentrate, the patient was treated with fresh frozen plasma. The initial dose was for normalizing factor XIII; subsequent monthly doses were designed for preventing the occurrence of serious bleeding.

A Large Case Series on Surgical Outcomes in Congenital FXIII Deficiency Patients in Iran

BackgroundFXIII requires low plasma FXIII levels for normal hemostasis. The lack of accepted standardized surgical guidelines necessitates dependence on the treating physicians' and centers' experiences.AimOur aim is to evaluate surgical outcomes on a large group of congenital FXIII deficiency (FXIIID) patients.MethodsA case series study was conducted on congenital FXIIID patients in two major referral centers located in Iran from 2010 to 2016. All patients were on prophylaxis using plasma factor XIII concentrate (10 U kg−1, every 28 days) except three patients prior to surgery. One single dose of 10 U kg−1 and 30 U kg−1 plasma factor XIII concentrate before a minor procedure and circumcision were given, respectively. Two doses of plasma factor XIII concentrate, one 30 U kg−1 prior to the procedure and the second dose of 30 U kg−1 on post-operative day 3, were given for major surgery. The plasma factor XIII concentrate dose was 50 U kg−1 both before and after the procedure for neurosurgery.ResultsOne hundred sixty-two FXIIID patients underwent minor, major and obstetrical and gynecological surgeries. The median age of the patients was 14 years (ages ranged 15 days to 47 years). The male-to-female ratio was 89/73. Five post-operative complications, two bleeding and three thrombosis, were recorded for two patients who were undiagnosed prior to surgery.ConclusionOur study showed excellent hemostasis in FXIIID patients undergoing surgeries. Of these surgeries, we observed only 1.8% post-operative complications. Surgery can be performed safely in FXIIID patients, and the proposed treatment regimens lead to adequate hemostatic coverage with minimal risk for both minor and major surgeries. DisclosuresPeyvandi:Freeline, Kedrion, LFB, Octapharma: Consultancy; Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau.

Expression and methylation status of vascular endothelial growth factor and thrombospondin-1 genes in congenital factor XIII-deficient patients with intracranial hemorrhage.

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

Congenital factor XIII deficiency in Iraq: An 8-year single-center study

BACKGROUND: Congenital FXIII deficiency is a rare genetic bleeding disorder that is inherited in an autosomal recessive pattern with a frequency of 1/2 million individuals in the human population. Deficiency of FXIII is associated with significant bleeding disorders.AIMS: This study aimed to evaluate the demographic parameters, clinical presentations, and outcome of patients who were diagnosed with congenital factor XIII deficiency.SUBJECTS AND METHODS: A retrospective descriptive study of patients who were diagnosed with congenital FXIII deficiency over a period from August 2008 to August 2016 was conducted. The study included patients who were diagnosed by having bleeding tendency and normal standard coagulation tests (normal platelet count, normal prothrombin time; normal partial thromboplastin time, and normal bleeding time) and the diagnosis was confirmed by clot solubility test in 5M urea. The diagnosis was made in the Hemophilia Ward, Children Welfare Teaching Hospital, Medical City, Baghdad.RESULTS: There were 111 cases of other coagulation factors' deficiency (rare bleeding disorders) registered in the center, congenital FXIII deficiency represented 24 (22%) of them. Males represented 14 (58.3%) and females 10 (41.7%) of patients. Most of the patients (41.7%) had their symptoms during the 1st year of life. Positive consanguinity was found in 100% of patients and 14 (58.3%) patients had a family history of FXIII deficiency. Umbilical cord bleeding and gum bleeding were present in 37.5% and 20.8%, respectively, and they were the most common first presenting symptoms of FXIII-deficient patients, while muscle hematoma (28.5%) and joint bleeding (24.7%) were the most common presenting symptoms in follow-up visits. The majority of the patients (79.1%) did not develop complications, the complications were developed in 3 (12.4%) patients, which were intracranial bleeding in 2 (8.3%) patients and liver hematoma in 1 (4.1%) patient. One patient (4.1%) developed recurrent abortion and one patient (4.1%) developed hepatitis C. No death was reported during the study period.CONCLUSIONS: FXIII deficiency founded to be a more common rare bleeding disorder among Iraqi patients, with a high rate of consanguineous marriage. Umbilical cord bleeding and gum bleeding were the most common presenting symptoms for FXIII deficiency. There was a considerable delay in the diagnosis of FXIII deficiency in the majority of patients.

How to Assess Founder Effect in Patients with Congenital Factor XIII Deficiency.

Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with estimated prevalence of one per 2 million in the general population. The disorder causes different clinical manifestations such as intracranial hemorrhage (ICH), recurrent miscarriage, umbilical cord bleeding, etc. High incidence of the disorder might be due to founder effect. To assess founder effect, haplotype analysis is an important step. For this purpose, suitable and reliable genetic markers such as microsatellites (Hum FXIIIA01 and HumFXIIIA02) and single nucleotide polymorphisms (SNP) are suggested. In the present study we tried to describe evaluation of founder effect in patients with congenital FXIII deficiency via haplotype analysis using suitable genetic markers.

Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency

IntroductionCongenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations. MethodsWe conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity <10 IU dL−1 were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded. ResultsAmong 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0–35), and at inclusion it was 30 years (range: 15–63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution. ConclusionAltogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines.

Novel deep intronic mutation in the coagulation factor XIII a chain gene leading to unexpected RNA splicing in a patient with factor XIII deficiency

BackgroundCoagulation factor XIII (FXIII) plays an essential role in maintaining hemostasis by crosslinking fibrin. Deficiency in FXIII affects clot stability and increases the risk of severe bleeding. Congenital FXIII deficiency is a rare disease. Recently, we identified a Chinese family with FXIII deficiency and investigated the pathogenesis of congenital FXIII deficiency, contributing non-coding pathogenic variants.MethodsWe performed common tests, coding sequencing by targeted next-generation sequencing (NGS), whole-genome sequencing and splice-sites prediction algorithms. The pathogenesis was investigated via minigene and nonsense-mediated mRNA decay (NMD) by experiments in vitro.ResultsThe proband is homozygote for a novel deep intronic c.799-12G > A mutation in the F13A1 gene. Through direct sequencing of the minigenes mRNA, we found 10 bases of intron 6 insert in the mRNA of mutant minigenes mRNA. The relative expression of EGFP-F13A1 was higher by suppression of NMD in vitro. Furthermore, we found the proband with enhanced thrombin generation (TG).ConclusionWe reported a novel deep intronic c.799-12G > A mutation of F13A1 which produced a new acceptor site and frame shifting during translation introducing a premature termination codon. Our results support the premature termination codon triggered NMD. We need to pay attention to the position of potential alterable splicing sites while counselling and genetic test. The finding of enhanced TG indicated that we should be aware of the risk of thrombosis in patients with FXIII deficiency during replacement therapy.

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.

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

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.