Faktor 11 brist
You have full access to this open access article. Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide.
Traditional anticoagulants like heparin and vitamin K antagonists VKAs have shown efficacy in faktor 11 brist and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants DOACstargeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern.
Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI FXIhas attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding.
Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease ESRDmyocardial infarction, and ischemic stroke.
Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural faktor 11 brist, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints.
Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlights the rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.
Factor XI FXIa kDa glycoprotein serine protease, exists as a dimer with two identical subunits, each comprising faktor 11 brist acids and linked by disulfide bonds. Factor XI Structure and Function. Based on crystallographic structure analysis, FXI contains 4 "apple domains" shown as ribbons in gold, magenta, green, and blue, that form a disk-like structure with extensive interfaces at the base of the catalytic domain.
The characterization of the apple disk structure, and its relationship to the catalytic domain, provide important insights into the binding of factor XI with substrates like factor IXa, thrombin and its interaction with platelets through the glycoprotein GP Ib receptor. This interaction leads to the conversion of factor X into its active form, activated factor X FXa.
FXa then initiates a series of events that ultimately lead to the activation of factor II, leading to the formation of fibrin and the production of a hemostatic clot [ 9 ]. In fact, FXI has a relatively minor role in hemostasis where it is primarily activated to FXIa by thrombin, and this process consolidates the final hemostatic clot through activation of FIX [ 9 ].
Factor XI: structure, function and therapeutic inhibition
The classic pathways of blood coagulation including intrinsic, extrinsic, common pathways and the role of FXI are illustrated in Fig. Intrinsic Coagulation Pathway. The intrinsic system of coagulation, also referred to as the intrinsic pathway includes surface contact activating factors XII and XI. Fibrin is the primary component of hemostatic and pathological thrombosis. Unlike its more modest role in hemostasis, FXI plays a major role in pathological thrombus formation [ 10 ].
Pathological thrombosis can be triggered by two main pathways: the tissue factor pathway and the contact pathway.
Factor XII Deficiency
In either case, thrombin is generated during the faktor 11 brist phase, which subsequently activates "Faktor 11 brist" XI. In turn, FXI drives thrombus growth and propagation in a process called amplification [ 11 ]. This fundamental role of FXI in thrombosis is supported by several animal studies in which FXI-deficient or inhibited animal models had reduced incidence of thrombosis [ 12 ].
Furthermore, individuals with high levels of FXI were found to have a higher risk for venous thromboembolism VTE [ 13 ] while those with FXI deficiency had a lower incidence of DVT when compared to the general population [ 14 ]. Based on the different contributions of FXI in hemostasis and thrombosis discussed above, inhibition of FXI has emerged as a promising approach to uncouple the therapeutic benefits and the adverse effects of anticoagulant treatments; in other terms, by targeting FXI, it is possible that we might be able to reduce the risk of thrombotic complications without simultaneously increasing the likelihood of bleeding, which is a major concern with other types of anticoagulants.
Different inhibition strategies aimed at FXIa have been developed, and include antisense oligonucleotides, monoclonal antibodies, and small molecule inhibitors [ 15 ] Fig. Several of these inhibitors have demonstrated strong specificity for FXIa, leading to prolonged plasma clotting time, and have shown protective effects against thrombosis in different animal models without affecting the bleeding time [ 101617 ].
Factor XI deficiency
The mechanisms, pharmacodynamics, and pharmacokinetics of FXI inhibitors that are tested in clinical trials are summarized in Table 1 [ 18192021222324252627282930313233 ]. FXI inhibitors in different stages of development are illustrated in Fig. Anti-sense oligonucleotides ASO inhibit the hepatic synthesis of factor XI in the intracellular space.
The classes of inhibitors include monoclonal antibodies, small molecules, aptamers, anti-sense oligonucleotides, and natural inhibitors. Representation of factor XI and factor XIa inhibitors in varied clinical conditions according to the phase of development in color coding format. They are highly bound to plasma proteins with limited renal clearance. Additionally, they have a slow onset of action and long half-life.
Therefore, and coupled with the h half-life of FXI reversal of their action would require long-term FXI replacement with a faktor 11 brist XI concentrate [ 34 ]. These drugs are synthetic compounds with low molecular weight.