F XI Deficiency Mutation Database^©

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;

1. The extrinsic pathway is activated by exposure of tissue factor from the vessel wall to blood, which forms a complex with factor VII (FVII) and then activates factor IX (FIX) and factor X (FX). Activated FX then converts prothrombin to thrombin. Thrombin itself can catalyse the activation of Factor XI (FXI), acting as a positive feedback loop and amplifying its own production.
2. The intrinsic pathway is activated by contact with non-endothelial surfaces with factor XII (FXII) that forms complexes with prekallikrein (PK) and high molecular weight kininogen (HK). This then activates FXI that then interacts with the extrinsic pathway, activating FIX.
3. The final common pathway involves the conversion of fibrinogen to fibrin by thrombin. Thrombin also activates factor XIII (FXIII) which cross links fibrin, making it resistant to dispersion by blood pressure.

Thrombin also activates an anticoagulant pathway of negative control proteins to maintain the balance between coagulation and thrombus formation that can lead to complications such as thrombosis.

FXI is a unique coagulation protease in that it contains four tandem apple (Ap) domains, also known as PAN modules. These Ap domains show sequence homology with each other and other Ap domains in proteins such as Hepatocyte growth factor and prekallikrein. FXI also contains a serine protease (SP) domain that is homologous to the serine protease domains of other coagulation factors.

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.

• Antifibrinolytic agents are used as bleeding is especially associated with areas of high fibrinolytic activity in FXI deficiency. An example of an antifibrinolytic agent is tranexamic acid, which, due to ease of administration (it can be given orally as a tablet or mouthwash) is one of the most frequently used agents and is particularly effective in preventing bleeding after dental extractions.
• FXI replacement is achieved using fresh frozen plasma or FXI concentrate. While this is effective in the prevention of surgical bleeding, lack of availability or contra-indications to fresh frozen plasma or FXI concentrate may preclude FXI replacement in a significant number of patients.
• Recombinant factor VIIa has been used successfully in the prevention of surgical bleeding in a small number of FXI deficient patients.