Authors: Puneet Tomar1 and Mariarosaria Miranda2
Affiliations: 1University of Milan, 2Stichting Sanquin Bloedvoorziening
When blood loss - either outside of the body or blood vessels - takes place, a process to prevent and stop bleeding occurs, this is called hemostasis. Hemostasis involves two main phases, primary and secondary hemostasis. Primary hemostasis refers to platelet aggregation and platelet plug formation. Platelets are activated in a multifaceted process and as a result they adhere to the site of injury and to each other, plugging the injury. The secondary hemostasis occurs simultaneously, coagulation factors interact in a cascade to form fibrin strands, which strengthen the platelet plug.
Coagulation cascade of secondary hemostasis (Figure 1) is classified into intrinsic (contact activation pathway) and extrinsic (tissue factor pathway). The aim of the tissue factor pathway is to generate a ‘thrombin burst’. Following damage to the blood vessel, factor VII leaves the circulation and comes into contact with tissue factor (TF) forming an activated complex (TF-FVIIa). Tissue-factor factor VIIa (TF-FVIIa) activates factor IX and factor X. Factor VII is itself activated by thrombin, factor XIa, factor XII, and factor Xa. The activation of factor X (to form factor Xa) by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitors (TFPI). Factor Xa and its co-factor factor Va form the prothrombinase complex, which activates prothrombin to thrombin. Thrombin then activates other components of the coagulation cascade, including factor V and factor VIII (which forms a complex with factor IX), and activates and releases factor VIII from being bound to von Willebrand factor. Factor VIIIa is the co-factor of factor IXa, and together they form the "tenase" complex, which activates factor X; so the cycle continues. The intrinsic pathway begins with the formation of a primary complex on collagen by prekallikrein (PK) and factor XII. Prekallikrein is converted to kallikrein and Factor XII becomes factor XIIa. Factor XIIa converts factor XI into factor XIa. Factor XIa activates factor IX, which with its co-factor factor VIIIa form the tenase complex, which activates factor X to factor Xa. The goal of the intrinsic pathway is to initiate clot formation.
Factor VIII (antihemophilic factor) - an essential blood clotting protein - serves as a critical component in the intrinsic blood coagulation pathway, and acts as a cofactor for factor IXa. Insufficient expression of factor VIII or expression of nonfunctional factor VIII results in hemophilia A, a recessive X-linked coagulation disorder. Conversely, people with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism.
Human factor VIII is a single chain of about 300 kDa consisting of domains described as A1-A2-B-A3-C1-C2. The protein undergoes processing prior to secretion into blood resulting in a heavy chain (A1-A2-B) and a light chain (A3-C1-C2) linked by metal ions (Figure 2).
Factor VIII is synthesized by various tissues, including liver, lung and kidney, as an inactive single-chain protein (Figure 3). After extensive post translational processing, factor VIII is released into the circulation as a set of heterodimeric proteins. This heterogeneous population of factor VIII molecules readily interacts with von Willebrand factor, which is produced and secreted by vascular endothelial cells. Upon triggering of the coagulation cascade and subsequent generation of serine proteases, factor VIII is subject to multiple proteolytic cleavages. These cleavages are associated with dramatic changes of the molecular properties of factor VIII, including dissociation of von Willebrand factor, and development of biological activity. After conversion into its active conformation, and participation in the factor X activating complex, activated factor VIII rapidly loses its activity.
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 Figure one sources: https://commons.wikimedia.org/wiki/File:Coagulation_simple.svg
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