Introduction

The coagulation process

• The coagulation process that leads to haemostasis involves a complex set of reactions involving approximately 30 different proteins1
  • These reactions convert fibrinogen, a soluble protein, to insoluble strands of fibrin, which, together with platelets, forms a stable thrombus
• Several coagulation cascade models have been proposed

The intrinsic and extrinsic pathway model

• The intrinsic and extrinsic pathway model divides the initiation of coagulation into two distinct parts1
  • The extrinsic pathway is thought to be responsible for the initial generation of activated Factor X (Factor Xa)
  • The intrinsic pathway leads to amplification of Factor Xa generation
• Factor Xa plays a central role in the coagulation cascade because it occupies a point at which the intrinsic and extrinsic pathways converge

The cell-based model

• The cell-based model includes the important interactions between cells directly involved in haemostasis (i.e. TF-bearing cells and platelets) and coagulation factors
  • It more accurately represents the interaction between cellular activity and coagulation proteins that leads to thrombus formation and haemostasis2
• The cell-based model identifies the membranes of TF-bearing cells and platelets as the sites where activation of specific coagulation factors occurs in a three-phase process:2
  • Initiation
  • Amplification
  • Fibrin formation

Initiation

• Initiation occurs after vascular injury, when TF-bearing cells bind to and activate Factor VII
• This leads to the production of a small amount of thrombin

Amplification

• A small amount of thrombin activates platelets
• Prothrombinase complex (comprising Factor Xa and co-factors bound to activated platelets) causes a burst of thrombin production

Fibrin formation

• A series of protease reactions causes the conversion of the soluble protein fibrinogen to insoluble fibrin strands by thrombin, leading to thrombus formation
• Thrombin also activates Factor XIII, which stabilizes the thrombus by cross-linking fibrin
  • The resulting fibrin mesh traps and holds cellular components of the thrombus (platelets and/or red blood cells)1

The central role of Factor Xa in thrombus formation

• Factor Xa plays a central role in the coagulation process that leads to haemostasis in both the original extrinsic/intrinsic model, as well as in the more recently proposed cell-based model
  • Factor Xa, with activated Factor V (Factor Va) as a co-factor, propagates coagulation by converting prothrombin (Factor II) to thrombin (Factor IIa)2
  • Factor Xa is a crucial site of amplification in the coagulation process
  • One molecule of Factor Xa catalyses the formation of approximately 1000 thrombin molecules3
• The development of drugs that inhibit Factor Xa is, therefore, an attractive area of pharmaceutical research

Fibrinolysis: restoring blood flow

• Fibrinolysis is the process that dissolves fibrin, leading to dissolution of the thrombus
  • Plasminogen, the precursor of plasmin, breaks up fibrin in the thrombus
  • During initial thrombus formation, plasminogen activators are inhibited
  • Endothelial cells begin to secrete tissue plasminogen activators to start dissolving the thrombus as the structural integrity of the blood vessel wall is restored
• Fibrinolysis must occur for normal blood flow to be re-established
• Drugs that convert plasminogen to plasmin are used to treat acute, life-threatening thrombotic disorders, such as MI and ischaemic stroke4

The role of microparticles and P-selectin

• Research has identified other components of the coagulation process, including microparticles and P-selectin
• Microparticles are irregularly shaped vesicles that are smaller than platelets (<1 μm in diameter)
  • They arise from the plasma membrane of blood-borne cells during cell activation, programmed cell death, or exposure to shear stress5
• P-selectin is a cell adhesion molecule found on the inner surface of blood vessels and on activated platelets6
• Both microparticles and P-selectin promote thrombosis during the amplification phase of coagulation6
  • During thrombus formation, platelets accumulate at the site of vascular injury, become activated and express P-selectin6
  • P-selectin, in turn, binds to TF-bearing microparticles, allowing them to bind to activated platelets
  • TF from the microparticles then binds to and activates Factor VII

Imbalances in the coagulation system

• Thrombophilia is an inherited or acquired imbalance in the coagulation system that leads to an increased risk of thrombosis
• Thrombophilia is typically seen in:
  • Patients with recurrent VTE or a life-threatening VTE
  • Patients aged <45 years with VTE
  • Patients with VTE and a family history of VTE
  • Patients who develop VTE with no apparent exposing risk factors
  • Women who experience multiple spontaneous abortions or stillbirths7
• Approximately one in three patients with VTE has an inherited thrombophilia8
  • Common forms involve genetic mutations affecting Factor V (known as Factor V Leiden) and prothrombin (Factor II)
  • Rare causes include deficiencies in the natural anticoagulants protein C, protein S and antithrombin7