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PubMed1998

Pregnancy in women with von Willebrand's disease or factor XI deficiency.

OBJECTIVE: To assess the obstetric outcome in women with von Willebrand's disease or factor XI deficiency. SETTING: Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital. POPULATION: Women with von Willebrand's disease (n = 31) and with factor XI deficiency (n = 11) registered at the Royal Free Hospital Haemophilia Centre who had had a pregnancy within the previous 17 years (1980-1996), including 84 in women with von Willebrand's disease and 28 in women with factor XI deficiency. METHODS: Women were interviewed and details of the obstetric history were obtained. The records of the Haemophilia Centre and the women's maternity records were also reviewed. RESULTS: Threatened miscarriage occurred in 33% and 14% of pregnancies with von Willebrand's disease and factor XI deficiency, respectively. Excluding recurrent miscarriages, 14/68 (21%) of pregnancies with von Willebrand's disease and one pregnancy with factor XI deficiency miscarried spontaneously. There was an increased incidence of primary and secondary post-abortal bleeding complications. Factor VIII and von Willebrand factor antigen and activity levels increased significantly in pregnancy in all women apart from those with severe von Willebrand's disease. Factor XI, however, did not show any significant change. No neonatal haemorrhagic complications in association with the birth process were reported, although ventouse and difficult forceps deliveries were avoided. Extensive perineal bruising and haematoma was reported in three women with von Willebrand's disease; two of these were associated with forceps delivery. The incidence of primary postpartum haemorrhage was 18.5% in von Willebrand's disease and 16% in factor XI deficiency. Blood transfusion was required in six cases of von Willebrand's disease and two cases of factor XI deficiency. Ten of fourteen instances of primary postpartum haemorrhage occurred when maternal factor levels were < 50 IU/dL with no prophylactic treatment for labour. The incidence of secondary postpartum haemorrhage was 20% in von Willebrand's disease and 24% in factor XI deficiency. None of the women who had prophylactic treatment during labour or the puerperium suffered any significant bleeding complications. There were three neonatal bleeding complications. CONCLUSION: Pregnancy, labour and the puerperium are associated with significant bleeding problems in women with von Willebrand's disease or factor XI deficiency, but these are largely preventable. Specialist obstetric care in close liaison with the haemophilia centre is essential to minimise maternal and neonatal complications.

Abortion, Spontaneous↗
PubMed1991

Factor XI deficiency in Ashkenazi Jews in Israel.

BACKGROUND AND METHODS: Severe factor XI deficiency, which is relatively common among Ashkenazi Jews, is associated with injury-related bleeding of considerable severity. Three point mutations--a splice-junction abnormality (Type I), Glu117----Stop (Type II), and Phe283----Leu (Type III)--have been described in six patients with factor XI deficiency. Clinical correlations with these mutations have not been carried out. We determined the relative frequency of the mutations and their association with plasma levels of factor XI clotting activity and bleeding, analyzing the mutations with the polymerase chain reaction and restriction-enzyme digestion. RESULTS: The Type II and Type III mutations had similar frequencies among 43 Ashkenazi Jewish probands with severe factor XI deficiency; these two mutations accounted for 49 percent and 47 percent, respectively, of a total of 86 analyzed alleles. Among 40 of the probands and 12 of their relatives with severe factor XI deficiency, patients homozygous for Type III mutation had a significantly higher level of factor XI clotting activity (mean [+/- SD] percentage of normal values, 9.7 +/- 3.8 percent; n = 13) than those homozygous for Type II mutation (1.2 +/- 0.5 percent, n = 16) or compound heterozygotes with Type II/III mutation (3.3 +/- 1.6 percent, n = 23), as well as significantly fewer episodes of injury-related bleeding. Each of these three groups had a similarly increased proportion of episodes of bleeding complications after surgery at sites with enhanced local fibrinolysis, such as the urinary tract, or during tooth extraction. CONCLUSIONS: Type II and Type III mutations are the predominant causes of factor XI deficiency among Ashkenazi Jews. Genotypic analysis, assay for factor XI, and consideration of the type and location of surgery can be helpful in planning operations in patients with this disorder.

Alleles↗
PubMed1986

Management of factor XI deficiency in gynecologic and obstetric patients.

Deficiency of factor XI (plasma thromboplastin antecedent) can result in severe bleeding in women undergoing obstetric or gynecologic procedures, with the highest risk in women of Ashkenazi Jewish background. Most patients do not bleed if treated with sufficient fresh frozen plasma to maintain a factor XI level of 30% or more but occasionally patients may require higher levels. Plasma infusion should be continued for several days, even if bleeding does not seem excessive, since delayed bleeding is not uncommon. The use of hepatitis B vaccine and of plasma from a single donor, may reduce the risk of hepatitis.

Adult↗
PubMed1986

The factor of factor XI deficiency in thyroid neoplasia.

Forty-three patients with factor XI deficiency detected by prolonged partial thromboplastin times were reviewed over an 11-year period. They were predominantly Ashkenazim--18 men and 25 women--ranging in age from 20 to 92 years. Thirteen patients had a history of bleeding, and eight had a family history of factor XI deficiency. Six patients with thyroid disease with four significant tumors were found for a 9% incidence of associated neoplasia. These consisted of two adenomas and two papillary-mixed cancers in two men distinguished by an aggressive course by virtue of extensive nodal disease, local recurrence, and systemic metastases in whom factor XI was profoundly decreased. It would appear that there is an undue association of factor XI deficiency and thyroid neoplasia suggestive of a shared genetic disturbance. These cases illustrate the benefit of routine preoperative coagulopathy screening by use of prothrombin time, partial thromboplastin time, and platelet counts. Factor XI deficiency is an infrequent cause of excessive bleeding, and the operative morbidity of surgical management of affected individuals can be avoided by the use of fresh-frozen plasma before and after surgery.

Adult↗
PubMed2006

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 VII↗
PubMed1976

Factor XI activity and factor XI antigen in homozygous and heterozygous factor XI deficiency.

A relatively potent antiserum against highly purified, unactivated human factor XI antigen was raised in a rabbit. This antiserum, after concentration, neutralized 50% of the factor XI clotting activity of a standard normal plasma at an antiserum dilution of 1/900. The antiserum was used in a neutralization-inhibition assay to study the relation between factor XI clotting activity and factor XI antigen in plasma from ten unrelated patients with homozygous factor XI deficiency and from 12 heterozygous family members of these patients. No evidence of factor XI antigen significantly in excess of factor XI activity was found in either group. All data to date have been consistent with the hypothesis that hereditary factor XI deficiency represents a genetic disorder resulting from the absence of factor XI molecule. Severity of bleeding in factor XI deficiency could not be correlated with the level of factor XI activity or factor XI antigen.

Animals↗
PubMed1994

Coagulation factor XI deficiency in Holstein cattle: expression and distribution of factor XI activity.

Factor XI (F XI) is a plasma protein that participates in the blood coagulation process. A study of the expression of F XI activity in Holstein cattle has confirmed that the inheritance of F XI deficiency is autosomal with severe deficiency in homozygotes (mean F XI level 2%, SD 1%), and partial deficiency in heterozygotes (mean F XI level 38%, SD 10%; normal mean F XI level 94%, SD 21%). In a total of 1469 males evaluated for F XI levels, 47 or 3.1% were identified as heterozygous and only one as homozygous for the disorder. In part because of the lack of a discrete distinction in the expression of F XI between heterozygous and normal animals, not all of the animals tested could be uniquely classified on the basis of the plasma F XI values. A mean F XI value of 53% (SD 7%) was found in a group of animals that were categorized as low normal/high heterozygous. If this group of cattle had been classified on the basis of the criterion used to classify human beings then these animals would have been categorized as heterozygous since the mean F XI value for proven bovine heterozygotes is approximately 20% lower than the values found in the human counterpart. Like the human form of the disease, however, there appears to be a low frequency of hemorrhagic episodes associated with F XI deficiency in cattle.

Animals↗
PubMed1986

Factor XI kinetics after plasma exchange in severe factor XI deficiency.

Plasma exchange in a patient with factor XI deficiency allowed the determination of the factor XI disappearance time. The decay curve showed a biphasic pattern with a t1/2 of h. After a loading dose by means of plasma exchange with fresh frozen plasma (FFP) up to a factor XI level of 65%, administration of 0.5 liter FFP every 12 h was necessary to maintain the factor XI concentration between 40 and 60%. The clearances of factor XI, calculated from the results of plasma exchange and from the maintenance dose, correlated very well and showed that the t1/2 of factor XI did not change after surgery. The patient underwent major surgery uneventfully but ultimately died 3 1/2 weeks after operation from cerebral damage due to cardiac arrest, which occurred on the 2nd postoperative day.

Factor XI↗
PubMed2004

Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.

Antithrombin III↗
PubMed2003

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.

Asian People↗
PubMed2002

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.

Adolescent↗
PubMedDate not supplied

[Postoperative haemorrhagia in a girl with congenital factor XI deficiency - successful treatment with desmopressin (DDAVP, Minirin(R))].

UNLABELLED: The rare factor XI deficiency is associated with different profuse bleeding without correlation to the severity of reduction of factor XI. Accordingly, traumata or surgical procedures may cause unexpected excessive bleeding in asymptomatic patients. After surgery of a nine-year-old girl with factor XI deficiency (8 per cent) profuse bleeding occurred which could only be stopped after infusion of desmopressin. After administration the factor XI activity was increased to 31 per cent, the factor VIII even to 290 per cent over the normal range. We suppose that the favorable clinical effectiveness is not only related to the increasing factor XI activity but also to the elevation of the factor VIII/von-Willebrand-complex. CONCLUSION: It is recommended to give desmopressin as firstline therapy of bleeding by factor XI deficiency since the only effective alternative such as substitution of factor XI by transfusion of fresh frozen plasma is associated with the risk of transmission of virus infections.

Child↗
PubMed1997

A murine model of factor XI deficiency.

To facilitate investigations into the physiologic and pathologic roles of factor XI, we have developed a murine model of severe factor XI deficiency using the technique of homologous recombination in embryonic stem cells. The factor XI gene was disrupted by introducing a neomycin phosphotransferase gene into the fifth exon. The activated partial thromboplastin times of homozygous null mice were prolonged (158- > 200 s) compared with wild type (25-34 s) and heterozygous null (40-61 s) litter mates. Factor XI activity was absent from the plasma of mice homozygous for the null mutation and factor XI mRNA was undetectable by Northern blot and reverse transcription/PCR in the livers of homozygous null animals. The genotypes of progeny from matings of mice heterozygous for the factor XI null allele followed the expected Mendelian ratio (1:2:1, wild type 26%, heterozygote null 54%, homozygous null 20%), indicating that severe factor XI deficiency did not result in increased intrauterine death. Results of a tail transection bleeding time assay were similar for wild type and homozygous null animals with, at most, a tendency for slightly prolonged bleeding in the homozygous null animals. The factor XI deficient mice are a unique tool for evaluating the role of factor XI in normal hemostasis and pathologic coagulation.

Animals↗
PubMed1990

Factor IX is activated in vivo by the tissue factor mechanism.

Despite significant progress in elucidating the biochemistry of the hemostatic mechanism, the process of blood coagulation in vivo remains poorly understood. Factor IX is a vitamin K-dependent glycoprotein that can be activated by factor XIa or the factor VII-tissue factor complex in vitro. To investigate the role of these two pathways in factor IX activation in humans, we have developed a sensitive procedure for quantifying the peptide that is liberated with the generation of factor IXa. The antibody population used for the immunoassay was raised in rabbits and chromatographed on a factor IX-agarose immunoadsorbent to obtain antibody populations with minimal intrinsic reactivity toward factor IX. We determined that the mean level of the factor IX activation peptide (FIXP) in normal individuals under the age of 40 years was 203 pmol/L and that levels increased significantly with advancing age. The mean concentration of FIXP was markedly reduced to 22.7 pmol/L in nine patients with hereditary factor VII deficiency (factor VII coagulant activity less than 7%) but was not significantly different from normal controls in nine subjects with factor XI deficiency (factor XI coagulant activity less than 8%). These data indicate that factor IXa generation in vivo results mainly from the activity of the tissue factor mechanism rather than the contact system (factor XII, prekallikrein, high molecular-weight kininogen, factor XI). Our results may also help to explain the absence of a bleeding diathesis in many patients with deficiencies of the contact factors of coagulation.

Adult↗
PubMed1988

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.

Adolescent↗
PubMed1982

Acquired factor XI deficiency in systemic lupus erythematosus.

A variety of coagulation abnormalities has been described in systemic lupus erythematosus (SLE). We report a unique SLE patient with an acquired factor XI deficiency. The low factor XI levels were not due to a classical coagulation inhibitor, but to a plasma factor (probably an immunoglobulin) that selectively bound factor XI. The factor XI deficiency improved after treatment with corticosteroids. Thus it is possible that in SLE immune complexes may bind clotting factors making them unavailable for use in the coagulation cascade.

Blood Coagulation Tests↗