Factor XI in Clinical Bleeding and Thrombotic Disorders
Authors: Seligsohn Uri , Salomon Ophira 
Published: October 2019

Abstract SCI-21

Severe inherited bleeding disorders have served as models for unraveling the role of specific coagulation factors in hemostasis and thrombosis and for design of antithrombotic agents. Factor XI (FXI) deficiency, was described in 1953 as a mild to moderate autosomal dominant bleeding disorder. Later studies indicated that inheritance is autosomal recessive with homozygotes or compound heterozygotes having a major deficiency of FXI and heterozygotes exhibiting a minor deficiency. FXI deficiency is the most frequent entity among rare inherited bleeding disorders; in worldwide surveys and registries, its relative frequency ranged between 24–60%. The prevalence of heterozygous FXI deficiency is very high in Ashkenazi Jews (1:11) in whom two predominant mutations, Glu117X and Phe283Leu, of similar frequency were described, with allele frequencies of 0.0217 and 0.0254, respectively. The Glu117X is also found in Iraqi Jews, Arabs and Italians at decreasing prevalences. A Cys38Arg mutation is prevalent in French Basques, and a Cys128X is prevalent in Britons with allele frequencies of 0.005 and 0.009, respectively. More than 185 additional mutations have been described usually in individual patients (www.factorXI.org). The common presentation of severe FXI deficiency is injury related bleeding, e.g. tooth extractions. Alternatively, a pronged aPTT in a routine examination leads to the diagnosis. Surgery or trauma at sites with increased fibrinolytic activity can be associated with excessive bleeding in 53–67% of untreated patients (Salomon et al. Haemophilia 2006, 12:490). The frequency of bleeding in heterozygotes with partial FXI deficiency is substantially lower than in patients with a severe deficiency. An additional hemostatic abnormality in such instances is likely. The procoagulant and antifibrinolytic effects of FXI mediated by augmented thrombin generation and activation of thrombin activatable fibrinolysis inhibitor could imply that elevated FXI levels confer an increased risk of thrombosis. This was indeed found in patients with deep vein thrombosis and ischemic stroke but is controversial in acute myocardial infarction suggesting that low levels of FXI might be protective at least against ischemic stroke and deep vein thrombosis. This assumption is also supported by animal models of venous and arterial thrombosis in which severe FXI deficiency confers protection against thrombosis yet without causing bleeding. In a cohort of 115 patients older than 45 years with severe FXI deficiency, we recently showed that 19 have had a myocardial infarction, implying a frequency that was expected in the Israeli population. In contrast, only 1 patient had an ischemic stroke, whereas the expected number of ischemic strokes in an Israeli health survey of 9509 subjects was 8.56 (p=0.0037) after adjustment for ischemic stroke risk factors (Salomon et al. Blood 2008, 111:4113). In another cohort of 219 patients with severe FXI deficiency, the expected number of subjects with deep vein thrombosis derived from a population based study was 4.65, whereas the observed number was 0 (p=0.019). These data suggest that severe FXI deficiency provides protection against deep vein thrombosis and ischemic stroke but not against myocardial infarction. These variable manifestations probably stem from differences in the aforementioned vascular beds. Collectively, these observations warrant development of means to induce FXI deficiency for potential use as new antithrombotic treatment modalities.

Disclosures:

Seligsohn: ISIS Pharmaceuticals, U.S.A.: Membership on an entity's Board of Directors or advisory committees.