Factor XI (FXI) is a plasma glycoprotein that participates in the propagation phase of blood coagulation augmenting thrombin generation by activating Factor IX (FIX). The Coagulation cascade can be divided into 3 smaller pathways;
FXI circulates as a dimer with two identical FXI monomers linked by non-covalent interactions between the Ap4 domains and by a Cys321-Cys321 disulphide bond, although this bond is not essential for dimerisation. FXI can be activated by thrombin or by activated FXII, or may undergo auto-activation. Activation of FXI results in cleavage of the scissile bond at Arg369-Ile370 to form a heavy chain containing the Ap domains and a light chain containing the SP domain with the catalytic triad at His413, Asp462 and Ser557. FXI is activated when bound to activated platelets. The Ap3 domain within FXI binds to the platelet glycoprotein (GP) Ib-IX-V complex in the presense of HK and zinc ions or prothrombin and calcium ions. Binding sites for HK and PK have been mapped to the Ap1 domain and a binding site for FXIIa has also been proposed on the Ap4 domain. The Ap2 and Ap3 domains both seem to be involved in binding of the substrate FIX that is cleaved by the SP domain.
Mutations within the FXI gene can cause FXI deficiency
leading to a disorder with a variable clinical phenotype, also known as Haemophilia C, Plasma thromboplastin antecendent deficiency and Rosenthal syndrome.
FXI coagulant activity (FXI:C) in normal human plasma is 70-150 U/dL. Severe FXI deficient patients have FXI:C levels of < 1-20 U/dL, whereas partially deficient FXI deficient patients possess FXI:C levels of 20-70 U/dL. Individuals with severe FXI deficiency are homozygous or compound heterozygous for causative mutations, whereas individuals who are partially deficient are heterozygous, with one mutated allele.
FXI deficiency is associated with a variable injury-related bleeding diathesis with bleeding symptoms associated with trauma or surgery and a lack of spontaneous bleeding. The majority of severely deficient individuals bleed excessively after invasive procedures but this is not universal. Up to 50% of partially deficient patients have a history of bleeding. In females, menorrhagia (heavy or prolonged bleeding during menstruation) and post-partum hemorrhage (bleeding after pregnancy) are particular features. The bleeding tendency varies considerably between patients with similar FXI levels and may also vary within the same individual. Bleeding is more common after surgical procedures on areas of high fibrinolytic activity such as the oral and nasal cavities, prostate and uterus.
Current available therapy for FXI deficiency consists of antifibrinolytic agents and FXI replacement.