Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations.

Factor XI (plasma thromboplastin antecedent) deficiency is a blood coagulation abnormality occurring in high frequency in Ashkenazi Jews. Three independent point mutations that result in a blood coagulation abnormality have been identified in the factor XI gene of six unrelated Ashkenazi patients. These mutations either disrupt normal mRNA splicing (type I), cause premature polypeptide termination (type II), or result in a specific amino acid substitution (type III). The three different genotypes were present in the six patients as type I/II, type II/III, and type III/III. Thus far no correlation was found between the three genotypes and the bleeding tendency in these patients.     

Four novel FXI gene mutations in three factor XI- deficient patients.

Hereditary factor XI deficiency is a mild bleeding disorder, which is highly prevalent among Ashkenazi Jews, but has been reported in all populations. In Ashkenazi Jews, two factor XI gene mutations Glu 117X (type II) and Phe283Leu (type III) are particularly common. In other ethnic groups, factor XI deficiency is a rare bleeding disorder and is related to a variety of mutations throughout the factor XI gene. Three cases of quantitative factor XI deficiency in relation with four novel missense mutations are reported: a compound heterozygosity for two novel mutations (Ala 181 Val and Ala 412 Thr) with a severe factor XI deficiency and two missense mutations (His 388 Pro and Trp 407 Cys) in heterozygous patients with partial factor XI deficiency.     

A molecular genetic study of factor XI deficiency

Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.     

Mendelian diseases among Roman Jews: implications for the origins of disease alleles

The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin.     

Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene

Inherited factor XI deficiency is an injury-related bleeding disorder that is rare in most populations except for Jews, in whom 2 mutations, a stop mutation in exon 5 (type II) and a missense mutation in exon 9 (type III), predominate. Recently, a cluster of 39 factor XI-deficient patients was described in the Basque population of Southwestern France. In this study, we determined the molecular basis of factor XI deficiency in 16 patients belonging to 12 unrelated families of French Basque origin. In 8 families, a nucleotide 209T>C transition in exon 3 was detected that predicts a Cys38Arg substitution. Four additional novel mutations in the factor XI gene, Cys237Tyr, Tyr493His, codon 285delG, and IVS6 + 3A>G, were identified in 4 families. Expression studies showed that Cys38Arg and Cys237Tyr factor XI were produced in transfected baby hamster kidney cells, but their secretion was impaired. Cells transfected with Tyr493His contained reduced amounts of factor XI and displayed decreased secretion. A survey of 206 French Basque controls for Cys38Arg revealed that the prevalence of the mutant allele was 0.005. Haplotype analysis based on the study of 10 intragenic polymorphisms was consistent with a common ancestry (a founder effect) for the Cys38Arg mutation.     

Prevalence,causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.     

Factor XI deficiency and its management

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype.
Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups.
Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain

The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild-type polypeptide. We studied 2 unrelated patients with fXI levels less than 20% of normal and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In cotransfection experiments with a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast, cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion about 50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which nonsecretable mutant fXI polypeptides trap wild-type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency.     

A mutation in LMAN1 (ERGIC-53) causing combined factor V and factor VIII deficiency is prevalent in Jews originating from the island of Djerba in Tunisia.

Combined deficiency of factor V and factor VIII is a rare autosomal recessive bleeding disorder that is caused by mutations in the LMAN1 or MCFD2 genes. These genes encode for proteins that form a complex that takes part in the transport of factor V and factor VIII from the endoplasmic reticulum to Golgi. Two mutations in LMAN1 have been observed in Jews: a guanine (G) insertion in exon 1 among Middle Eastern Jewish families, and a thymidine (T) to cytosine (C) transition in intron 9 at a donor splice site among Tunisian families. For each mutation, haplotype analysis revealed a founder effect. Because all affected Tunisian families belong to an ancient Jewish community in the island of Djerba off the coast of Tunisia, we screened members of this community for the intron 9 T --> C transition. Among 233 apparently unrelated individuals five heterozygotes were detected, predicting an allele frequency of 0.0107 (95% confidence interval, 0.0035-0.0248), while among 259 North African Jews none was found to carry the mutation. The prevalence of the mutation in Djerba Jews is consistent with the observation that all affected Tunisian Jewish families have origins in Djerba and with the finding of a common haplotype for the 9 + 2 T --> C mutation. The G insertion in exon 1 was found in one of 245 Iraqi Jews, predicting an allele frequency of 0.0022 (95% confidence interval, 0.0001-0.0123), but in none of 180 Iranian Jews examined. In view of the relatively low frequency of the mutations in the respective populations it seems reasonable to advocate carrier detection and prenatal diagnosis only in affected families.     

An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)-transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.     

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.     

New observations on factor XI deficiency

Summary.  Factor (F) XI is an injury-related bleeding tendency that commonly occurs when trauma involves tissues rich in fibronolytic activators. Severe FXI deficiency is defined when the activity of FXI in plasma is less than 15 U dL⁻¹. The disorder is inherited as an autosomal recessive trait manifesting in homozygotes or compound heterozygotes, and infrequently in heterozygotes. So far 53 mutations in the gene of FXI have been described and four of them were found to be prevalent in Ashkenazi Jews, Iraqi Jews, Basques or the English population. For each of the four mutations a founder effect was discerned. Inhibitors can develop in patients with FXI level < 1U dL⁻¹ who were exposed to plasma which seriously complicates their management during surgery. No correction of a prolonged aPTT by normal plasma is indicative of the presence of an inhibitor. In contrast to patients with haemophilia A, severe FXI deficiency provides no protection against myocardial infarction. In patients with severe FXI deficiency undergoing surgery, fresh frozen plasma is the treatment of choice. FXI concentrates can also be used but cause thrombosis in approximately 10% of patients, particularly those with cardiovascular disease. Recombinant FVIIa has successfully prevented bleeding during or after surgery in patients with FXI inhibitors.     

Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group

Tay-Sachs disease is an inherited disorder in which the alpha chain of the lysosomal enzyme beta-N-acetylhexosaminidase A bears the mutation. Ashkenazi Jews are found to be carriers for a severe type of Tay-Sachs disease, the classic form, 10 times more frequently than the general population. Ashkenazi Jewish patients with classic Tay-Sachs disease have appeared to be clinically and biochemically identical, and the usual assumption has been that they harbor the same alpha-chain mutation. In this study I have isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and compared its nucleotide sequences with that of the normal alpha-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. Only one difference was observed between these sequences: at the 5' boundary of intron 12, a guanosine in the conserved splice junction dinucleotide sequence G-T had been altered to a cytidine. The alteration is presumed to be functionally significant and to result in aberrant mRNA splicing. Utilizing the polymerase chain reaction to amplify the region encompassing the mutation, I developed an assay to screen patients and heterozygote carriers for this mutation. Surprisingly, in each of two Ashkenazi patients, only one alpha-chain allele harbored the splice junction mutation. Only one parent of each of these patients was positive for the defect. Another Ashkenazi patient did not bear this mutation at all nor did either of the subject's parents. In addition, 30% of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. The data are consistent with the presence of more than one mutation underlying the classic form of Tay-Sachs disease in the Ashkenazi Jewish population.     

Apparently dominant transmission of a recessive disease: deficiency of factor VII in Iranian Jews

In inherited disorders transmitted as autosomal recessive traits the children of affected individuals are usually asymptomatic and phenotypically normal because they are heterozygous for the defect. In an Iranian Jewish family with moderately severe deficiency of coagulation factor VII (an autosomal recessive bleeding disorder) the son of an affected woman was also affected. DNA analysis of the factor VII gene showed that this unusual situation was due to the fact that he inherited an abnormal allele with the Ala244Val missense mutation from both the homozygous mother and the heterozygous father. The parents, although not overtly consanguineous, belong to the same ethnic group of Iranian Jews, among whom this factor VII gene mutation reaches high frequencies (between 2 and 3%) in the heterozygous state.     

Severe factor XI deficiency in a Korean woman with a novel missense mutation (Val498Met) and duplication G mutation in exon 13 of the F11 gene

Hereditary factor XI (FXI) deficiency is a rare bleeding disorder inherited in an autosomal recessive manner. The genetic background of FXI deficiency is the mutations in the F11 gene on the chromosome band 4q35. The prevalence is known to be particularly high in Ashkenazi Jews with well documented recurrent mutations; however, founder mutations in F11 have also been reported in non-Jewish patients. In this report, we describe a Korean patient with severe FXI deficiency whose causative mutations were identified by molecular genetic tests. The patient was a 33-year-old pregnant woman. Routine gynecologic workup revealed prolonged activated partial thromboplastin time. Her FXI level was severely decreased at 1% (reference range, 60-140%). Direct sequencing analysis of the F11 gene was performed to identify the causative mutations. The patient was shown to have two different mutations, c.1546 G>A (Val498Met) and c.1560dupG (Tyr503ValfsX32) in the F11 gene. Val498Met is a novel missense mutation, and the Tyr503ValfsX32 mutation was recently reported in a Japanese patient. Both mutations occurred in the exon 13 of F11 and were believed to disrupt the catalytic domain of the FXI protein, leading to severe FXI deficiency. To the best of our knowledge, this is the first genetically confirmed case of severe FXI deficiency in Korea, and more cases are needed to find any signature of founder effect in the Korean population and its potential relationship with other Asian populations.     

The spectrum of factor XI deficiency in Italy

Factor XI (FXI) deficiency is a rare inherited bleeding disorder invariably caused by mutations in the FXI gene. The disorder is rather frequent in Ashkenazi Jews, in whom around 98% of the abnormal alleles is represented by Glu117X and Phe283Leu mutations. A wide heterogeneity of causative mutations has been previously reported in a few FXI deficient patients from Italy. In this article, we enlarge the knowledge on the genetic background of FXI deficiency in Italy. Over 4 years, 22 index cases, eight with severe deficiency and 14 with partial deficiency, have been evaluated. A total of 21 different mutations in 30 disease‐associated alleles were identified, 10 of which were novel. Among them, a novel Asp556Gly dysfunctional mutation was also identified. Glu117X was also detected, as previously reported from other patients in Italy, while again Phe283Leu was not identified. A total of 34 heterozygous relatives were also identified. Bleeding tendency was present in very few cases, being inconsistently related to the severity of FXI deficiency in plasma. In conclusion, at variance with other populations, no single major founder effect is present in Italian patients with FXI deficiency.     

Multiple congenital coagulopathies co-expressed with Von Willebrand''s disease: the experience of Hemophilia Region III Treatment Centers over 25 years and review of the literature

The haematologist medical directors of the Hemophilia Region III Treatment Centers in the mid-Atlantic Region III of the United States identified individuals in their databases diagnosed with additional congenital coagulopathies co-expressing with Von Willebrand's disease (VWD) and its variants. Sixteen individuals from 14 unrelated families, originating from five institutions, had been evaluated comprehensively. They represented approximately 1.5% of the calculated VWD population (n=986) registered in region III at the end of year 2002. Eleven of the 16 (68.75%) had type 1 VWD; two (12.5%) had type 2A; two (12.5%) had type 2 Normandy (2N) and one (6.25%) had coexisting type 2B and type 2N VWD. The accompanying coagulopathies consisted of severe or moderate factor VIII (FVIII) deficiency (haemophilia A) in six (37.5%); severe or moderate factor IX deficiency (haemophilia B) in three (18.75%); severe or moderate factor XI deficiency in two (12.5%); severe factor VII deficiency in two (12.5%); combined factor XI and XII deficiencies in one (6.25%); qualitative platelet abnormality in one (6.25%); and one had combined type 2B and type 2N VWD (6.25%). The reversal of overt bleeding often required multiple therapeutic modalities, mandated by the specific combination of coagulation disorders. This included administration of specific purified clotting factor concentrates, cryoprecipitate, fresh frozen plasma, 1,8 deamino-d-arginine vasopressin, antifibrinolytic agents, platelet transfusions, etc. In summary, combined inherited coagulopathies coexisting with VWD are uncommon and frequently are phenotypically divergent from VWD. Successful therapy required an individualized approach, employing multiple replacement strategies, based on the laboratory definition of the specific additional coagulation defect.     

Severe factor XI deficiency in an Arab family associated with a novel mutation in exon 11

We investigated an 8-year-old Arab girl with severe factor XI deficiency; one sibling and her father also have severe factor XI deficiency. Her parents and her father's parents are first cousins. Restriction analysis and DNA sequencing excluded the type I, II, III and IV mutations. We demonstrated a previously undescribed C → A mutation at nucleotide 1254 in exon 11 resulting in a threonine to asparagine (T → N) substitution at amino acid 386. We postulate that this substitution interferes with folding and secretion of the molecule.     

Identification of five novel mutations in the factor XI gene (F11) of patients with factor XI deficiency.

Factor XI (FXI) deficiency is an inherited autosomal recessive disorder associated with bleeding of variable severity. However, many cases of dominant disease transmission have been recently described. This disorder is rare in the general population, whereas it is commonly found in individuals of Ashkenazi Jewish ancestry. This study reports the molecular genetic analysis of FXI deficiencies in 11 unrelated families of different origin. Five novel mutations have been identified. Severe FXI deficiency of two unrelated patients resulted from two novel mutations: one deletion (960-961delGT) in exon 9 predicting a frameshift, and a Ser-4Leu mutation located in the signal peptide. In addition, three novel missense mutations associated with partial FXI deficiency have been identified: Cys122Tyr, Glu297Lys and Glu579Lys.     

Coagulation factor XI: a database of mutations and polymorphisms associated with factor XI deficiency.

Hereditary factor XI deficiency is a rare bleeding disorder that is found worldwide. Rapidly increasing numbers of mutations and polymorphisms in various populations have been reported. However, the number of identified mutations given in recent literature and available databases is named to be not more than 35. We assumed that this is clearly too low and that to date no comprehensive survey of mutations associated with factor XI deficiency is available. To provide a complete database of mutations and polymorphisms associated with factor XI deficiency we collected all available data on hereditary factor XI deficiency from main biological and medical databases [http://ncbi.nlm.nih.gov/pubmed and http://ncbi.nlm.nih.gov/omim (OMIM reference 264900) and the Human Gene Mutation Database for F11 mutations http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/119891.html] as well as from contributions to international congresses. As of 8 June 2004 the number of reported causative mutations is 81, of which 12 have been described in unrelated individuals by more than one study group. For three frequently observed mutations [type II and type III mutations (Gln116Stop and Phe283Leu) and Cys38Arg] common founders have been described. Furthermore, 20 polymorphisms have been described in association with factor XI deficiency, three of which have been reported by two independent study groups. For the majority, allele frequencies have been published for in the Caucasian and/or Black population.