Inherited factor XI deficiency: a concise review

Inherited factor XI (FXI) deficiency, also called Hemophilia C, is an uncommon autosomal recessive disorder, which is associated with a variable bleeding tendency that usually manifests after trauma or surgery. This concise report reviews current knowledge regarding the pathogenesis, genetics, diagnosis, clinical manifestations and management of this inherited bleeding disorder.     

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 use of desmopressin in congenital factor XI deficiency: a systematic review

Factor XI (FXI) deficiency is a rare inherited coagulation disorder characterized by infrequent spontaneous bleeding, but increased risk of hemorrhagic complications especially after trauma or surgery. Treatment options for FXI-deficient patients include virus-inactivated fresh frozen plasma, plasma-derived FXI concentrates, and activated recombinant FVII. Inhibitors of fibrinolysis, such as tranexamic acid, and desmopressin (DDAVP) have also been used in these patients, especially in mild cases. The current knowledge on the use of the latter agent in this congenital bleeding condition is systematically reviewed here. Although limited, the available literature data suggest the potential role of DDAVP for either treatment of bleeding episodes or the prevention of postoperative bleeding in patients with milder FXI defects. However, these findings need to be supported by further trials on large population of patients.     

Two factor XI mutations in a Chinese family with factor XI deficiency

We describe a Chinese family with factor XI deficiency, the first reported to date. The proband had factor XI activity of 1% and was heterozygous for two nonsense mutations, an exon-8 C713-->T mutation resulting in Gln263-->Term, and an exon-10 C979-->A mutation resulting in Tyr351-->Term. Two daughters were heterozygous for the Gln263-->Term mutation and two for the Try351-->Term mutation. All showed a reduction of factor XI activity to about 50%. The Gln263-->Term mutation has been described in two Japanese families, and it remains to be determined whether a common founder exists between the three kindreds. The Try351-->Term mutation is novel.     

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.     

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.     

Heterozygous factor XI deficiency associated with three novel mutations

To determine the utility of single-stranded conformation polymorphism (SSCP) analysis for screening mutations in the factor XI (fXI) gene, we investigated three patients with heterozygous factor XI deficiency. DNA sequence analysis confirmed three novel mutations; a CGC --> TGC (Arg308Cys) mutation in exon 9, a GCT-->GTT (Ala412Val) mutation in exon 11 and an AGC --> AGA (Ser576Arg) mutation in exon 15. We postulated on the structural implications of these missense mutations. Our results demonstrated that genotypic analysis is a useful tool for conclusive differentiation between heterozygous factor XI deficiency and normal subjects.     

An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency

Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.     

Factor XI deficiency

Summary. Although factor XI (FXI) deficiency has a particularly high incidence in Ashkenazi Jews, it is now frequently diagnosed in other ethnic groups. This review gives an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency. The correlation between FXI levels and the bleeding phenotype is much less clear than in the haemophilias, and consequently the bleeding risk can be difficult to predict. Two well‐characterized mutations in the F11 gene are responsible for the majority of Jewish cases, but new mutations are becoming increasingly recognized. The publication of the crystal structure has greatly enhanced our understanding of the structure–function relationship in FXI. The impact of recent studies on our understanding of the role of FXI in coagulation is discussed.     

A case of chronic myelomonocytic leukaemia and factor XI deficiency with a circulating anticoagulant

Inhibitors against factor XI (FXI) have been frequently described in patients who acquired inhibitors (due to auto-immune disorders, malignancies or infections), but less often in those with a congenital deficiency of this factor, who had received plasma infusions. The present report concerns one such inhibitor found in the plasma of a patient with chronic myelomonocytic leukaemia and infected by B19 parvovirus, who was neither a heterozygote nor a homozygote for FXI deficiency, and who had no bleeding tendency despite a very low FXI level. Taking this case into account, we discuss and present the clinical and biological features of acquired FXI deficiency caused by an inhibitor.     

A case of factor XI deficiency caused by compound heterozygous F11 gene mutation

Summary.  Inherited factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder in most populations except for Ashkenazi Jews. In this report, a 25-year-old Chinese female FXI deficiency case has been studied. Routine clotting tests showed significantly prolonged activated partial thromboplastin time (69.5 s, control 35 ± 10 s) while prothrombin time (12.3 s, control 13 ± 3 s) was normal. FXI:C and FXI:Ag were 2.6% and 2.5%, respectively, indicating that this case was cross-reacting material negative. The activities of other coagulation factors and liver function were in normal range. The DNA sequence results of the 15 exons and their boundaries of F11 gene revealed a novel G3733C missense mutation in exon 2, and a recurrent C16642T nonsense mutation in exon 8. The G3733C mutation caused G-1R substitution in FXI signal peptide, which might impair the protein's secretion and introduced a new BssSI enzyme digestion site. The C16642T mutation led a premature stop codon at amino acid position 263(Q263Term). G-1R and Q263Term compound heterozygous mutations in F11 gene were the cause of FXI deficiency for this proband. G-1R mutation was a novel F11 gene mutation causing inherited FXI deficiency.     

Factor XI deficiency in women

Factor XI (FXI) deficiency is an uncommon autosomally transmitted coagulopathy found predominantly in Jewish kindreds. It is associated with variable bleeding tendency that usually manifests after trauma, surgery, or other challenges to hemostasis. Therefore, women with FXI deficiency are at risk of excessive bleeding during their menstrual periods, childbirth, and after surgery. Increased awareness and close collaboration among hematologists, obstetricians, and gynecologists and availability of management guidelines is essential to minimize these risks. This review provides data from current research in FXI deficiency and pregnancy care, menstrual problems, and the role of screening for this disorder in women referred with menorrhagia. Am. J. Hematol. 60:48–54, 1999. © 1999 Wiley-Liss, Inc.