coagulation pathways

see also:

• thrombosis
• deep venous thrombosis (DVT)
• DVT prophylaxis
• DVT prophylaxis for the surgical patient
• DVT prophylaxis, anticoagulation and spinal anaesthesia or spinal cord injured patients
• Ix of suspected pulmonary embolism (PE)
• Mx of suspected DVT
• Mx of lower limb DVT
• Rx of venous thrombosis (DVT/PE) and superficial thrombophlebitis - American College of Chest Physicians guidelines 2012
• DVT and post-thrombotic syndrome (PTS)
• upper limb DVT
• thrombophlebitis
• thrombophilia
• anticoagulants

• the coagulation cascade pathways are complex with many triggers and inhibitors to generally provide clotting as needed to control blood loss or as part of the innate immune system to trap organisms - although some organisms produce clot breakdown enzymes escape from these clots (eg. coagulase and streptokinase)
• blood clots are formed from cross-linked fibrin which is the end product of the coagulation cascade
• there is a mechanism to break down the clot via the protein plasmin producing fibrin degradation products

• damaged endothelium exposes collagen
  • platelets become bound to site of injury
    • ⇒ circulating platelets bind to collagen via collagen-specific glycoprotein Ia/IIa surface receptors
      • ⇒vWF is released from endothelium and from platelets and stabilises the bond between platelets and collagen via forming additional links between the platelets' glycoprotein Ib/IX/V and A1 domain
      • localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI
        • binding of collagen to glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins
          • activated integrins mediate tight binding of platelets to the extracellular matrix
  • activation of platelets
    • activated platelets release the contents of their stored granules into the blood plasma which, in turn, activate additional platelets
      • ADP, serotonin, platelet-activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2)
      • granules' contents activate a Gq-linked protein receptor cascade, resulting in increased calcium concentration in the platelets' cytosol.
        • calcium activates protein kinase C, which, in turn, activates phospholipase A2 (PLA₂)
          • PLA₂ then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen.
  • platelet aggregation and primary haemostasis
    • activated platelets change shape from spherical to stellate
    • fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets
  • inhibition of platelet granule release
    • prostacyclin (PGI₂) inhibits granule release
      • prostacyclin (PGI₂) is released by endothelium and activates platelet Gs protein-linked receptors which activates adenylyl cyclase, which synthesizes cAMP
        • cAMP inhibits platelet activation by decreasing cytosolic levels of calcium

• two pathways, each of which lead to a common pathway to form cross-linked fibrin and resultant clot

• activated by contact with surfaces
  • formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor).
    • prekallikrein is converted to kallikrein
    • factor XII (Hageman factor) is activated
      • antithrombin degrades factor XIIa
      • factor XI is activated
        • antithrombin degrades factor XIa
        • factor IX is activated
          • antithrombin degrades IXa
          • with factor VIII, platelet membrane phospholipid and calcium, factor X is activated to factor Xa

• thrombin, FXIa, FXII, and FXa all can activate factor VII
• circulating factor VIIa leaves the blood vessel at injury site, enters tissue and binds to tissue factor TF expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes)
  • TF-VIIa complex activates factor X to factor Xa
    • this activation is almost immediately inhibited by tissue factor pathway inhibitor (TFPI)

• NB. antithrombin degrades factor Xa
• factor Xa with co-factor Factor Va form prothrombinase
  • ⇒ converts prothrombin to thrombin
    • thrombin, via binding to a cell surface protein thrombomodulin, converts protein C to activated protein C (APC)
      • APC with protein S and a phospholipid as cofactors, degrades FVa and FVIIIa hence provides negatively feedback on the cascade
        • protein C deficiency, protein S deficiency or Factor V Leyden mutation which causes impaired action of APC leads to thrombophilia
    • thrombin converts fibrinogen to fibrin
    • thrombin activates factor XIII (fibrin stabilising factor) which then helps fibrin form a stable clot

Courtesy of wikipedia

• Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z
  • warfarin type anticoagulants inhibit this synthesis

• neutrophil extracellular traps (NETs) can cause microvascular thrombosis and thrombotic events
  • NETs can increase platelet activation as well as local thrombin formation via the excess extracellular histones associated with NETs having prothrombotic activity by inhibiting thrombin-dependent protein C activation
  • NETs have been closely implicated in thrombotic events such as deep vein thrombosis, myocardial infarction, and thrombotic microangiopathy
  • the extent of platelet-neutrophil aggregates are linked to disease severity and hypercoagulability and these aggregates express high TF levels, which is the main trigger of intravascular coagulation and thrombosis
  • neutrophils can also produce a large amount of TF during COVID-19 coronavirus (2019-nCoV / SARS-CoV-2)
  • glucocorticoid treatment does not affect neutrophil priming and NET formation
  • see Neutrophil extracellular traps (NETs)