Blood Coagulation

• What are the 3 mechanisms involved in normal haemostasis?

  Cellular - platelets

  Humoral - coagulation

  Tissue - vessels
• What does normal haemostasis do?

  Stop/prevents haemorrhage

  Maintains flow
• What is disordered haemostasis?

  Thrombosis OR Haemorrhage
• What is thrombosis?

  Excess/inappropriate 'clotting'

  Can be arterial or venous
• What is haemorrhage?

  Excess/inappropriate 'bleeding'
• What is von Willebrand disease?

  Most common bleeding disorder

  Deficient of dysfunctional vWF (von Willebrand Factor)

  TREATMENT: desmopressin (similiar to ADH)
• What does the endothelium produce?

  Vasoactive mediators (e.g. endothelin & NO)

  Haemostatic agents (e.g. von Willebrand Factor (vWF))
• Arterial thrombosis tends to be more platelet driven.

  Venous thrombosis tend to be more coagulation (clotting factors).
• What happens when there is vessel injury?

  Vessel injury -> vasospasm -> reduced blood loss -> exposure of pro-thrombotic mediator (vWF, collagen, tissue factor) -> initiates coagulation
• What does collagen do?

  'Captures' and activates platelets -> initiates coagulation
• What does tissue factor do?

  Initiates coagulation
• What does thrombin do?

  Activates platelets

  Cleaves fibrinogen
• What is fibrinogen? What does it do?

  Factor I

  Soluble glycoprotein

  Synthesised in liver, mostly in plasma (some in platelets)

  ACTIVITY: Cross-links platelets -> aggregation
• What is fibrin? What does it do?

  Factor Ia

  Insoluble protein

  Formed by action of thrombin on fibrinogen

  ACTIVITY: Spontaneously polymerises -> forms fibrin blot -> coagulation
• What is prothrombin? What does it do?

  Factor II

  Inactive enzyme

  Vitamin K dependent factor

  Have residues which have a strong negative charge -> binds to Ca+2
• What is thrombin? What does it do?

  Factor IIa

  Active enzyme

  Formed by action of Factor Xa on prothrombin

  ACTIVITY: Cleaves alpha & beta chains of fibrinogen & activates platelets
• What is thrombin a target for (drugs)?

  -gatran drugs
• What is Factor X? What does it do?

  Stuart-Power Factor

  Inactive enzyme

  Vitamin K dependent factor

  Has residues which have a strong negative charge -> binds to Ca+2

  Localised to the surface of activated platelets
• What is factor Xa? What does it do?

  Active enzyme

  Formed by action of Factor VIIa or Factor IXa on Factor X

  ACTIVITY: Forms complex with Factor Va -> cleaves prothrombin
• What is factor Xa a target for (drugs)?

  -xaban drugs
• What is Factor V?

  Proaccelerin

  Inactive co-factor

  Plasma glycoprotein
• What is Factor Va? What does it do?

  Accelerin

  Active co-factor

  Formed by action of thrombin on Factor V

  ACTIVITY: Forms a complex with Factor Xa -> cleaves prothrombin to thrombin
• What is the prothrombinase complex?

  Factor Xa

  Factor Va

  Ca+2 & Phospholipid (co-factors)
• What causes haemophilia A?

  Deficiency of Factor VIII
• What is Factor IX?

  Christmas Factor (intrinsic)

  Inactive enzyme

  Formed by action of Factor XIa

  Vitamin K dependent factor
• What is factor VII?

  Inactive enzyme (extrinsic)

  Activated by Xa, XIIa, IXa and IIa

  Vitamin K dependent factor
• What is tissue factor? What does it do?

  Factor III

  Transmembrane glycoprotein

  Co-factor

  Expressed on sub-endothelial tissues

  Forms complex with Factor VII & VIIa -> increases activity -> more Factor X cleaved to Factor Xa
• What is antithrombin III? What does it do?

  SERPIN C1 (Serine Protease Inhibitor)

  Plasma glycoprotein

  ACTIVITY: Inhibits IIa (thrombin), IXa, Xa, XIa, XIIa

  Activity is enhanced by heparin
• What does fondaparinux do?

  Drives activity of antithrombin III?
• What is the difference between the activity of heparin, LMWH and fondaparinux?

  ATIII/Heparin -> inhibits Factor IIa & Xa

  ATIII/Fondaparinus -> inhibits Factor Xa

  ATIII/LMWH -> inhibits Factor Xa
• Thrombin is NOT membrane-associated.
• What is the function of vitamin K epoxide reductase?

  Converts vitamin K epoxide (formed during post-translational modification of glutamate residues (e.g. in prothrombin)) back to the active form of vitamin K
• What is a Gla domain?

  Protein domain that contains gamma-carboxyglutamate residues

  Has a strong negative charge
• What does thrombin (IIa) do?

  Activates…

  • fibrinogen
  • Factor V & VIII
  • Factor VII
  • Factor XIII
  • Protein C
  • Platelets (via proteinase-activated receptors (PARs))
• What is Factor XIII? What does it do?

  Inactive anzyme

  Activated by thrombin

  ACTIVITY: Crosslinks glutamate to lysine in fibin (Ca+2 is co-factor)
• What is fibrinolysis?

  Plasmin starts to dissolve thrombus (clot)
• What is D-dimer?

  One of the breakdown products of fibrinolysis
• What is plasminogen?

  Proenzyme

  Binds ro lysine residues in fibrin

  Activated by urokinase or tissue plasminogen activator (tPA) -> forms plasmin
• What is the activity of plasmin?

  Cleaves fibrin -> releases degradation products (e.g. D-dimer)
• What part of the coagulation cascade does prothrombin time (PT) 'test'?

  Extrinsic pathway