Flashcards in EXAM #2: HEMATOLOGICAL AGENTS Deck (59):
Outline the roles of the the five major hemostasis systems: vascular, platelet, coagulation, anti-coagulation, and fibrinolytic.
1) Vascular= vasoconstriction
2) Platelet= platelet plug
3) Coagulation= insoluble clot with fibrin
4) Anti-coagulation= inhibits coagulation
5) Fibrinolytic system= degrades clot
What is the role of GP1b in platelet activation?
GP1b binds vWF, to bind to collagen and activate platelets
What factors are secreted by platelets when activated? What is their function?
****Activate GP IIb/IIIa, which eventually allows for the platelet plug to form and function as vasoconstrictors*****
What is the function of activated GP IIb/IIIa platelets?
Binding to fibrinogen; the glue that binds platelets together to form the platelet plug
What is the is the role of thrombin in hemostasis?
1) Cleaves fibrinogen into fibrin
2) Further activates platelets by binding and activating PAR
Draw the coagulation system: intrinsic; extrinsic: and common pathway.
What is the source of TF in the extrinsic pathway?
Tissue Factor is released from damaged tissue to cause the cessation of bleeding from external trauma
What are the two mechanisms of the anti-coagulation system?
1) Prevent thrombin mediated clot formation by inhibiting thrombin and Xa
2) Destruction of fibrin
Draw the anticoagulation system.
What are the roles of Protein S and C in the anticoagulation system
1) Destruction of: VIIIa and Va
2) Reduce thrombin
What is anti-thrombin?
Circulating plasma protease that inhibits thrombin and Factor Xa
What speeds up the activity of anti-thrombin?
What binds the active site of thrombin?
Fibrinogen; this is where fibrinogen is converted to fibrin
What binds the E1 site on thrombin?
What is the purpose of Fibrin binding to thrombin at the E1 site?
This limits the diffusion of thrombin away from the clot
What is important to remember about thrombin bound to fibrin?
Antithrombin/heparin CANNOT inhibit thrombin already bound to fibrin at E1
What are the characteristics of a venous thrombosis?
- High RBC i.e. red
- Platelet poor
- Occur where flow is slow
****Can lead to venous and pulmonary embolism*****
What is important to remember about venous thrombosis from a management standpoint?
Antiplatelet therapies are NOT as useful b/c the clot are PLATELET-POOR
What are the characteristics of an arterial thrombosis?
- Rich in platelets
- Often occur on top of ruptured atherosclerotic plaques
What is important to remember about arterial thrombosis from a management standpoint?
Platelet-RICH; therefore, good targets for antiplatelet therapy
What are the common causes of hereditary thrombophilias?
*Factor V Liden Deficiency (cannot interact with proteins C and S)*
- Protein C defieicny
- Protein S deficiency
- Antithrombin deficiency
What are the major acquired causes of thrombosis?
3) Mechanical heart valve
4) Major surgery
6) Oral contraceptives
List the anti-platelet drugs.
What are the major uses of antiplatelet drugs?
1) Primary prevention of MI and CVA (white thrombus)
2) Secondary preventinon of recurrence
What is the mechanism of action of aspirin?
- Irreversible COX-1 antagonist
- Inhibits PG synthesis important in the production of Thromboxane A2
What is the role of Thromboxane A2 in platelet activation?
- Thromboxane A2 is a factor secreted by activated platelets causing them to aggregate
- ASA prevents the synthesis of this secretory product
What is the mechanism of action of Dipyridamole?
- First, elevated intracellular Ca++ ACTIVATES platelets
- cAMP reduces intracellular Ca++ in platelets
*Dipyridamole increases cAMP to REDUCE intracellular Ca++ and REDUCE platelet activation*
List the P2Y12 antagonists.
What is the mechanism of action of the P2Y12 antagonists?
- Platelets contain P2Y1 and P2Y12 GPCRs that bind ADP
- ADP is secreted from activated platelets; it exposes GpIIb/IIIa binding sites for fibrinogen
- P2Y12 antagonists BLOCK ADP from interacting with P2Y12 receptors
What is the difference between Clopidrogrel/ Prasugrel, and Ticagrelor/Cangrelor?
Clopidrogrel and Prasugrel=
- Pro-drugs that have be activated by the liver
Ticagrelor and Cangrelor =
- Do NOT need to be activated
What enzyme activates Clopidogrel? Why is this important?
- There is a high degree of polymorphism that may REDUCE the activity of Clopidogrel
- OMPEPRAZOLE inhibits CYP2C19 and may POTENTIATE effects
What are the important clinical considerations with the P2Y12 antagonists?
Preasugrel and Ticagrelor= superior results but more fatal bleeding
****CONTRAINDICATED in patients with hx of intracranial bleeding.
List the GP IIb/IIIa antagonists.
How is Abciximab typically used in clinical practice?
1) Adjunct therapy in patients undergoing PTCA/ PCI, and in conjunction with ASA and heparin
How are Tirofiban and Eptifibatide used clinically?
Unstable angina/ ACS
What is the mechanism of action of Abciximab?
Fab segment of a monoclonal antibody directed at GPIIb/IIIa, which prevents fibrinogen binding
*****Note that Abciximab also binds receptors for GPIIIb/IIIa on leukocytes, which may account for its anti-inflammatory and antiproliferative effects*****
What is the mechanism of action of Eptifibatide?
Peptide that binds and inhibits GPIIb/IIIa
What is the mechanism of action of Tirofiban?
Non-peptide small molecule that binds and inhibits GPIIb/IIIa
What are the adverse effects associated with GPIIb/IIIa antagonists?
What is the mechanism of action of Vorapaxar?
- Inhibits the protease activated receptor (PAR) on the platelet surface; recall, Thrombin binds this receptor and further activated platelets
- Vorapaxar is a PAR receptor antagonist
What is the adverse effect of Vorapaxar? When is Vorapaxar contraindicated?
Life-threatening intracranial bleeding
Thus, it is CONTRAINDICATED in patients with a history of previous stroke of intracranial bleed
What is DAPT?
Dual anti-platelet therapy:
- P2Y12 antagonist/ ADP antagonist
When is DAPT utilized clinically?
What is antiplatelet triple therapy?
ASA + Clopidigrel + Warfarin
What are the four different types of anticoagulant drugs?
1) Indirect inhibitors of thrombin or Xa i.e. activators of antithrombin
2) Direct thrombin inhibitors
3) Direct Factor Xa inhibitors
4) Vitamin K antagonists
List the indirect inhibitors of thrombin and/or Factor Xa.
List the direct thrombin inhibitors.
List the direct Factor Xa inhibitors.
List the vitamin K antagonists.
What are the indications for anticoagulants?
- Treatment and prevention of venous thrombosis/ venous thromboembolism
- Used in conjunction with antiplatelet drugs to treat MI
What is the mechanism of action of heparin?
- Recall heparin-sulfate endogenously binds and increases the activity of antithrombin
- Specifically, a specific pentasaccharide sequnce binds and changes the conformation of antithrombin
- Works are a molecular "bridge" to bring thrombin in close proximity to anti-thrombin (Factor Xa)
*****Only longer Heparin molecules can work as a molecular bridge****
Where does Heparin-sulfate come from?
Pig intestinal mast cells
What is unfractionated heparin?
Heparin with pentasaccharide chains of 5-30 kDa
Why is unfractionated heparin used in the hospital setting?
- Must be given IV
- Short 1/2 life
- Binds numerous plasma and tissue proteins that can make dosing challenging
- Clearance mechanisms make half-life dose dependent
How is Heparin cleared from the body? What are the treatment implications?
1) Kidney/ liver
2) Rapid binding on endothelial cells*****
There is a dose dependent clearance i.e. higher doses extend the half-life
How is Heparin monitored?
aPTT or PTT
*****Essentially a measure of the intrinsic pathway*****
What are the adverse effects of Heparin?
How do you manage severe bleeding in Heparin administration?
1) Discontinue use; heparin has a short-half life
2) Protamine in severe cases, a Heparin inhibitor