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

Abstract

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.

Factor XI in haemostasis and thrombosis: Past, present and future

“…Development of inhibitorstoFXI in patients withsevere FXI deficiencyhas been described.Inour recent study of 118 unrelatedpatients with severe FXIdeficiency, sevenwere foundwith an inhibitor (34). Theseven patients were among 21 patients who had received replacement therapyand were homozygotesfor the Glu117X mutation that is associated with extremelyl ow FXI levels.…”

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

“…These included four intragenic polymorphic sites [-231C>T in intron A, (CA)8-13 in intron B, HhaI polymorphism in intron E, and (AT)7-11 in intron M], previously reported to define two different haplotypes shared by Jewish FXI-deficient patients carrying the type II mutation [-231C, (CA)11, -431G (HhaI), (AT)9] or the type III mutation [-231T, (CA)10, -431G (HhaI), (AT) 9] 14 (nomenclature according to Bolton-Maggs et al). 18 Genotyping was performed both by DNA sequencing and by restriction fragmentlength polymorphism analysis.…”

“…8 Patients with very severe FXI deficiency can develop a FXI inhibitor, affecting FXI activation by thrombin or activated factor XII or inhibiting FIX activation by activated FXI. 9 Hereditary FXI deficiency is generally transmitted as an autosomal recessive trait, and both sexes are affected; however, cases of dominant transmission have also been reported. 10,11 Although the disease is rare in most populations (prevalence 1 case in 10 6 individuals), it is frequent in Ashkenazi Jews, in whom a heterozygosity rate of 9% was discerned and severe deficiency (FXI activity <15U/dL) was estimated to occur in 1 in 450 individuals.…”

Challenges in the Therapeutic Use of a “So-Called” Universal Hemostatic Agent: Recombinant Factor VIIa

“…40 However, in vitro data suggest that one half of the hemophilia A/B inhibitor dosing may be sufficient. 41 The implied higher risk for thrombotic complications in the off-label setting should enjoin clinicians treating these patients to establish realistic risk:benefit assessments. The latter should engender cautious dosing strategies commensurate with the perceived balance between excessive bleeding and risk for thromboembolic events.…”