Factor XI inhibitors

Alloantibody inhibitors to factor VIII or factor IX are well-recognized consequences of replacement therapy in hemophilia. Factor replacement is also a mainstay of treatment for factor XI deficiency, but reports of factor XI inhibitors are anecdotal and few are well characterized. Factor XI deficiency is an autosomal disorder common in Ashkenazi Jews, in whom the prevalence of severe (homozygous) disease is 0.1% to 0.3%. Two mutations account for more than 90% of abnormal alleles in this population. Homozygosity for the type II (Glu117Stop) mutation is associated with the absence of factor XI antigen in plasma. This mutation is also found in Iraqi, Middle Eastern, and Sephardic Jews and in Arabs and probably arose in the Middle East at least 2000 years ago. The type III mutation (Phe283Leu) is likely of more recent European origin and is associated with reduced, but detectable, antigen (about 10% of normal in homozygotes). Compound heterozygotes for the 2 mutations have factor levels of about 3%.

In this issue, Salomon and colleagues (page 4783) report on inhibitor formation in 118 Israeli patients with severe factor XI deficiency. Seven individuals with histories of plasma infusion had inhibitors. All 7 are homozygous for the type II nonsense mutation. This group represents a striking 33% of all patients with this genotype exposed to plasma. Prospective studies of factor VIII inhibitors in hemophilia A indicate that many are transient, so the actual incidence of inhibitors in factor XI type II homozygotes exposed to plasma may be considerably higher than 33%. Given this, it seems prudent to prospectively identify these patients and, when possible, use alternatives to plasma therapy such as antifibrinolytic agents. Accurately measuring very low factor XI levels with clotting assays is notoriously difficult. This study points out the importance of determining factor XI genotype in Jewish patients to identify those at high risk for developing inhibitors.