Clinical Profile of Congenital Factor XIII Deficiency in Children.

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.

Acquired FXIII Deficiency is Associated with High Morbidity.

BACKGROUND: A factor XIII (FXIII) level >30% is considered necessary to prevent spontaneous bleeding. Bleeding is also a risk in patients with acquired FXIII deficiency, but the hemostatic level of FXIII in this context remains to be determined. METHODS: We retrospectively analyzed all patients diagnosed with acquired FXIII deficiency at a large hospital over 3 years (study ID NCT04416594, http://www.clinicaltrials.gov) and assessed clinical data to identify the best cut-off point for FXIII activity to distinguish between low and high risk of major bleeding in a mixed medical and surgical population. RESULTS: Of the 97 patients who experienced bleeding despite a normal coagulation test, 43.2% had FXIII activity <70%. FXIII activity was significantly lower in surgical patients and patients admitted to the intensive care unit (ICU). Low FXIII activity was significantly associated with long ICU stays and a high incidence of major bleeding. CONCLUSION: Acquired FXIII deficiency is associated with high morbidity. The hemostatic level of FXIII in the setting of acquired FXIII deficiency might be above 30%.

Factor XIII deficiency in two Spanish families with a novel variant in gene F13A1 detected by next-generation sequencing; symptoms and clinical management.

Coagulation factor XIII (FXIII) has a major role in coagulation stabilizing the haemostatic clot. FXIII deficiency is associated with an increased risk of bleeding. Severe phenotypes lead to spontaneous, traumatic and surgical bleeding. Umbilical cord bleeding is especially common, and intracranial bleeding may occur in up to one third of patients without prophylaxis. In this work, we used NGS for screening all the coding and intronic boundary regions of F13A1 and F13B genes in two families affected by severe FXIII deficiency. Outcome confirmation analysis and variant studies in related patients was done by Sanger sequencing. Two variants were found: c.34A > G (p.Arg12Gly; NM_00129.3) and c.514C > T (p.Arg172Ter; NM_00129.3), both located in the F13A1 gene. The variant p.Arg172Ter is already described in literature and was found in homozygosis in one family and in compound heterozygosis in the other family. The variant p.Arg12Gly variant has not been described previously. This variant is located in the activation peptide of the FXIII A-subunit which is highly conserved among FXIII homologs. Given the high risk of dangerous bleeding and early manifestation in severe FXIII-deficient patients, a prompt genetic confirmation is imperative. In this sense, NGS technology allows a rapid and simultaneous analysis of all regions of all the genes involved in the pathology.

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

OBJECTIVES: The 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. METHODS: In 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). RESULTS: Significant 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). CONCLUSION: The ISTH-BAT score is an acceptable bleeding assessment tool for standardization and evaluation of patients with FXIII deficiency.

Molecular Basis of Congenital Factor XIII Deficiency in Iran.

Factor XIII deficiency (FXIIID) is an extremely rare autosomal recessive disorder that has the highest incidence in Iran. The FXIIID is primarily due to mutations in the FXIII-A gene, most of which are unique. In the current study, we report all identified mutations among Iranian patients. Among 483 patients, 366 (75.8%) were molecularly analyzed; 11 different mutations were observed. Of 11, 8 (72.7%) are missense, whereas the remaining 3 (27.3%) are deletion/insertion. Among these patients, 347 (94.9%) had the unique mutation of c.562T>C and 5 (1.4%) had the c.233G>A mutation. c.1226G>A, c.2111G>A, and c.1142T>A are also common, whereas other mutations, including 3 missense and 3 deletion/insertion, were observed only in single patient. Although, in most cases, FXIII mutations are unique and restricted to a specific family, this differs in Iran where a considerable number of identified mutations, recurrently observed, appear to be due to the high rate of consanguinity.

Factor XIII deficiency in south of Tunisia.

: Factor XIII deficiency is a rare autosomal recessive disorder of hemostasis characterized by a plasmatic factor XIII level less than 1% in homozygote and bleeding as of the youth. The aim of the study is to describe the clinical features and the outcome of the patients and to determine molecular characteristics. A retrospective study, was conducted on seven patients with factor XIII deficiency in the department of hematology and pediatrics, Hedi Chaker Hospital, Sfax, Tunisia during the period of 14 years (2001-2014). The activity of factor XIII in plasma of the patients was less than 1%. Seven patients from five unrelated families were recorded (four men and three women). Median age at diagnosis was 3.5 years. All patients had consanguineous parents. Six patients presented umbilical bleeding and only three patients had intracranial bleeding. Other bleeding features were seen, including skin and mucosal bleeding, muscular hematoma, and splenic rupture. Recurrent abortions were observed in one patient. The standard screening tests were normal. Genetic analysis identified two mutations interesting the subunit A of factor XIII. All patients received transfusion of fresh frozen plasma monthly. One patient was died because of intracranial hemorrhage.Factor XIII deficiency is a rare bleeding disorder which frequently increases in areas with high consanguinity. In our study, we identified a founder mutation. The prognosis of the disorder is related to hemorrhagic complications especially to life-threatening intracranial bleeding. Prophylaxis consists of factor XIII concentrate or recombinant factor XIII. If these are unavailable, fresh frozen plasma may be used.

Morbidity and mortality in a large number of Iranian patients with severe congenital factor XIII deficiency.

With 473 patients, Iran has about one third of the world's patients with severe congenital factor XIII (FXIII) deficiency. A considerable number of patients with FXIII deficiency (FXIIID) are affected by life-threatening bleeding episodes, such as central nervous system (CNS) bleeding or recurrent miscarriage and umbilical cord bleeding (UCB), that cause a high rate of morbidity and mortality in Iranian patients with FXIIID. Among 317 Iranian patients with FXIIID, 145 cases experienced 166 CNS bleeds (CNSBs) that recurred in 21 cases. CNSB caused different types of neurological complications in 69 patients. A total of 62 miscarriages were observed in 24 women of childbearing age, and 21 deaths were observed due to umbilical cord bleeding or mucosal bleeding. In fact, 49 deaths (15.4 %) were observed in these patients, which highlight the importance of early diagnosis and intensive health care among patients with FXIIID.

Establishment of a prenatal diagnosis schedule as part of a prophylaxis program of factor XIII deficiency in the southeast of Iran.

Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with a prevalence of 1 in 3 million in the general population. Compared to its global incidence, it has the greatest prevalence in Sistan and Baluchistan Province in the southeast of Iran. The high incidence of FXIIID in this region causes a high rate of morbidity and mortality among the affected individuals because of life-threatening episodes such as central nervous system (CNS) bleeding, umbilical cord bleeding, as well as miscarriage. CNS bleeding leads to a considerable number of neurological and behavioral complications. Therefore, we have designed an established prenatal diagnosis (PND) program to prevent the increasing incidence of life-threatening bleeding episodes and related complications among neonates with congenital FXIIID. This study was conducted from September 2013 to August 2014. A consent form was signed by the parents. Fetal sampling was done via abdominal chorionic villus sampling passage under local anesthesia and ultrasonic guidance within the first trimester of pregnancy. Fetal DNA was extracted, and PCR-restriction fragment length polymorphism was performed for the only reported mutation of FXIII (Trp187Arg) in the southeast of Iran. During the period of study, PND was performed on eight fetuses. Six fetuses were offspring of parental consanguineous marriages, and all of them had a positive family history of FXIIID. Seven out of the eight fetuses had a family member with CNS bleeding due to FXIIID. Four fetuses had a FXIIID-related death. One of the fetuses bore homozygous Trp187Arg mutation, whereas six were heterozygous, and one of the mothers gave birth to an unaffected fetus. To the best of our knowledge, PND is a possible solution to control high incidence of life-threatening episodes of FXIIID in southeast Iran.

First cases of severe congenital factor XIII deficiency in Southwestern Afghanistan in the vicinity of southeast of Iran.

Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with the highest global incidence in southeast of Iran. Southwestern Afghanistan (Nimruz Province) is located near the border with Iran in the vicinity of Sistan and Baluchestan Province in southeast Iran, and there seems to be a high prevalence of FXIIID in Nimruz. Thus, this cross-sectional study was designed to assess the prevalence of FXIIID, molecular basis as well as clinical manifestations of FXIIID in Southwestern Afghanistan. During the course of the study, all patients suspected of FXIIID were clinically examined and assessed by routine coagulation tests, including bleeding time, activated partial thromboplastin time, prothrombin time, as well as platelet count and clot solubility test. Patients with normal routine coagulation tests, but abnormal clot solubility test, underwent further investigations by FXIII activity, as well as molecular analysis for FXIII-A gene mutation (Trp187Arg) by PCR-restriction fragment length polymorphism that confirmed by sequencing. Patients with confirmed FXIIID deficiency were registered to receive prophylaxis treatment. All data including demographic information, clinical manifestations, as well as therapeutic response and type and duration of treatment, were recorded, and the data were analyzed by SPSS software. In this cross-sectional study, we found five patients with abnormal clot solubility test, among whom two patients abandoned the study, whereas three patients remained for a more precise study. All the patients were residents of Zaranj city, the capital of Nimruz Province. All these patients had undetectable activity of FXIII, which indicates a severe deficiency. Molecular analysis of patients showed mutation of Trp187Arg in all of them. Hematoma was the most common clinical presentation leading to diagnosis of FXIIID in these patients (100%). Epistaxis (67%), gum bleeding (33%), and hematuria (33%) were other recurrent clinical presentations of the patients. Three cases of death due to FXIIID were detected in the family of these patients. There was a high prevalence of FXIIID in Zaranj city with a population of 50 000, which was appropriately equal to the prevalence of the disorder in southeast of Iran, which seemed to have the highest global prevalence of FXIIID, and underlines that the same mutation (Trp187Arg) in both regions is same.

Factor XIII deficiency in Iran: a comprehensive review of the literature.

Factor XIII deficiency (FXIIID) is a rare bleeding disorder with an estimated prevalence of 1 in 2-million population worldwide. In Iran, a Middle Eastern country with a high rate of consanguineous marriages, there are approximately 473 patients afflicted with FXIIID. An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency. In this study, we have undertaken a comprehensive review on different aspects of FXIIID in the Iranian population. The distribution of this disease in different regions of Iran reveals that Sistan and Baluchestan Province has not only the highest number of patients with FXIIID in Iran but the highest global incidence of this condition. Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations. There are several disease causing mutations in Iranian patients with FXIIID, with Trp187Arg being the most common mutation in FXIIID in Iran. Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management. Various studies have evaluated the efficacy and safety of prophylactic regimens in different situations with valuable findings. Although the focus of this study is on Iran, it offers considerable insight into FXIIID, which can be applied more extensively to improve the management and quality of life in all affected patients.

The burden and management of FXIII deficiency.

Factor XIII congenital deficiency (FXIII CD) is a serious bleeding disorder resulting in a lifelong bleeding tendency, defective wound healing and recurrent miscarriage. The aim of this study was to review available literature on the burden and management of FXIII CD. To this end, Medline, Embase and Cochrane databases were searched. In current literature, FXIII CD is described as one of the most severe forms of a congenital coagulation disorder, primarily due to a high risk of severe bleeding events. The published literature suggests that over 50% of untreated FXIII CD patients experience severe bleeding symptoms. Intracranial haemorrhage (ICH)--a major cause of death and morbidity--is reported to occur in up to one-third of patients. Nonetheless, data on the social and financial burden in patients with FXIII CD are sparse. Identified reports on the effectiveness and safety of recommended treatments support that patients with FXIII CD should receive prophylactic treatment as early as possible in their lives to prevent the occurrence of bleeds, including potentially life-threatening ICHs. In conclusion, limited data on the social and economic consequences related specifically to FXIII CD have been published to date. However, it is widely acknowledged that the high risk of severe bleeds and ICH results in a high level of burden in patients with bleeding disorders. To inform future clinical decision-making and reimbursement decisions, further research is required to gain insight in how specifically FXIII CD affects quality of life and to fully understand associated economic consequences.

Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms.

The plasma circulating zymogenic coagulation factor XIII (FXIII) is a protransglutaminase, which upon activation by thrombin and calcium cross-links preformed fibrin clots/fibrinolytic inhibitors making them mechanically stable and less susceptible to fibrinolysis. The zymogenic plasma FXIII molecule is a heterotetramer composed of two catalytic FXIII-A and two protective FXIII-B subunits. Factor XIII deficiency resulting from inherited or acquired causes can result in pathological bleeding episodes. A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency. The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it. Recently however, with a growing understanding into the pleiotropic roles of FXIII, the fairly frequent milder form of FXIII deficiency caused by heterozygous mutations has become one of the subjects of investigative research. The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation. Here, we update the knowledge about the pathophysiology of factor XIII deficiency and its therapeutic options.

Intracranial hemorrhage pattern in the patients with factor XIII deficiency.

Intracranial hemorrhage (ICH) is one of the most severe and life-threatening manifestations occurring in the patients with factor XIII (F XIII) deficiency. The aim of this study was to describe the ICH pattern in the patients suffering from F XIII deficiency. In this case series, we investigated 38 patients with severe F XIII deficiency in south of Iran from January to May 2012. ICH pattern, neurologic complications, efficacy of treatment, and incidence of recurrence were reported. The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %). Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2. Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one. All the patients on prophylaxis showed good response without any episodes of recurrence, except for one. The most frequent site of ICH in our patients was intraparenchymal. It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency. Moreover, all the patients with severe F XIII deficiency even without severe bleeding symptoms are recommended to undergo prophylactic treatment.

Arg77His and Trp187Arg are the most common mutations causing FXIII deficiency in Iran.

The aim of this study was to review the literature for the genetic mutations causing inherited factoe XIII (FXIII) deficiency in patients from Iran, where the consanguineous marriage is common. Data were collected from 30 patients (18 males and 12 females) with FXIII deficiency, from 26 unrelated families. Data of mutation analysis were obtained from 2 previously published studies. A total of 7 mutations consisting of 5 new mutations and 2 previously reported mutations were identified. Of the 5 novel missense mutations, 2, Arg77His and Trp187Arg, were the most common in Iranian FXIII-deficient patients. In regions like Iran with high rate of consanguineous marriages, the identification of common mutations in disease like severe FXIII deficiency increases the capacity to make a precise screening and diagnosis assays to screen and diagnose families with high risk of FXIII deficiency for prevention of clinical complications in them.

Perioperative course of FXIII in children undergoing major surgery.

BACKGROUND: Acquired deficiency of FXIII because of perioperative hemodilution has been described several times in adults; however, data in children are scarce. We performed a prospective observational trial to evaluate the intraoperative course of FXIII in children undergoing elective major surgery. METHODS: Blood samples were repeatedly taken from 46 children aged 0.3-16 years undergoing major surgery. Concentrations of FXIII and fibrinogen, thrombelastometry by ROTEM®, and cell count were assessed intraoperatively. RESULTS: A significant decrease in FXIII concentration (median 60%; IQR 49-69%) was already noted at beginning of surgical procedures, while most ROTEM® traces remain unchanged. FXIII levels further deteriorated intraoperatively to minimal levels of 33% (15-61%). Lowest intraoperative clot strength (ExTEM) was 44 mm (34-50 mm), and fibrinogen plasma levels decreased to minimal levels of 130 mg·dl(-1) (95-160 mg·dl(-1) ). In 43 of 46 children, transfusion therapy was necessary. Despite of transfusion of fresh frozen plasma (cumulative total dose 22 ml·kg(-1) [11-32 ml·kg(-1) ]) in 21 of 46 children, FXIII level remains low in all children till the end of surgery at levels of 39% (20-46%). CONCLUSIONS: Coagulation factor XIII decreased early during major surgery owing to hemodilution. Overall intraoperative FXIII levels remain low despite of transfusion of fresh frozen plasma.