l8 Flashcards
Clot Formation
- Damaged endothelium reveals underlying collagen & other proteins
- Platelets aggregate and adhere to surface to form a temporary seal
- Blood clotting factors form strong, durable thrombin‐fibrin clot
Why interfere with blood clotting?
- Venous thrombosis
- Myocardial infarction (heart attack)
- Cerebral artery occlusion (stroke)
- Peripheral artery thrombosis,
Venous thrombosis
blood clot forms in a vein
Myocardial infarction
(heart attack)
Cerebral artery occlusion
(stroke)
Peripheral artery thrombosis
blood clot forms in peripheral arteries
Can prevent clood from travelling through to lung to the heart.
Explain how clotting factors work
- Clotting factor = serine protease - enzyme that speeds up the breakdown of another protein.
- The clotting factors are initially inactive and called zymogens.
- When placed with its glycoprotein co-factor, the clotting factor is activated and is then able to catalyze the next reaction
Explain the cascade and CF for an intrinsic damage
Abnormal blood vessel
- XII
- XI
- IX
- X
- prothrombin –(Xa)–> thrombin + fibrinogen
- Thrombin fibrin clot
Explain the cascade and CF for an extrinsic damage
Damage tissue
- VII
- x –(VIIa)–> Xa
3.5. prothrombin –(Xa)–> thrombin + fibrinogen - Thrombin fibrin clot
What inhibits thrombin
Antithrombin III
Agents that deplete functional clotting factors
– Warfarin
– Heparin
– Direct enzyme inhibitors: dabigatrin and rivaroxaban
- Agents that accelerate clot lysis
– Tissue plasminogen activator
- Antiplatelet drugs
– Aspirin
– Clopidogrel
Preventing clotting factor synthesis with
Warfarin
Vitamin K
cofactor for post‐ translational carboxylation of glutamic acid groups on Factors II, VII, IX & X
What does warfarin do to vitamin k
Warfarin inhibits Vitamin K recycling from KO (inactive) to KH2 (active
VKORC1
Vitamin K Epoxide Reductase Complex 1
Heparin will inhibit:
Inactivation of Xa and Thrombin
Heparin is
- Mixture of glycosaminoglycans
- Molecular weight ranges 3000 to 58000
- Strong acid, so strong electronegative charge
Heparin: mechanism of action
- Binds to Lysine on Antithrombin III (ATIII)
- Conformational change to ATIII.
- increase affinity for activated factors of intrinsic arm, esp. Xa & thrombin
- Accelerated inactivation of these
- Prevents conversion of fibrinogen to fibrin
- Stops clot propagation.
Direct enzyme inhibitors
Dabigatran inhibits what
IIa (2a) or thrombin
Direct enzyme inhibitors
Rivaroxaban inhibits what
Xa/10a
(tissue plasminogen activator) t‐PA
- Recombinant human protein
- IV Administration Immediate onset of action
- Relieves blockage of critical
- vessels, e.g. coronary artery occlusion (heart attack)
Clot lysis with t-PA
- Plasminogen is cleaved by t-PA
- Releases plasmin
- Plasmin facilitates lysis as it digests fibrin, fibrinogen and factor 2, 5, 7
Main point is that plasmin facilitates lysis for 3
Antiplatelet Drugs: Aspirin & Clopidogrel
- irreversible acetylation and inhibition of cyclooxygenase (COX) enzyme so no TxA2
- Clopidogrel’s active metabolite blocks platelet ADP receptors irreversibly
Aspirin (acetyl salicylic acid) in cox
- Acetylation of NH2‐terminal serine of cyclooxygenase (irreversible)
- Permanent loss of TxA2 production
- Defective platelet clot formation
- Protection from thrombotic disorders
Synthesis of ThromboxaneA2 (TxA2) in Platelets
- Arachidonic acid
cyclooxygenase - Prostaglandin G2
- Prostaglandin H2
- TxA2
TxA2 and ADP do what?
enhance platelet aggregation & adhesion
How is warfarin taken
– Oral; Vit K has to deplete before it works; – Needs regular monitoring of coagulation
How is heparin taken
IV
How is Factor IIa and Factor Xa inhibitors taken
– Oral,monitoring not needed in most patients
Dabigatrin and rivaroxaban
Why is aspirin and clopidogrel taken
Mostly for arterial disease ;Lower bleeding risk than anticoagulant drugs
How is Thrombolytic drugs taken
tissue plasminogen activator
– Treatment of established, life threatening thrombosis
IV
Warfarin is a teratogen
t/f
true
Tissue plasminogen activator (tPA) is particularly effective against platelet clots
t/f
false
Tissue plasminogen activator (tPA) can lyse thrombi in the coronary circulation, preventing myocardial damage from developing
t/f
true
