The management of factor XI deficiency

Summary. Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are 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.     

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.     

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.     

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 (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.     

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews [see comments]

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi- Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.     

Factor XI deficiency

Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity. Bleeding in this disorder occurs especially in areas of high fibrinolytic activity. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably persons of Ashkenazi descent and the Basque population of Southern France. In these populations, five mutations of the FXI gene have been identified and a founder effect has been confirmed for three of these. This paper reviews the role of FXI in coagulation and documents factors known to modify the bleeding tendency. Treatment of surgical bleeding in patients with FXI deficiency is reviewed with emphasis on the combined use of recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) and the antifibrinolytic agent, tranexamic acid.     

Combined dys-form of homozygous factor XI deficiency and heterozygous factor XII deficiency

A 12-year-old girl with lifelong hemorrhagic episodes was found to have both a dys-form of homozygous factor XI deficiency and heterozygous factor XII deficiency. The heredity of the coagulation defects was confirmed by family studies. Severe bleeding after dental surgery occurred in spite of replacement therapy and local measures including fibrin glue. Our findings suggest that the risk of bleeding in patients with homozygous factor XI deficiency must not be underestimated and that the most effective measure is the transfusion of sufficient amounts of fresh frozen plasma until at least the 5th postoperative day.     

Thromboembolic phenomena in patients with hereditary factor XI deficiency

Factor XI deficiency is an hereditary coagulopathy that is usually associated with milder tendency to bleeding with comparison to hemophilia A. While the failure of stable fibrin clot formation may lead to bleeding, it is speculated that the same process may provide a protection against thrombosis of injured arteries due to atherosclerotic plaque rupture. Whereas 2 studies indicate that hemophiliacs have decreased mortality rate from cardiovascular diseases, there is no similar data regarding factor XI deficiency patients. In here we report about 3 patients with severe factor XI deficiency who have a long-standing history of thromboembolic phenomena: 2 patients with myocardial infarctions, and one patient with transient ischemic attacks. We discuss the possible role of factor XI in thrombosis, and whether its deficiency may protect patients from thromboembolic phenomena.     

Plasma replacement therapy during labor is not mandatory for women with severe factor XI deficiency.

Severe factor XI deficiency is an injury-related bleeding disorder. The risk of excessive post-partum hemorrhage in affected women has so far been evaluated in a relatively small number of patients and it is uncertain whether prophylactic treatment with fresh frozen plasma or factor XI concentrate is needed during or after vaginal or cesarean delivery. We retrospectively analyzed bleeding manifestations related to vaginal and/or cesarean deliveries in a cohort of 62 women with factor XI activity < 17 U/dl and evaluated whether replacement therapy is essential. Fifty-one women had 139 vaginal deliveries, six women had 13 cesarean deliveries, and five women had seven vaginal as well as five cesarean deliveries. Forty-three of the 62 women (69.4%) never experienced post-partum hemorrhage during 93 deliveries (85 vaginal, eight cesarean). Hemorrhage occurred in 19 women, which in six women accompanied each one of their 17 vaginal deliveries. Post-partum hemorrhage had no relationship with the abnormal genotype that caused factor XI deficiency nor with factor XI level. These observations suggest that the use of fresh frozen plasma or factor XI concentrate during and/or after vaginal delivery is not mandatory in women with severe factor XI deficiency and can be reserved for patients who develop excessive hemorrhage. For women requiring cesarean section it appears that the same policy can be advocated but more observations are needed.     

Clinical experience of factor XI deficiency: the role of fresh frozen plasma and factor XI concentrate

Summary. Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centre's experience of the use of factor XI concentrate over a 6-year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients.
There were 156 procedures performed without haemo- static cover. The incidence of bleeding was greatest following tonsillectomy (71%) and dental extraction (Sl'h). There was a trend for bleeding complications to be associated with lower levels of factor XI but patients with all levels of factor XI suffered bleeding complica- tions. There were 38 procedures carried out under FFP cover, with only one patient suffering excessive bleeding and no serious complications.
Factor XI concentrate was given to 25 patients to cover 45 episodes. There were no bleeding complications. Three patients suffered serious complications. One patient, with a previous history of cardiovascular disease, died of a myocardial infarction and a second had an ischaemic episode resulting in a %day hospital admission. These episodes both occurred on the same day as the factor XI infusion. A third patient suffered bilateral pulmonary emboli 7 weeks after a prolonged course of factor XI concentrate.
These finding suggest that factor XI concentrate should be contraindicated in patients with a history of cardiovascular disease, when FFP should be used. Guide- lines for the use of factor XI concentrates should be revised, and work performed to establish the mechanism of these thrombotic events.     

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.     

A novel congenital haemostatic defect: combined factor VII and factor XI deficiency.

Isolated deficiencies of factors VII and XI are both rare. Not surprisingly, therefore, combined factor VII and XI deficiency has not been reported previously. We report here a kindred with a combined heterozygous deficiency for both factors VII and XI. The proposita is a 28-year-old woman who had both a prolonged prothrombin time (PT) and a prolonged activated partial prothrombin time (APTT) associated with a mild bleeding tendency. Coagulation studies were performed on the six available members of this kindred. The PT and APTT were normal or mildly abnormal in five of these individuals. Factor VII coagulant activity (VII:C) varied from 0.33 to 0.77 units/ml in affected subjects. In contrast, the concentration of factor VII-related antigen for the six individuals ranged from 0.68 to 2.10 units/ml. Comparable factor VII:C levels were obtained when each subject's plasma was tested with either a rabbit or a human thromboplastin reagent. Factor XI coagulant activity was less than 0.5 units/ml in three of the six subjects and normal (approximately 1.0 units/ml) in the other three. The concentrations of thrombin-antithrombin-III and prothrombin fragment 1.2 were within normal limits for all individuals. In addition to being associated with heterozygous factor XI deficiency, the abnormal factor VII molecule in the plasma of affected individuals in this kindred appears to represent a newly described mutation. This is suggested by the pattern of reactivity with thromboplastin from different species, the normal tissue factor binding and the bleeding tendency in heterozygous individuals in this kindred.     

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.     

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

Factor XI (FXI) deficiency is an autosomal inherited coagulation disorder characterized by bleeding symptoms mainly associated with injury or surgery. Although most of the FXI gene mutations in Ashkenazi Jews are represented by the Glu117stop or Phe283Leu mutations, considerable genetic heterogeneity has been reported in other populations. We report here the genotypic characterization of four families with severe inherited FXI deficiency from the Czech Republic. Seven different gene mutations (three novel) were identified, thus, excluding the existence of a major founder effect in this population. Interestingly, both Glu117stop and Phe283Leu were detected once, further demonstrating the occurrence of these mutations also outside the Jewish populations. In conclusion, we confirm that FXI deficiency in non-Jewish populations is because of different gene mutations; however, the presence of the Glu117stop and Phe283Leu mutations suggests that genetic testing in FXI-deficient patients can start with these two point mutations.     

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.     

Hereditary plasma thromboplastin antecedent (PTA,FXI)

A rare case of factor XI (PTA) deficiency was discovered in a Saudi family in the Riyadh area. Nine members of the family were studied. Two were found to have a severe PTA deficiency’ levels of factor XI clotting activity were 0.01 i.u./ml and 0.02 i.u./ml respectively. Both plasmas were markedly deficient in factor XI antigen and appeared to be negative for cross-reactive material (CRM-). The parents were first cousins and both were found to have a minor PTA deficiency. Factor XI levels were: mother 0.048 i.u./ml and father 0.33 i.u./ml. Another sibling was found to have a FXI level of 0.47 i.u./ml. Menorrhagia and bleeding for 1 day after tooth extraction were the main bleeding manifestations found in one member with severe PTA deficiency. Clinically this member presented with iron deficiency anaemia. Other family members had no significant history of bleeding tendency. This is the first report of a Saudi Arabian family with PTA deficiency.     

Inheritance and bleeding in factor XI deficiency

A study of 20 Jewish and four non-Jewish kindreds transmitting factor XI deficiency (164 individuals) confirmed inheritance to be autosomal with severe deficiency in homozygotes (mean factor XI level 3.8 u/dl, SD 2.91) and partial deficiency in heterozygotes (mean factor XI level 57 u/dl, SD 10.42; normal mean factor XI level 96 u/dl, SD 11.6). The probability of an individual being heterozygous can be predicted from the factor XI level using a graph derived from this data. The accuracy is increased by including the prior probability derived from the pedigree. A high frequency of heterozygote to heterozygote mating was observed in the Jewish families consistent with an estimated gene frequency of 13.4% in this racial group. The relationship between factor XI level and bleeding tendency is poor; a third of heterozygotes had bled excessively after surgery, including six with factor XI levels above 50 u/dl, showing this condition to have clear signs of expression in heterozygotes. The lower limit of the normal range (2 SDs from the mean) was found to be 72 u/dl.     

Hereditary plasma thromboplastin antecedent (PTA, FXI) deficiency in a Saudi family

A rare case of factor XI (PTA) deficiency was discovered in a Saudi family in the Riyadh area. Nine members of the family were studied. Two were found to have a severe PTA deficiency; levels of factor XI clotting activity were 0.01 i.u./ml and 0.02 i.u./ml respectively. Both plasmas were markedly deficient in factor XI antigen and appeared to be negative for cross-reactive material (CRM-). The parents were first cousins and both were found to have a minor PTA deficiency. Factor XI levels were: mother 0.048 i.u./ml and father 0.33 i.u./ml. Another sibling was found to have a FXI level of 0.47 i.u./ml. Menorrhagia and bleeding for 1 day after tooth extraction were the main bleeding manifestations found in one member with severe PTA deficiency. Clinically this member presented with iron deficiency anaemia. Other family members had no significant history of bleeding tendency. This is the first report of a Saudi Arabian family with PTA deficiency.