L8 anticoagulants Flashcards
Platelets
Abundant tiny cells that have no nucleus and is generated in the bone marrow.
has a role in clot formation.
Soluble clotting factors
- proteins
- Liver origin
Clot formation/coagulation simple
- Conversion of liquid blood into a clot
- platelets aggregate and will adhere to the surface of damage endothelium and form a temp seal.
- Blood clotting factors form strong durable thrombin-fibrin clot.
Condition when blood clot forms in vein
Venous thrombosis
Condition when blood clot forms in blood vessel of the heart
Myocardial infarction
Condition when blood clot forms in artery in the brain
Cerebral artery occlusion
Condition when blood clot forms in arteries of the arms or legs
Peripheral artery thrombosis
Coagulation cascade
- Series of steps in response to bleeding caused by tissue injury, where each step activates the next and ultimately produces a blood clot.
- Involves clotting factors (serine protease) that are autocatalytic
- Intrinisic (abnormal vessel wall) and Extrinsic (tissue damage)
The intrinsic cascade
Intrinsic
* XII -> XIIa (12)
* XI via XIIa -> XIa (11)
* same with IX to IXa via XIa (9)
* and X to Xa (10)
* Prothrombin (II) to thrombin via Xa -» thrombin fibrin clot
Extrinsic cascade
Damaged tissue to VII -> VIIa
X -> Xa
prothrmobin to thrombin to thrombin fibrin clot
Structure of prothrombin
Two sites
* Factor Xa cleaveage sites
* Active site of thrombin from cleavage of prothrombin by factor Xa
The extrinsic pathway begins how?
when there is injury to the endothelial tissue (i.e., skin tissue), exposing tissue factor (factor III) to the blood. Tissue factor then becomes bound with calcium and factor VIIa to activate factor X. Factor VII is present in the blood and requires vitamin K to be activated.
What is Fibrin?
Fibrin (factor Ia) is a long, thin protein with branches produced at the end of the coagulation cascade when fibrinogen (factor I) is converted to fibrin, which stabilizes the blood clot.
Antithrombin III
small glycoprotein that inactivates several enzymes during blood clot formation.
What does antothrombin III do?
Act as an inhibitor and bind to thrombin making it unactive so it cannot activate thrmbin-fibrin clot and leads to clot lysis.
* Can bind with heparin allow to have greater affinity and effeciency with thrombin.
*
Fibrinogen
glycoprotein synthesized by the liver and is the major structural component of a clot. It is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot.
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
Vitamin K
- Fat soluble vit
- Cofactor for post translational carboxylation of lutamic acid groupd of factor II, VII, IX and X (2, 7, 9, 10)
- Similar structure to warfarin
Warfarin
- Vit k antagonist
- oral antocoagulants
- Competes for Vit K epoxide reductase component 1 (VKORC1)
- So it inhibits Vit K recycling from KO to KH (inactive to active)
Precusor of prothrombin
Decarboxy prethrombin
Carboxykation of Vit K results in what?
Reduces Vit K as a cofactor.
Vitamin K epoxide reductase complex 1
responsible for the recycling of reduced vitamin K from vitamin K epoxide.
Warfarin target
Vitamin K epoxide reductase complex 1 not just Vit K
Heparin
- Anticoagulent
- Inactives Xa and thrombin
- Is a mixture of glycosaminoglycans
- Molecular weight ranges 3000 to 58000
- Strong acid, so strong electronegative charge
Heparin: mechanism of action
- Bind to the lysine on Antithrombin III (ATIII)
- Will change conformation and increase ATII affinity for activated thrombin and Xa
- Accelerate inactivation
- Prevents conversion of fibrinogen to fibrin
- Stops clot propagation
Pharmacology of heparin
- High MW
- Intravaneous
Direct enzyme inhibitors of Xa & IIa (thrombin)
- Apixaban and rivaroxaban
- Dabigatran (synthetic)
Both orally active and predictable so no monitoring
Promoting Clot Lysis: Tissue plasminogen activator (t‐PA)
- tPA catalyses the conversion of plasminogen, an inactive precursor, into plasmin, an active enzyme.
- Plasmin facilitates clot lysis
- dissolves fibrin clots
- Intravaneous
t‐PA
- Recombinant human protein IV Administration
- Immediate onset of action
- Relieves blockage of critical vessels, e.g. coronary artery occlusion (heart attack)
Antiplatelet Drugs:
Aspirin & Clopidogrel
Aspirin & Clopidogrel
- Aspirin works by irreversibly inhibiting the enzyme cyclo-oxygenase (COX-1) which is required to make the precursors of thromboxane-A2 within platelets.
- Clopidogrel reduces platelet activation and aggregation by inhibiting the binding of ADP to its platelet receptor.
Contact with damaged arterial
wall activates platelets to release what
- ‐ Thromboxane A2
- ADP
what two things enhance platelet aggregation & adhesion
Tx A2 and ADP
Synthesis of Thromboxane A2 (TxA2) in Platelets
- Arachidonic acid released
- Cyclooxygenase reveals the cyclisation of FA and pushing of O2 onto the FA precursor
- Prostaglandin G2
- Prostaglandin H2 (both from arachidonic acid and COX as enzyme)
- Thromboxane synthase, then converts PGH2 into thromboxane A2 (TxA2).
Aspirin (acetyl salicylic acid)
- Acetylation of NH2‐terminal serine of cyclooxygenase (irreversible)
- Permanent loss of TxA2 production
- Defective platelet clot formation
- Protection from thrombotic disorders
Clopidogrel
- Contact with damaged arterial wall activates platelets lead to ADP release
- Clopidogrel’s active metabolite blocks platelet ADP receptors irreversibly
- Heparin
– Given parenterally, works immediately - Warfarin
– Oral; Vit K has to deplete before it works;
– Needs regular monitoring of coagulation - Factor IIa and Factor Xa inhibitors
– Oral, monitoring not needed in most patients - Antiplatelet drugs
– Mostly for arterial disease; Lower bleeding risk than
anticoagulant drugs - Thrombolytic drugs
– Treatment of established, life threatening thrombosis
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