natural anticoagulant system and fibrinolysis Flashcards Preview

Hematology > natural anticoagulant system and fibrinolysis > Flashcards

Flashcards in natural anticoagulant system and fibrinolysis Deck (9)
Loading flashcards...
1
Q

What are the different roles of thrombin?

A
  1. Procoagulant
    - fibrinogen to fibrin
    - activates FV, FVIII, FXI to their FVa, FVIIIa, FXIa form
  2. Anticoagulant
    - tPA release
    - Protein C activation
  3. Angiogenesis
    - PAR activation
    - VGEF release
    - Metaloprotease activation
  4. Inflammation
    - induction of Il-6 and Il-8
    - Chemotaxis and activation of monocytes
2
Q

List the natural anticoagulants and what they act on.

A
  1. TFPI-Tissue factor inhibitor: inhibits TF:FVIIa and Xa, prevents from forming tenase complex
  2. Protein C and Protein S system: Protein C binds to EPCR, is activated by thrombin/thrombomodulin complex. APC binds to endothelial cells and platelets in complex with Protein S and destroys FVIIIa and FVa
  3. Antithrombin: assoc with heparin like proteoglycan, inhibits thrombin irreversibly, also FIXa, and FXa
3
Q

How does the protein C and protein S system work?

A
  • Protein C is bound to endothelial protein C receptor (EPCR) and is activated by thrombin/thrombomodulin complex
  • APC binds to platelets and endothelial cells in complex with protein S and degrades F VIIIa and F Va.
  • inhibition is sequential, the APC/PS complex degrades F Va first then degrades F VIIIa
4
Q

How does antithrombin promote anticoagulation?

A
  • active form when bound to heparin-like preoteglycan (- charge), which bind to + lysine domain on antithrombin
  • anthithrombin inhibits thrombin, F IXa and FXa, but prefers thrombin
  • high molecular weight heparin complexes with AT and thrombin, prefers to inhibit thrombin
  • small heparin molecules activate AT so that it prefers inhibition of F Xa (therapeutic)
  • Also Heparin Cofactor II: function unknown
5
Q

Describe what is needed for the activation and inhibition of plasminogen to plasmin.

A
  • Tissue plasminogen activator (tPA) and Urokinase Plasminogen activator (uPA) activate plasminogen to plasmin
  • plasmin is a serine protease, binds to lysine residues on fibrin and cleaves fibrin as well as other proteins
  • alpha-2-plasmin inhibitor (a-2-PI) inhibit plasmin
  • –in mature clot: a-2-PI linked to fibrin by F XIIIa, resistant to plasmin degradation
6
Q

What is the role of plasmin in angiogenesis?

A
  • can degrade basement membrane proteins

- can activate metalloproteinases, which degrade collagen

7
Q

Describe how tPA activates plasminogen

A
  • tPA actively secreted by endothelial cells after activation by thrombin +cytokines
  • tPA requires either fibrin or Annexin II cofactors
  • fibrin binds tPA and plasminogen to its surface via lysine residues–>allows plasmin to be formed on fibrin
  • annexin II is on endothelial surface and bind plasminogen and tPA, plasmin remains on surface of endothelial cell
8
Q

How does uPA activate plasminogen to plasmin

A
  • single chain uPA (sc-uPA) made and secreted by endothelial cell
  • sc-uPa requires cofactor, believed to be urokinase plasminogen activator receptor (uPAR)
  • uPAR lowers Kd for sc-uPa
  • uPA receptors on monocytes and macrophages
9
Q

How is fibrinolysis inhibited?

A
  • tPA and uPA inhibited by Plasminogen Activator Inhibitor 1 (PAI-1)
  • in plasma is inactive, only activated when bound to sub endothelial matrix protein vitronectin (unless tPA actively secreted, then active PAI-1 secreted by endothelial cell or released by activated platelets
  • Thrombin Activated Fibrinolysis Inhibitor (TAFI) -activated by thrombin/thrombomodulin complex - removes lysine and arginine residues from fibrin - reduces binding of plasmin and plasminogen to fibrin molecules, inhibits the making and activity of plasmin