Coagulation Flashcards
- Define hemostasis.
The cessation of blood loss from a damaged vessel. Primary hemostasis involves platelet aggregation whereas secondary hemostasis involves the coagulation of the platelets and stabilization with fibrin. Inactive fibrinogen is activated to fibrin via thrombin.
- Define fibrinolysis.
Fibrinolysis is the digestion of fibrin+platelet aggregation via plasmin. Inactive plasminogen is converted to the proteolytic enzyme plasmin.
- What are platelet aggregation inhibitors?
Platelet aggregation inhibitors decrease synthesis or action of chemical signals that promote platelet aggregation. The platelets are being directly acted on. This category includes: COX inhibitors, ADP receptor blockers, phosphodiesterase inhibitors and blockers of platelet IIb/IIIa receptors.
- What is the MOA of Aspirin (acetylsalicylate)?
Aspirin is an irreversible cyclooxygenase inhibitor used to antagonize thromboxane A2 synthesis. Aspirin acetylates COX enzymes and due to the lack of platelet nuclei there is an inability to synthesize more COX in the individual platelet. Therefore, once the platelet COX enzyme is acetylated it will be unable to produce COX again and therefore will be inactive during its 10 day lifetime. Thromboxane A2 normally causes platelet aggregation and degranulation. TXA2 usually activates the Gq receptor signal leading to PLA2 activation and fibrinogen binding to GPIIb/IIIa. [fibrinogen forms bridges between adjacent platelets] By inhibiting TXA2 there is no platelet aggregation therefore a prolonged bleeding time.
- What are the clinical uses of Aspirin (cyclooxygenase inhibitor)?
- prophylactic tx for transient cerebral ischemia
- reduce incidence of recurrent MI
- decrease mortality in post MI pts
- Give examples of ADP receptor blockers.
- Clopidogrel (Plavix) – preferred over Ticlopidine due to fewer adverse effects
- Ticlopidine
- What is the MOA and uses of ADP receptor blockers?
Clopidogrel and Ticlopidine are irreversible inhibitors of P2Y12 (located on surface of platelet). They are used to reduce the rate of stroke, MI and death in pts with recent MI, stroke and acute coronary syndrome. This can be given as an alternative to pts who are unable to tolerate Aspirin.
- What are the different drug interactions to watch out for with use of Clopidogrel?
- Clopidogrel is consumed as a prodrug that needs to be activated by CYP2C19. Pts who are CYP2C19 poor metabolizes have lower plasma levels of active Clopidogrel therefore it does not reach therapeutic level and is not effective. Therefore alternative treatments need to be considered with these patients.
- Omeprazole (CYP2C19 inhibitor) reduces levels of CYP2C19 in the body therefore making Clopidogrel prodrug not metabolically active. Therefore, concurrent use of Clopidogrel and Omeprazole should be avoided.
- Give an example of Phosphodiesterase inhibitors.
Dipyridamole
- What is the MOA and use of phosphodiesterase inhibitors?
Phosphodiesterase normally breaks down cAMP and cGMP. An increased amt of cGMP allows for vasodilation. When Dipyrodamole is given, it inhibits phosphodiesterase preventing a decrease in cAMP/cGMP levels allowing for coronary vasodilation. Dipyrodamole is used prophylactically to treat angina pectoris. This drug has little beneficial effect when used alone but does have therapeutic effect when used in combination with warfarin or aspirin.
- What is the MOA and uses of blockers of platelet GP IIb/IIIa receptors?
Fibrinogen binds to GP IIb/IIIa on platelets. Activation of the receptor is the final common pathway for platelet aggregation. These blockers are used to reduce thrombotic CV events in pts with non-STEMIs. It is also used as an adjunct to PCI (?) for the prevention of cardiac ischemic complications.
- What are examples of blockers of platelet GP IIb/IIIa receptors?
- Abciximab – monoclonal Ab against the GP IIb/IIIA receptor
- Eptifibatide – cyclic peptide reversible antagonist of the GP IIb/IIIa receptor
- Tirofiban – non-peptide reversible antagonist of the GP IIb/IIIa receptor
- What are the different categories of indirect thrombin and factor Xa inhibitors?
- unfractionated heparin (UFH)
- low-MW heparins (LMWH)
- Fondaparinux
- What are the UFH and LMWH?
Heparin is a mixture of straight chain, sulfated mucopolysaccharides give as an injectable, RAPIDLY ACTING ANTICOAGULANT, used acutely to interfere with formation of thrombi. UFH has a molecular weight range of 5,000-30,000 [wide range!]. LMWH is produced by depolymerized UFH that ranges from 1,000-5,000. LMWH have equal efficacy to UFH, higher bioavailability, longer half-life and less frequent dosing requirements therefore are replacing UFHs in many clinical situations.
- What specific drugs fall under the LMWH category?
- Enoxaparin
- Dalteparin
- Tinzaparin
- What is the MOA of heparin?
Heparin with antithrombin III inhibits clotting factor proteases (thrombin, IXa, Xa). Without heparin, antithrombin III inhibits them very slowly therefor the binding of heparin (which acts as a cofactor) to antithrombin III accelerates the inhibition. Different MW of heparin have different anticoagulant activities.
UFH → efficiently inactivates both thrombin and factor Xa b/c due to its large structure can wrap around ATIII and inhibit/bind IIa
LMWH → efficiently inhibits Xa but has less effect on thrombin b/c the structure is unable to wrap around and inhibit IIa after binding ATIII
- How are Heparin levels monitored?
Heparin is monitored with activated partial thromboplastin time assay (aPTT). aPTT is a test of integrity of the intrinsic and common pathways of coagulation. LMWH dosing provides a much more predictable plasma levels therefore monitoring is not required. Potency of LMWH can be assessed with anti-factor Xa assay.
