Anticoagulants and antiplatelet agents
used to treat thrombotic disorders or unwanted clot inside a blood vessel which can lead to heart attack or stroke
Review:
【Covid-19】Causes & mechanisms that promote thromboinflammation in COVID-19
【Covid-19】Drug for thrombosis in COVID-19: Western medicine & a TCM Prescription
Content:
2. Platelet aggregation inhibitors
3. Coagulation cascade
4. Anticoagulants
5. Thrombolytics
6. Reference
1. Clotting process
- In the absence of injury, the endothelial cells that make up the inner surface of blood vessels release nitric oxide and prostacyclin
- nitric oxide: dilate blood vessels
- prostacyclin: bind to receptors located on platelets
- prevent platelet activation and aggregation
- When there is a damaged blood vessel,
- less nitric oxide and prostacyclin
- blood vessels become constricted
- platelets become activated
- with the help of von willebrand factors, platelets adhere to exposed collagen which in turn causes them to change shape
- activated differently shaped platelets begin to release granules, such as
- ADP
- thrombin
- thromboxane A2
- serotonin
- platelet activating factor
- attract and activate even more platelets that come to the site of injury
- Activation of the glycoprotein 2b/3a receptors
- bind circulating fibrinogen
- fibrinogen binds to these receptors on two separate platelets
- cross-linking platelets to form aggregates
2. Platelet aggregation inhibitors
Drugs that can disrupt this platelet plug formation
Drug: Aspirin
- most widely known
- when platelet becomes activated
- arachidonic acid is released from the membrane phospholipids
- it gets converted to prostaglandin H2 by cyclooxygenase-1 enzyme (Cox-1)
- Prostaglandin H2 is further metabolized to thromboxane A2
- released from the platelet to stimulate activation of new platelets &
- promote their aggregation
Summary: Aspirin irreversibly inactivates Cox-1 enzyme, thus effectively disrupting clot formation
【Pharmacology】Pharmacology Hack 11. Aspirin
Drug:
- Clopidogrel
- Ticagrelor
- Ticlopidine
- Prasugrel
- work by blocking the action of ADP receptor, specifically P2Y12 subtype
- activated platelets release ADP
- ADP binds to P2Y12 receptor
- activation of the glycoprotein 2b/3a receptors which are required for fibrin mediated platelet cross-linking
- By blocking P2Y12 ADP receptors,
- effectively inhibit platelet aggregation and thus clot formation
Drug:
- Abciximab
- Eptifibatide
- Tirofiban
- glycoprotein 2b/3a receptor blockers
- inhibit platelet aggregation by binding to the glycoprotein 2b/3a receptors on platelets
- preventing fibrinogen from binding to platelets
- unable to crosslink
Glycoprotein 2b/3a inhibitors are administered only intravenously
Drug:
- Dipyridamole
- Cilostazol
- phosphodiesterase inhibitors
- inhibit enzyme called phosphodiesterase
- responsible for breaking down cyclic AMP to AMP
- increase intracellular levels of cyclic AMP
- decrease in intracellular calcium
- inhibition of platelet activation
- inhibit phosphodiesterase in the vascular wall & uptake of adenosine
- promotes vasodilation
- Cilostazol: used to treat symptoms of peripheral artery disease, such as
- narrowing of vessels that supply blood to legs
Side effect
- Bleeding
- Dipyridamole and Cilostazol: Headaches
- due to their vasodilating properties
3. Coagulation cascade
- Plug is usually not enough to secure the site of injury
- to strengthen the platelet plug
- a clot must form the formation of clot involves cascade of enzyme reactions
- transform various clotting factors to their active forms
- ultimately producing web-like fibrin mesh
Two pathways involved with a clotting cascade:
Intrinsic pathway: Activated by damage directly to the blood vessel wall
- starts with clotting factor 12
- activated when blood comes into contact with a collagen in the damaged vascular wall
- leads to activation of factor 11
- activates factor 9
- activates factor 10
- activated factor 10 then converts prothrombin to thrombin
- thrombin converts fibrinogen to fibrin which forms mesh that strengthens the platelet plug
Extrinsic pathway: Activated by trauma to the vascular wall & surrounding tissue
- triggered by tissue factor released from damaged cells outside the circulating blood
- starts with an activation of factor 7
- activates factor 10
- converge into a common pathway
- results in formation of fibrin clot
4. Anticoagulants
work by disrupting coagulation cascade
Drug:
- Heparin
- Low-molecular-weight Heparin: Enoxaparin and Dalteparin
- bind to our natural anticoagulant circulating in blood called antithrombin 3
- the primary function of antithrombin: inactivate factor 10a and thrombin
- Heparin drugs
- bind to antithrombin
- they accelerate its activity
- results in rapid inactivation of both factor 10a and thrombin
- Low-molecular-weight Heparins
- very little effect on inactivation of thrombin
- selectively accelerate inactivation of factor 10a
- Fondaparinux
- selectively accelerate inactivation of factor 10a
- doesn't bind to any other plasma proteins
- has no direct effect on thrombin
Side effects
- Bleeding
- Reversal agent: Protamine sulfate
- used to treat excessive bleeding caused by Heparin drugs
- works by binding to Heparin or low-molecular-weight Heparins to form stable inactive complex
- Fondaparinux doesn't have any specific antidote
- Heparin agents: Heparin induced thrombocytopenia (HIT)
- a disorder caused by immune system making antibodies to Heparin when it's bound to platelet-derived protein called platelet factor-4
- Once the antibodies bind to these Heparin platelet factor-4 complexes,
- they begin to activate platelets which clump together
- causing formation of unwanted clots and fall in platelet count
Drug:
- Apixaban
- Rivaroxaban
- direct inhibitors of factor 10a agents
- they both bind directly to the active side of factor 10a
- preventing it from converting prothrombin to thrombin
- Advantage: available in oral formulation
- Disadvantage: bleeding & specific antidote is currently not available
Direct thrombin inhibitors
- subdivided into two classes:
- univalent direct thrombin inhibitors
- bind only to the active site
- Drug:
- Argatroban
- Dabigatran
- bivalent direct thrombin inhibitors
- bind to both active site and the exosite-1 that is fibrinogen binding site
- this bivalent binding contributes to their high affinity and high specificity for thrombin
- Drug:
- Bivalirudin
- Desirudin
- Advantages of direct thrombin inhibitors over indirect thrombin inhibitors, Heparin
- don't bind to platelet factor-4
- useful in treatment of Heparin induced thrombocytopenia
- Disadvantages: bleeding & no specific antidote available
Drug: Warfarin
- oldest anticoagulants that's still on the market
- the role of vitamin K in the coagulation cascade:
- required for synthesis of factors 2 7 9 and 10
- these coagulation factors are biologically inactive until they are carboxylated by vitamin K
- reduced vitamin K is oxidized to the vitamin K epoxide
- in the presence of oxygen and carbon dioxide yielding carboxylated fully active clotting factors
- oxidized vitamin K is recycled back to the reduced form by enzyme called vitamin K epoxide reductase
- Warfarin inhibits this enzyme
- disrupts this vitamin K dependent synthesis of biologically active clotting factors & other regulatory factors
- Disadvantages:
- narrow therapeutic window
- associated with many drug-drug and drug-food interactions
- clinicians need to closely monitor patients on Warfarin by using the International normalized ratio measurement (INR)
- adjust the dose when necessary to balance the risk of bleeding against the risk of clotting
- fortunately in the event of bleeding anticoagulant effects of Warfarin,
- can be overcome by administration of vitamin K
- however reversal can take up to 24 hours
- Therefore, in the event of emergency, infusion of fresh frozen plasma might be necessary
5. Thrombolytics
- act on the existing clot
- causing it to dissolve by directly or indirectly activating circulating protein called plasminogen
- plasminogen turns into plasmin
- plasmin is an enzyme that breaks cross-links between fibrin molecules
- dissolving the clot
Drug:
- Alteplase
- Reteplase
- Tenecteplase
- produced by recombinant DNA technology
- to mimic our naturally occurring tissue plasminogen activator
- Urokinase
- naturally occurring thrombolytic produced from cultured human kidney cells
- Streptokinase
- derived from streptococcal bacteria
Main differences between these agents
selectivity for fibrin-bound plasminogen & free circulating plasminogen
- Alteplase: tissue plasminogen activator
- more clot selective
- acts to dissolve the fibrin in the thrombus
- Streptokinase & Urokinase
- less clot selective
- more likely to cause internal bleeding into any organ system
Side effect: bleeding
- managed by administration of Aminocaproic acid or Tranexamic acid
- stop fibrinolysis by inhibiting binding of plasminogen to fibrin & conversion of plasminogen to plasmin
6. Reference
https://youtu.be/eZBtQ0rDnG4
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