Anti-thrombotic Dr. Roane Flashcards
Dr. Roane EXAM III
How do platelets become activated?
Willebrand Factor
Plasma/tissue/platelet protein binding to platelets and collagen
What is released upon platelet activation?
-ADP -> activates more platelets
-TXA2 (thromboxane) -> activates more platelets
-serotonin (increases muscle tone -> vasoconstriction)
-> Attraction and activation of other platelets
Function of fibrin
-coating aggregated platelets
-binding platelets together in a plug
How does the platelet activation cascade get deactivated?
-by undamaged adjacent cells
-PGI2 (prostacyclin) and NO (nitric oxide
Intrinsic Pathway
Clotting pathway
12 - 11 - 9 - 10 - Prothrombin to Thrombin
Vessel damage -> Collagen exposed
Collagen on 12: 12 to 12a
12a activates 11: 11 to 11a
11a activates 9: 9 to 9a
9a activates 10: 10 to 10a
10a activates: Prothrombin: to Thrombin
Thrombin: positive loop to 5, 8, and 11
Extrinsic pathway
Clotting pathway
Vessel damage -> subendothelial exposure to blood -> Tissue factor activates 7: 7 to 7a
7a activates 9: 9 to 9a
9a activates 10: 10 to 10a
10a activates: Prothrombin: to Thrombin
7a also activates 10 directly: 10 to 10a
Thrombin: positive loop to 5, 8, and 11
(8 helps 9, 5 helps 10)
What is the role of Thrombin?
-Thrombin can also activate Fibrin:
Fibrinogen to loose Fibrin
-Thrombin activates 13: 13 to 13a
13a activates loose fibrin: loose fibrin to stabilized fibrin (bind platelets together)
-Thrombin acting in a positive loop to further stimulate the clotting cascade
Function of Antithrombin III
-turns off the intrinsic pathway (12-11-9-10): acts on 12a, 11a, 9a and 10a
-turns off the common pathway: 10a and Thrombin
Where is Antithrombin III synthesized?
-in the liver
-naturally occurring
plasma protein
-Human recombinant ATIII is
available as the drug
What is the indirect thrombin inhibitor?
Heparin (naturally polysaccharid), variable lenght of chains
-Unfractionated heparin (UFH): all chain
-Low molecular weight heparin (LMWH) - short chain
Which form of heparin is known to be very short?
Fondaparinux (Arixtra)
How does Heparin work?
it attaches Antithrombin III to Thrombin
-Antithrombin turns Thrombin off and terminates the clotting pathway
half-life, onset, formulation
-injectable
-short-halflife
-quick onset
-very potent (can also be turned off quickly)
What do all heparin forms have in common?
all contain a penta(5)saccharide sequence
How are the heparin forms different?
-vary in the length of the GAG tail
-UFH: has a long GAG + penta(5)saccharide
long links Antithrombin and thrombin
links antithrombin and factor 10a (also 12a, 11a, 9a)
-LMWH: has a short GAG + penta(5)saccharide
links antithrombin and 10a
-Fondaparinux has no GAG, only the penta(5)saccharide
links antithrombin and 10a
How is the short form of heparin different in therapy?
they only link ATIII with 10a, so not as potent, lower risk of causing bleeding
Low molecular weight heparin drugs
-parin
Enoxaparin, Dalteparin, Tinzaparin
-short form of heparin
-activity at Xa and Thrombin 2a?
-t1/2 of 4h, renal clearance !!!
Side effects
-Bleeding
-platelet activation and clotting (paradox)
-Thrombocytopenia (low number of platelets bc destroyed by immune cells or used up heparin-induced thrombocytopenia)
-LMWH can cause kidney damage: contraindicated in GFR < 30 ml/min
What are the antidotes of heparin?
-for UFH: Protamine sulfate
-for Fondaparinux: PCC (prothrombin complex concentrate)
Which form of heparin is preferred to spare the kidneys?
-UFH (long chain form) bc of the short half-life
MOA of Warfarin
-factors 7, 9,10 (extrinsic), and 2 (Prothrombin) need the reduced form of Vitamin K and carboxylation to be activated
-Warfarin blocks the enzyme VKORC1: reduction of Vitamin K
-Warfarin is a competitive inhibitor of Vitamin K, with enough Vitamin K intake, the potency of warfarin is lowered
Warfarin pharmacokinetic profile
100% oral bioavailability
99% protein bound to albumin (watch out for other protein binders -> displace warfarin from albumin and increases warfarin’s potency -> bleeding)
-long half-life, long onset
-racemic mixture: L-isomer is 4x potent
What is the antidote of warfarin?
-PCC (prothrombin complex concentrate)
-also the antidote of Fondaparinux
What are the available clotting tests?
-PT: prothrombin time (12sec): evaluates the extrinsic and common pathway (so it contains the tissue factor)
-INR: international normalized ratio: more accurate and useful for patients taking Vitamin K antagonists (like warfarin) -> bc Vitamin K needed to build Prothrombin
-aPTT: activated partial thrombin time (30-45 sec): evaluates the intrinsic and common pathway
more sensitive to patients on heparin
-> bc heparin binds to the factors in the intrinsic pathway and thrombin
Name the oral Factor Xa inhibitors
-Rivaroxaban (Xarelto)
-Apixaban (Eliquis)
-Edoxaban (Savaysa)
-don’t need monitoring (like heparin or warfarin)
-Most seen in DVT prevention
What is the antidote for Factor Xa inhibitors?
-Andexanet alfa (recombinant gene product)
-injected
-decoy binding site for Rivaroxaban, Apixaban, Edoxaban -> the drugs will bind andexanet alfa instead of Factor Xa
Direct thrombin inhibitor (factor 2a)
-block the thrombin catalytic site and the substrate
binding site on thrombin
-> blocks the conversion of Fibrinogen to loose fibrin and to stabilized fibrin
-Hirudin
-Bivalirudin
-quick onset, short-acting, safer than heparin
What are the large molecule thrombin inhibitors?
-Hirudin
-Bivalirudin
-quick onset, short-acting, safer than heparin
What are the small molecule thrombin inhibitors?
-Argatroban, IV (contraindicated in hepatic dysfunction)
-Dabigatran, PO: slow onset long half-life - renal elimination
What is the reversal agent Dabigatran?
Idarucizumab
Thrombolytics
-TA: tissue plasminogen activator
-convert Plasminogen to Plasmin (Clotbuster, cuts clots)
-Streptokinase
-Urokinase
-Altepase (t-PA)
-Reteplase
-Tenecteplase
Where are thrombolytics used?
-to remove clots
-MI
-ischemic stroke
Platelet activation
-exposure of collagen -> GPV1 protein on moving platelets bind to collagen
Activation of:
-COX-1 -> TxA2 (thromboxane): recruits other platelets
-GPIIb/IIa: activates fibrinogen receptor for platelet clotting
-ADP: stimulates GPIIb/IIa and TxA2 in other recruited platelets
-Serotonin: vasoconstriction
What is the receptor on platelets that respond to soluble thrombin (IIa)?
PAR-1/PAR-4
-thrombin binds to PAR-1/PAR-4 for platelet recruiting and activation via TxA2
-blocked by the drug: Vorapaxar
Which molecules inhibit platelet aggregation?
-PGI2 (prostacyclin)
-NO (nitric oxide)
-from adjacent endothelial cells
Antiplatelet drugs
-Aspirin (blocks irreversibly COX-1 -> no platelet recruiting)
-Vorapaxar (Zontivity) (blocks thrombin from binding to thrombin receptor PAR-1/PAR-4 -> no platelet recruiting via TxA2)
-Clopidogrel (prodrug CYP2C19)
-Prasugrel (prodrug)
-Cangrelor (short-acting)
-Ticagrelor (reversible, AE: dyspnea)
-> blocking ADP receptor irreversibly
-Abciximab
-Eptifibatide
-Tirofiban
-> Blocking GPIIa/IIb for platelet fusion
Why are high doses of aspirin harmful?
-because it not only blocks COX-1 but also inhibits PGI2 (prostacyclin) which stops the platelet cascade
Which drug is used to stop bleeding?
MOA
-Amino caproic acid (Amicar)
-used esp after surgery
-binds to Plasminogen, inhibits conversion to active Plasmin (inhibits the “clot cutter”)
Treatment of the inherited bleeding disorder Hemophilia
Hemophilia A (missing factor 8)
Hemophilia B (missing factor 9)
-administration of the missing factor
