blood coagulation 1 and 2

• haemostasis - stop haemorrhage, prevent haemorrhage or maintain flow
• what are the three mechanisms to maintain haemostasis?

  cellular = platelets

  humoral = coagulation

  tissue = vessels
• disordered haemostasis has 2 main types: thrombosis (which is excess clotting) and haemorrhage (which is excess bleeding)
• thrombosis examples:

  Arterial ~ platelets

  •Coronary thrombosis

  •Thrombotic stroke

  Venous ~ coagulation

  •DVT / PE
• what are common classes of drugs used in the treatment of haemodynamic conditions?

  • anticoagulants
  • antiplatelets
  • procoagulants
  • fibrinolytic drugs
• list common anticoagulants


  • warfarin
  • citrate and ETDA
  • heparin, dalteparin, fondaparinux (-parin)
  • riveroxaban (-oxaban)
  • dibigatran (-gatran)
• list common antiplatelets


  • aspirin
  • clopidogrel (-grel)
  • ticagrelor (-grel)
  • tirofiban (-fiban)
  • dipyradamole
• example of a fibrinolytic

  alteplase
• example of a procoagulant

  transexamic acid
• soluble fibrinogen (factor I) is converted into insoluble fibrin (factor II). What is the difference between what fibrinogen and fibrin does?

  fibrinogen -> cross links platelets -> aggregation

  fibin -> forms fibrin clots -> coagulation
• in the clotting cascade, how is fibrin built on to form fibrin fibrils?

  fibrinogen -> fibrin monomer -> fibrin polymer -> fibrin fibrils
• what is the difference between prothrombin and thrombin?

  prothrombin -> factor II, inactive enzyme (zymogen), vitamin K dependent

  thrombin -> factor IIa, active enzyme

  • Formed by the action of FXa
  • cleaves the alpha and beta chain off fibrinogen -> FIa/ fibrin
  • (also activates platelets)
• which drugs target thrombin

  those ending in -gatran (anticoagulants)
• what classes of drugs does dibigatran fall under?

  • direct thrombin inhibitor
  • NOACs - novel/non-Vit-K oral anticoagulants
  • DOACs - direct oral anticocagulants
• what is the mechanism of action and target for dibigatran? what is the antidote for dibigatran?

  here

  cizu = cardiovascular and humanised

  
• what is Factor X? what does it become and its function? which drugs is it a target for?

  • FX -> inactive enzyme (zymogen), soluble, vitamin K dependent, has a negatively charged Gla domain that binds strongly to Ca
  • becomes FXa -> forms a complex with FVa (Ca2+ and PL) to cleave thrombin
  • drugs ending in -xaban (FX think X)
• what classes of drugs is rivaroxaban?

  • direct FXa inhibitor
  • NOACs
  • DOACs
• what is the mechanism of action and antidote to rivaroxaban?


  here

  
• what is factor V? Factor Va and what does it do?

  • factor V is an INACTIVE COFACTOR
  • factor Va is an ACTIVE COFACTOR and it forms a complex wiith FXa and Ca2+ and PL to cleave prothombin to thrombin
• what is meant by intrinsic/extrinsic 'tenase' and 'prothrombinase'? what are the enzymes, cofactors, substrates and products involved?


  here

  the writing in black is right

  
• what doe factor IX do?

  • zymogen ->
  • vitamin-K dependent factor
  • binds strongly with Ca due to negatively charged Gla residues
  • primary enzyme in the 'intrinsic tenase' complex
• what does factor VII do?

  • zymogen -> enzyme
  • vitamin-K dependent factor
  • strongly binds to calcium due to its strong negatively charged Gla residue
  • primary enzyme in the 'extrinsic tenase' complex
• what is factor III/tissue factor? where is it found? what does it do?

  • transmembrane glycoprotien, found in the subendothelial tissues
  • Co-factor - forms a complex with factor VIIa to increase activity -> extrinsic tenase complex
  • aka 'thromoplastin' / tissue factor
• what makes up extrinsic 'tenase' and what does it do?

  FVIIa and FIII = extrinsic 'tenase'

  cleaves/activates FX
• Heparins are a type of glycosaminoglycan (GAG), a group of complex carbohydrates that play crucial roles in various biological processes.

  its made of a repeating sequence of sulfated disaccharides

  binds to antithrombin III -> increases antithrombin III's ability to bind to and inhibit thrombin and proteases in clotting
• what is the difference between UFH and LMWH?

  • unfractionated more range
  • LMWH -> ends in -parin, gives a more consistent response with fewer adverse effects
• what is antithrombin III and its function? which drug enhances its activity?

  • SERPIN C1 (SERine Protease INhibitor - role in regulating the activity of proteases)
  • inhibits IIa, IXa, Xa, XIa, XIIa
  • heparin increases the activity of antithrombin III
• heparin is bigger than LMWH and fondaparinux, explain how these different drugs binding to ATIII wiht IIa vs with Xa cause a difference?

  here

  
• outline the coagulation cascade

  here

  
• outline the mechanism of action of Warfarinand when is normally used?


  • vitamin K antagonist -> inhibit production of vitamin K by vitamin K epoxide reductase. Reduced vitamin K = cofactor in γ-carboxylation of factors 2/7/9/10. Carboxylation induces a conformational change allowing the factors to bind Ca2+ and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. 
  • CLASS: Vit K-dependent oral anticoagulant
  • vitamin K structural analogue
  • prophylaxis of PE/VT
• what are other names for PL/Phospholipid and Ca2+ which are commonly seen in the extrinsic and intrinsic 'tenases' and prothrombinases


  PL = phospholipid = PS = phosphatidylserine = PF3 = platelet factor 3 Ca²⁺ = Factor IV
• explain what happens on the surface of platelets when there is platelet activation in terms of PS/PL and Ca2+


  • platelet activation causes the flip-floping of the PLBL which switches the hydrophilic tails of PL to the outside
  • this creates a negative charge on the surface of platelets and attracts Ca2+
  • this allows for the formation of tenase and prothrombinase complexes on the surface of platelets -> quickens the conversion of prothrombin to thrombin
  • this helps to stabilise clots and achieve haemostasis
• what is the function of FVIII?

  • inactive enzyme activated by FIIa
  • a plasma transglutaminase -> involved in the last stage in the formation of a clot
  • covalently crosslinks glutamine to serine lysin in fibrin
  • Calcium is a cofactor
• which factors/ molecules does factor IIa cleave/activate?

  factors 1, 5, 7, 8, 13

  protein C

  activates platelets via proteinase-activated receptors (PARs)
• how is fibin built up to a cross-linked fibrin polymer and broken down?

  fibrin -> fibrin monomer -> fibrin polymer -> fibrin fibrils -> cross-linked fibrin polymer -> degraded into final digestion products
• how are fibrin polymers broken down in the coagulation cascade?

  • plasminogen is converted into plasmin by urokinase or tPA
  • this cleaves the fibrin polymer
  • production of dissolution/digestion products, including D-dimer
• what drug class is alteplase? what is the mechanism of action of alteplase?

  class - fibrinolytic

  chem - human recombinant tPA

  pharm - plasminogen -> causes enzymatic activation -> increased endgoenous plasmin activity -> clot dissolution

  use - MI, PE, ischaemic stroke
• what are the two blood coagulation tests?

  PT -Prothrombin time

  aPTT - activated partial thromboplastin time

  both are performed with a citrated blood sample to prevent the sample from coagulating
• what is being measured in PT? what is used to trigger the coagulation?

  • EXTRINSIC PATHWAY (+common pathway)
  • Factors 1, 2, 5, 7, 10 could prolong PT
  • e.g., deficiencies in FVII or warfarin use
  • triggered by thromboplastin (FIII and PL/PS) and calcium
• what is being measured in aPTT? What triggers the coagulation?


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