How the coagulation system works

Oct 22: Warfarin, heparins, LMWH, heparinoids, direct thrombin inhibitors

Oct 29: How the coagulation system works

Nov 5: Anti-platelet agents


Bhatt, D.(2018). Advances in atherosclerosis, atrial fibrillation, and valvular disease. Nature Reviews Cardiology 15(2), 71-72. https://dx.doi.org/10.1038/nrcardio.2017.212

Platelets

Hemostasis

Objectives

  • The mechanism of platelet aggregation and propagation
  • Understanding the intrinsic pathway
  • Understanding the extrinsic pathway
  • Understanding the common pathway 

 

 

 


Engelmann, B., Massberg, S.(2013). Thrombosis as an intravascular effector of innate immunityNature Reviews Immunology 13(1), 34-45. https://dx.doi.org/10.1038/nri3345

The Platelet Plug

McFadyen, J., Schaff, M., Peter, K.(2018). Current and future antiplatelet therapies: emphasis on preserving haemostasisNature Reviews Cardiology 15(3), 181-191. https://dx.doi.org/10.1038/nrcardio.2017.206

Platelet Adhesion

  • Pseudopod formation
  • Binding to surface receptors:
    • GPIb/IX/V complex  --> VWF
    • GPIa/IIa and VIa complex --> collagen

Platelet aggregation 

Mediated by Receptor GPIIb/IIIa

  • In active platelets --> binds fibrinogen
  • Interacts with VWF --> platelet "spread" and retraction


Meijden, P., Heemskerk, J.(2018). Platelet biology and functions: new concepts and clinical perspectivesNature Reviews Cardiology 16(3), 1. https://dx.doi.org/10.1038/s41569-018-0110-0

Platelet activation

  • Strong activators

    • Thrombin *activates the core of the platelets*

      • Activated by:

        • PAR-1(Receptor)  [Vorapaxar (antagonist)]

        • PAR-4 (Receptor)

    • Collagen *bear integrins e.g. GPIa/IIa and GPVIa that interact with platelets*

  • Weak activators:

    • ADP *acts on loosely packed platelets*

      • Binds GPcR:

        • P2Y1: Ca mobilization, platelet shape change, reversible aggregation

        • P2Y12: Platelet secretion and stable aggregation  e.g. [Thienopyridine  (antagonist)]

      • Platelet aggregation --> more ADP release --> more aggregation

    • Epinephrine

McFadyen, J., Schaff, M., Peter, K.(2018). Current and future antiplatelet therapies: emphasis on preserving haemostasisNature Reviews Cardiology 15(3), 181-191. https://dx.doi.org/10.1038/nrcardio.2017.206

Platelet secretion

  • Alpha Granules: VWF, P-selectin, platelet factor 4
    • Repair of smooth muscle cells (/mediate atherosclerosis): PDGF
    • Fibrinogen
    • Re-inforce + stabilize clot: Fibronectin, thrombospondin
  • Dense Granules:
    • Recruit more platelets: ADP, serotonin
    • ATP, Ca++, histamine
  • ​Vasoconstriction and platelet aggregation: Thromboxane A2: prostaglandin

Borissoff, J.I., Spronk, H.M. and ten Cate, H., 2011. The hemostatic system as a modulator of atherosclerosis. New England Journal of Medicine, 364(18), pp.1746-1760.

Clot propagation

CLOTTING CASCADE

Melnikova, I.(2009). The anticoagulants marketNature Reviews Drug Discovery 8(5), 353-353. https://dx.doi.org/10.1038/nrd2851

Multicomponent complexes

  • Extrinsic X-ase (VIIa + TF + X): X-->Xa + IX-->IXa
  • Intrinsic X-ase (IXa + VIIIa + X): X--> Xa
  • Prothombinase (Xa+Va+ prothrombin)
  • Protein C anticoagulant complex: IIa+ thrombomodulin + protein C

Common Pathway

FACTOR X

PROTHROMBIN --> THROMBIN

FIBRINOGEN --> FIBRIN

  • Thrombin begets more thrombin:
    • VIIa --> thrombin formation --> activates XI
  • Final plug:
    • Activated platelets: initial plug + more multicompent complexes
    • Endothelial cells: binding site for coagulation factors