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Peripheral Artery Disease: causes and consequences

Coronary Artery Disease: causes and consequences

Introduction

This section describes the mechanistic basis of the coagulation cascade and the roles of its various components

Coagulation Cascade Explained

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  • 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 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 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 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

 

  • 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

 

  • 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

 

  • 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 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

 

  • Ongoing 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

 

  • 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
References
  • Colman RW, Clowes AW, George JN et al. Overview of hemostasis. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th edn. Colman RW, Clowes AW, George JN et al. (editors). Philadelphia: Lippincott, Williams & Wilkins; 2006. p. 1–16. Return to content
  • Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am 2007;21:1–11. Return to content
  • Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost 2003;1:1504–1514. Return to content
  • Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451:914–918. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451:914–918. Return to content
  • Davizon P, Lopez JA. Microparticles and thrombotic disease. Curr Opin Hematol 2009;16:334–341. Return to content
  • Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008;359:938–949. Return to content
  • Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222–1231. Return to content
  • Merli GJ. Pathophysiology of venous thrombosis, thrombophilia, and the diagnosis of deep vein thrombosis-pulmonary embolism in the elderly. Clin Geriatr Med 2006;22:75–92, viii-ix. Return to content

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