Hereditary coagulation factor XI deficiency: a rare or neglected disease? Results from a retrospective, single-centre cohort in northern Italy.

To examine real-life clinical data regarding hereditary factor XI (FXI) deficiency from a secondary care centre. Retrospective review of clinical records for every FXI:C 0.7 IU/ml or less reported from 2012 to 2020. Seventy-nine patients were included. Six (7.6%) had a severe deficiency (FXI:C <0.2 IU/ml). Only 55 (69.6%) patients were referred to the Haemostasis Centre. Among them, six (15%) were subsequently not identified at increased haemorrhagic risk before a surgical/obstetrical procedure. Thirty-three (41.8%) experienced at least one bleeding event, minor (25 patients) and/or major (16 patients). Minor bleedings were predominantly spontaneous and more frequent in women, major events were mainly provoked. No correlation was found between FXI:C and risk of bleeding ( P  = 0.9153). Lower FXI:C, but not a positive bleeding history, was related with higher likelihood of being referred to the Haemostasis Centre ( P  = 0.0333). Hereditary FXI deficiency prevalence is likely underestimated, real-life clinical practices outside reference centres could be suboptimal.

Global epidemiology of factor XI deficiency: A targeted review of the literature and foundation reports.

INTRODUCTION: Hereditary factor XI (FXI) deficiency is a rare coagulation disorder that may result in excessive bleeding requiring intervention to restore haemostasis. AIM: The aim of this review was to report the current knowledge of the worldwide incidence and prevalence of FXI deficiency. METHODS: A targeted PubMed search using terms related to FXI deficiency was conducted to identify studies published from April 2002 through April 2022. A manual search supplemented the electronic search. Studies were eligible for data abstraction if they reported population-based incidence proportions/rates or prevalence proportions for FXI deficiency. RESULTS: The electronic and manual searches returned 253 publications. After applying exclusion criteria, seven publications were included in the analysis, including a global report from the World Federation of Haemophilia (WFH). Six publications provided information on the prevalence of FXI deficiency that included 74 countries and regions. The estimated prevalence of FXI in the WFH report ranged from 0/100,000 in several countries to 55.85/100,000 individuals in the United Kingdom. Prevalence estimates in the PubMed findings ranged from .1 to 246.2/1,000,000 inhabitants with varying methods of case identification and time periods of analysis. One study estimated the incidence of FXI deficiency in Yecla, Spain at 2% of blood donors and .09% of hospital inpatients/outpatients with activated partial thromboplastin time (aPTT) tests. CONCLUSION: FXI deficiency is rare across the world, but additional steps could be taken to improve incidence and prevalence estimation, for example, development of a consistent FXI deficiency definition and incorporating genetic testing into a clinical routine to better identify and characterise cases.

Factor XI deficiency: About 20 cases and literature review.

INTRODUCTION: Factor XI deficiency is a rare coagulation disorder with variable bleeding manifestations. AIM: To evaluate the correlation between the degree of factorXI deficiency and the clinical expression of the disease. METHODS: Retrospective study, spanning 10 years from January 1, 2010 to December 31, 2019, concerning patients followed at the Hemophilia Center at Aziza Othmana Hospital in Tunis. The data were collected from the medical records. The determination of PT, APTT, fibrinogen level and coagulation factors are performed by coagulometric technique on STA® compact / ACL TOP®. FactorXI deficiency was confirmed on two different samples. Statistical analysis of the clinical-biological correlation was performed using the chi-square test. The significance level was 0.05. RESULTS: Twenty patients were collected. The mean age of discovery was 25 years with a sex ratio (M/F) =0.33. The circumstances of discovery were incidental in 14 patients. A family history of bleeding was reported in 30% of cases. Eight patients underwent surgery, six of whom had a simple postoperative course. The APTT was prolonged and isolated in 75% of cases. The hemostasis test was normal in 5 cases. The average FactorXI level was 24%. The tendency to bleed did not seem to be correlated with FactorXI levels. CONCLUSION: Prospective multicenter studies including molecular study would be necessary to better elucidate this rare disorder.

High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study.

INTRODUCTION: Factor XI (FXI) deficiency is a rare disorder with molecular heterogeneity in Caucasians but relatively frequent and molecularly homogeneous in certain populations. AIM: To characterize FXI deficiency in a Spanish town of 60 000 inhabitants. METHODS: A total of 324 764 APTT tests were screened during 20 years. FXI was evaluated by FXI:C and by Western blot. Genetic analysis of F11 was performed by sequencing, multiplex ligation-dependent probe amplification and genotyping. RESULTS: Our study identified 46 unrelated cases and 170 relatives with FXI deficiency carrying 12 different genetic defects. p.Cys56Arg, described as founder mutation in the French-Basque population, was identified in 109 subjects from 24 unrelated families. This mutation was also identified in 2% of the general population. p.Cys416Tyr, c.1693G>A and p.Pro538Leu were identified in 7, 6 and 2 unrelated families, respectively. NGS analysis of the whole F11 gene revealed a common haplotype for each of the four recurrent mutations, suggesting a founder effect. The analysis of plasma FXI of four p.Pro538Leu homozygous carriers revealed that this variant was not activated by FXIIa. We identified four mutations previously described in other Caucasian subjects with FXI deficiency (p.Lys536Asn; p.Thr322Ile, p.Arg268Cys and c.325G>A) and four new gene defects: p.(Cys599Tyr) potentially causing a functional deficiency, p.(Ile426Thr), p.(Ile592Thr) and the first worldwide duplication of 1653 bp involving exons 8 and 9. Bleeding was rare and mild. CONCLUSIONS: Our population-cohort study supplies new evidences that FXI deficiency in Caucasians is more common than previously thought and confirmed the wide underlying genetic heterogeneity, caused by both recurrent and sporadic mutations.

Clinical manifestations and mutation spectrum of 57 subjects with congenital factor XI deficiency in China.

Congenital factor XI (FXI) deficiency is a rare bleeding disorder with unpredictable bleeding tendency. Few studies in a large cohort have been reported regarding associations between FXI activity (FXI:C) or genotypes and bleeding symptoms currently. This study characterized clinical manifestations and mutation spectrum of 57 subjects with FXI deficiency in China. Clinical data were collected and mutations were identified by direct sequencing and determined by mRNA analysis. The result revealed bleeding symptoms were only found in 12 patients (12/57, 21.1%) with severely reduced FXI:C, and prolonged bleeding post injury/surgery as well as easy bruising were the commonest bleeding manifestations presented in respective 5 cases (5/12, 41.7%). A total number of 37 mutations were identified including 19 missense mutations, 9 nonsense mutations, 6 splice site mutations and 3 small deletions. Among them, 4 missense mutations, 5 splice mutations, 3 small deletions and a nonsense mutation were newly detected. W228*, G400V, Q263* and c.1136-4delGTTG with a total frequency of 48.3% were the most four common mutations in Chinese patients. RT-PCR analysis was carried out and confirmed that both c.596-8T>A and c.1136-4delGTTG were pathogenic due to frameshift resulting in respective truncated proteins. Our findings suggested clinical manifestations had little to do with FXI:C or genotypes, which required further study. This study, the largest investigation of FXI deficiency in China revealed that the F11 mutation spectrum of Chinese population was distinct from those of other populations earlier established.

The prevalence of hemophilia in mainland China: a systematic review and meta-analysis.

The prevalence of hemophilia in mainland China was unclear; therefore, we can conducted a meta-analysis using existing data to evaluate the prevalence of hemophilia and its subtypes hemophilia A (HA), hemophilia B (HB), hemophilia C (HC) and Von Willebrand disease (VWD) in mainland China. We conducted a systematic literature review during August, 2011 using PubMed, EMBASE, and Cochrane Library in English and CBMDISK, CNKI, VIP and Wanfang Database in Chinese. We also carried out a search of general and specific hemophilia related websites. Reference lists of key reviews were hand-searched for further relevant research. Studies providing data of the prevalence of hemophilia or its subtypes were included. Meta-analysis was done using the generic inverse variance model. Twenty-two studies were included in the meta-analysis. The overall weighted prevalence of hemophilia was 3.6 per 100,000 and the prevalence among males was 5.5 per 100,000. The prevalence based on community studies was 2.9 per 100,000. The proportions of HA, HB, HC and VWD were 70.97%,16.13%,6.45% and 2.90%, respectively. The prevalences calculated in our study were higher than any previous studies in mainland China, but lower than the world-wide prevalences. The registration rate of hemophiliacs was extremely low. HA and HB were the major subtypes of hemophilia.

Revisiting the molecular epidemiology of factor XI deficiency: nine new mutations and an original large 4qTer deletion in western Brittany (France).

Constitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11 .

Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis.

Factor XI (FXI) plays a dual role in haemostasis and thrombosis. It contributes to thrombin generation and promotes inhibition of fibrinolysis. Severe FXI deficiency was shown to confer protection against arterial and venous thrombosis in animal models without compromising haemostasis. We have previously shown that patients with severe FXI deficiency have a low incidence of ischaemic stroke, but display the usual incidence of myocardial infarction. In the present study, we compared the incidence of deep-vein thrombosis (DVT) in 219 unrelated patients with severe FXI deficiency aged 20-94 to the incidence in a large population-based study. No cases of DVT were observed in the FXI-deficient cohort, a result that is significantly lower than the expected number (4.68) computed from the population-based study. The low incidence remains statistically significant when compared to three other population-based studies. These data suggest that severe FXI deficiency provides protection against DVT.

Screening for bovine leukocyte adhesion deficiency, deficiency of uridine monophosphate synthase, complex vertebral malformation, bovine citrullinaemia, and factor XI deficiency in Holstein cows reared in Turkey.

BACKGROUND: Bovine leukocyte adhesion deficiency (BLAD), deficiency of uridine monophosphate synthase (DUMPS), complex vertebral malformation (CVM), bovine citrullinaemia (BC) and factor XI deficiency (FXID) are autosomal recessive hereditary disorders, which have had significant economic impact on dairy cattle breeding worldwide. In this study, 350 Holstein cows reared in Turkey were screened for BLAD, DUMPS, CVM, BC and FXID genotypes to obtain an indication on the importance of these defects in Turkish Holsteins. METHODS: Genomic DNA was obtained from blood and the amplicons of BLAD, DUMPS, CVM, BC and FXID were obtained by using PCR. PCR products were digested with TaqI, AvaI and AvaII restriction enzymes for BLAD, DUMPS, and BC, respectively. These digested products and PCR product of FXID were analyzed by agarose gel electrophoresis stained with ethidium bromide. CVM genotypes were detected by DNA sequencing. Additionally, all genotypes were confirmed by DNA sequencing to determine whether there was a mutant allele or not. RESULTS: Fourteen BLAD, twelve CVM and four FXID carriers were found among the 350 Holstein cows examined, while carriers of DUMPS and BC were not detected. The mutant allele frequencies were calculated as 0.02, 0.017, and 0.006 for BLAD, CVM and FXID, respectively with corresponding carrier prevalence of 4.0% (BLAD), 3.4% (CVM) and 1.2% (FXID). CONCLUSION: This study demonstrates that carriers of BLAD, CVM and FXID are present in the Turkish Holstein population, although at a low frequency. The actual number of clinical cases is unknown, but sporadic cases may appear. As artificial insemination is widely used in dairy cattle breeding, carriers of BLAD, CVM and FXID are likely present within the population of breeding sires. It is recommended to screen breeding sires for these defective genes in order to avoid an unwanted spread within the population.

Low plasma concentrations of coagulation factors II, VII and XI indicate increased risk among elderly with symptoms of heart failure.

Heart failure is a serious condition, and it is, therefore, important to identify patients at high risk as early as possible in order to initiate appropriate treatment. The condition results in complicated disease mechanisms including disturbances in blood coagulation. The aim of the present study was to evaluate whether low plasma concentrations of coagulation factors (F) II, VII and XI influence cardiovascular mortality in an elderly population with possible heart failure. A cardiologist evaluated 450 elderly patients who attended primary healthcare because of symptoms associated with heart failure. He recorded new patient history, conducted a clinical examination, took blood samples, determined concentrations of B-type natriuretic peptide and FII, FVII, FXI and performed Doppler echocardiography. The patients were followed over almost a 10-year period during which all mortality was registered. In patients with suspected heart failure, those with low plasma concentrations of FII, FVII, FXI or all had a significantly higher mortality rate during the follow-up period of 10 years as compared with those with higher plasma concentrations, in contrast with findings in previous reports on patients with acute coronary syndromes. In the group with a plasma concentration of the first versus the ninth decile of FII, FVII, FXI or all, the risk of cardiovascular mortality increased two to three times.

Factor XI deficiency in humans.

Factor XI (FXI) deficiency is an autosomal recessive injury-related bleeding tendency, which is common in Jews particularly of Ashkenazi origin. To date, 152 mutations in the FXI gene have been reported with four exhibiting founder effects in specific populations, Glu117stop in Ashkenazi and Iraqi Jews and Arabs, Phe283Leu in Ashkenazi Jews, Cys38Arg in Basques, and Cys128stop in the United Kingdom. Severe FXI deficiency does not confer protection against acute myocardial infarction, but is associated with a reduced incidence of ischemic stroke. Inhibitors to FXI develop in one-third of patients with very severe FXI deficiency following exposure to blood products. Therapy for prevention of bleeding during surgery in patients with severe FXI deficiency consists of plasma, factor XI concentrates, fibrin glue and antifibrinolytic agents. In patients with an inhibitor to FXI, recombinant factor VIIa is useful.

Factor XI deficiency in Southern Iran: identification of a novel missense mutation.

Factor XI (FXI)-deficiency is a rare coagulation disorder inherited as an autosomal recessive trait, which is most common in Ashkenazi Jews, but also found in other groups like Moslems. We have reviewed for the first time cases of FXI deficiency in southern Iran in order to analyze their mutations related to factor XI, the main clinical and biological features, levels of circulating factor XI, and bleeding history. All 15 exons and exon-intron boundaries of F11 were polymerase chain reaction amplified using sets of primers designed on the basis of the known genomic sequence of the gene. Among bleeding disorder cases, five were FXI-deficient. FXI clotting activity ranged 0.39-16%. All were severely deficient. In all analyzed patients, functional level of FXI was markedly reduced, confirming the diagnosis of quantitative FXI deficiency. Sequencing of F11 identified three mutations: (1) a highly prevalent type II nonsense mutation (Glu117stop) in a homozygous patient, (2) a previously reported missense (Glu547Lys), and (3) novel missense (Gly372Ala) mutation. No causative mutation was found in the sequenced regions of other patients. One novel mutation and two previously described mutations were identified in patients living in southern Iran. No recurrent mutation was found, perhaps because there is a more intense population mixing in southern Iran. Screening a higher number of FXI-deficient patients will also be necessary to reveal the existence of a founder effect for these mutations in the Iranian population.

Simultaneous genotyping of coagulation factor XI type II and type III mutations by multiplex real-time polymerase chain reaction to determine their prevalence in healthy and factor XI-deficient Italians.

BACKGROUND: Factor XI deficiency is a rare autosomal recessive coagulopathy, which is, however, common among Ashkenazi Jews, in whom the so-called type II (E117X) and type III (F283L) mutations account for 98% of alleles. In non-Jewish populations, a higher level of allelic heterogeneity has been reported. However, the type II mutation was found in individuals from England, Portugal, and Italy, and haplotype analysis confirmed its Jewish origin. The aims of this study were to develop a rapid and accurate assay for the simultaneous detection of type II/type III mutations and to determine the frequency of these mutations in a large Italian population of healthy individuals and in a cohort of factor XI-deficient Italian patients. DESIGN AND METHODS: Type II and III mutations were detected using a newly developed multiplex four-color real-time polymerase chain reaction assay. Haplotype analysis was performed by either DNA sequencing or fragment-length analysis. RESULTS: Both type II and type III mutations were found among 3879 healthy Italians with an allele frequency of 0.00064 and 0.00051, respectively. Among the 31 analyzed factor XI-deficient patients, the type II mutation was found in three individuals in the homozygous state and in eight individuals in the heterozygous state (one compound heterozygote type II/III). Haplotype analysis revealed the Jewish origin of both mutations. CONCLUSIONS: The newly developed assay is highly specific and reliable (0.02% false positives); and offers a useful means for the molecular diagnosis of factor XI deficiency. Type II and III mutations are present in the Italian population and should be searched for first in factor XI-deficient patients.

[Appropriate laboratory investigation in women with menorrhagia]. / Bonne pratique et valeur diagnostique de la biologie : hémostase-hématologie.

Inherited bleeding disorders are potentially causes of menorrhagia and must be investigated if no specific cause is identified. The reported prevalence of inherited bleeding disorders is high in women with menorrhagia compared to the general population. The most frequent disorders reported are von Willebrand's disease and Factor XI deficiency. Menorrhagia is, also, a frequent finding in women with congenital bleeding disorders. Morever, menorrhagia represents the major cause of iron-deficiency anemia among women of reproductive age. Primary evaluation for an underlying disorder of hemostasis in a woman wih menorrhagia is a focused history for familiy and personal history of bleeding symptoms and a complete blood cell count. This will rule out thrombocytopenic bleeding and also assesses for the degree, if any, of anemia. Those women with a positive screen and normal platelet count should be evaluated with laboratory investigation including prothrombin time, activated partial thromboplastin time, factor VIII, VWF ristocetin cofactor and antigen. If initial hemostasis testing above is normal, then further hemostasis testing can be considered, especially in terms of platelet aggregation, in a multidisciplinary clinic.

Women with bleeding disorders.

Menorrhagia, or excessive menstrual bleeding, is a common clinical problem affecting reproductive-age women; however, the cause is undetermined in 50% of cases. Von Willebrand disease (VWD) or other bleeding disorders may be the underlying source of heavy bleeding. Women with menorrhagia and/or VWD are at increased risk for several conditions including anemia, bleeding during pregnancy, post-partum hemorrhage, and reduced quality of life (OOL). Proper diagnosis and management can decrease complications and unnecessary surgical interventions. The Division of Blood Disorders (DBD) at the Centers for Disease Control and Prevention (CDC) has implemented studies to ascertain physician awareness of bleeding disorders, establish prevalence in the U.S., and determine the best treatment options.

Carrier rate of Factor XI deficiency in stunted Japanese black cattle.

Blood examinations and genotyping of Factor XI (F11) were performed in growth retardation Japanese Black cattle and their dams. Genotyping of F11 revealed that the recessive homozygous and heterozygous genotype frequencies were 5.2% and 50.0% in the Claudin-16 (CL-16) deficiency group (n=58), 0% and 14.2% in the renal dysplasia group (n=7), 0% and 26.1% in the non-CL-16 deficiency nephritis group (n=23), 8.9% and 46.7% in the hypogenesis syndrome group (n=45), 6.2% and 25.0% in the neonatal weak calf syndrome group (n=32), 9.1% and 38.6% in the respective dams group (n=44), 0% and 23.1% in the normal cattle group (n=13), and 5.9% and 38.2% in total (n=222), respectively. These results showed that the carrier rate of F11 deficiency was high in Japanese Black cattle, and that the CL-16 deficiency, hypogenesis syndrome, neonatal weak calf syndrome, and dams groups had a large amount of recessive homozygous genotype than the other groups. No abnormal bleeding was observed clinically in the present study, and 4 of the recessive homozygous dams showed normal growth and parturition.

United States' factor XI-deficiency patients need a safer treatment.

A replacement factor for Factor XI with is virally inactivated is not available in the U.S. Elsewhere an inactivated concentrate has been used. A review of the experience over 15 years suggests that this product is safe and effective and suggests its potential use in the U.S. The most serious complication of the factor was a slight increase in DIC and thrombotic events.

Inherited factor XI deficiency confers no protection against acute myocardial infarction.

BACKGROUND AND PURPOSE: Factor XI (FXI) contributes to thrombin generation thereby affecting fibrin formation and to down regulation of fibrinolysis by activation of thrombin-activatable fibrinolysis inhibitor (TAFI). The purpose of this study was to evaluate whether patients with severe FXI deficiency are protected against acute myocardial infarction (AMI). METHODS: The incidence of AMI in patients with severe FXI deficiency (FXI activity less than 15 U dL(-1)) whose age was 35 years or more was compared to the incidence of AMI in age and gender matched persons of the general population. Atherosclerotic risk factors were assessed in FXI deficient patients and blood was tested for prothrombotic parameters such as FV Leiden, prothrombin G20210A, lupus anticoagulant, and platelet membrane polymorphisms. The common mutations causing FXI deficiency in Jews were also examined. RESULTS: Of 96 patients with severe FXI deficiency (55 women and 41 men) 16 had a history of AMI (6 women and 10 men). The median age at the time of AMI was 64.5 for women and 58 for men. The calculated annual rate of AMI in men was similar to the expected in the general Israeli population, whereas in women it was almost 2-fold higher, but this difference did not reach statistical significance. One or more atherosclerotic risk factors were observed in 13 of 16 patients (81.3%) with AMI compared to 44 of 79 patients (55.7%) without AMI (P < 0.001). The frequency distributions of platelet polymorphisms and of prothrombotic polymorphisms were not different between patients with severe FXI deficiency who experienced or not an AMI. None of the patients had lupus anticoagulant. The common genotypes which cause FXI deficiency in Jews were similarly distributed in patients with and without AMI. CONCLUSIONS: Severe FXI deficiency does not confer protection against AMI.