Phospholipid Activator for the Extrinsic Pathway
The phospholipid activator for the extrinsic coagulation pathway is phosphatidylserine (PS), a negatively charged anionic phospholipid that provides the essential membrane surface for assembly and function of the tissue factor (TF)-Factor VIIa complex. 1
Mechanism of Phospholipid Involvement
Phosphatidylserine serves as the critical membrane surface component that enables the extrinsic pathway to function efficiently:
The extrinsic pathway begins with tissue factor (TF), a transmembrane protein that acts as a receptor for Factor VII, forming the TF-Factor VIIa complex (also called the "extrinsic tenase" complex). 1
This TF-Factor VIIa complex requires negatively charged phospholipids, specifically phosphatidylserine, to achieve optimal catalytic activity for activating Factor X. 1
The formation of the extrinsic tenase complex requires a membrane surface that exposes negatively charged phospholipids, which is present on activated platelets and extracellular vesicles (EVs). 1
Calcium-Dependent Binding
Calcium ions (Ca²⁺) are absolutely required for coagulation factors to bind to the procoagulant phospholipid membrane:
Several coagulation factors involved in the extrinsic pathway (Factor II, VII, IX, X) require Ca²⁺ ions for binding to the procoagulant membrane surface. 1
Ca²⁺ is essential for the stimulatory effects of phospholipids, allowing Factor VIIa to bind tissue factor and the negatively charged phospholipid surface. 2
Anticoagulants that chelate Ca²⁺ ions inhibit coagulation by preventing the formation of the tenase and prothrombinase complexes on phospholipid surfaces. 1
Quantitative Impact on Catalytic Efficiency
The presence of phosphatidylserine dramatically enhances the catalytic efficiency of the extrinsic pathway:
In the presence of Ca²⁺, phospholipids (at 25 μM concentration) cause a 150-fold decrease in the apparent Km and a 2-fold increase in the apparent Vmax of Factor X activation. 2
The formation of the ternary complex of Factor VIIa with tissue factor apoprotein and phospholipid results in a 15 million-fold increase in the catalytic efficiency of Factor X activation. 2
Tissue factor requires the presence of phospholipids for optimal biological activity in initiating the extrinsic coagulation pathway. 3
Sources of Phosphatidylserine in Vivo
Phosphatidylserine becomes exposed on specific membrane surfaces during coagulation:
Activated platelets provide a catalytic phospholipid surface by exposing anionic phospholipids like phosphatidylserine on their plasma membranes. 3
Platelet-derived extracellular vesicles (EVs) promote coagulation by generating additional procoagulant membrane surface that exposes phosphatidylserine. 1
The exposure of phosphatidylserine is associated with shedding of microvesicles from the membranes of activated platelets. 3
Clinical Relevance
The phospholipid dependency of the coagulation system has important clinical implications:
The phospholipid dependency explains the prolongation of phospholipid-dependent clotting tests in patients with phospholipid-directed antibodies such as lupus anticoagulants. 3
Extracellular vesicles exposing tissue factor (EV-TF) can trigger coagulation by exposing both TF and anionic phospholipids, which are present in various diseases including infectious disorders, cancer, and COVID-19. 1