Drugs Used in Coagulation Disorders (Hock) Flashcards
What 4 types of drugs are used in coagulation disorders?
-Antiplatelets
-Anticoagulants
-Thrombolytics
-Coagulants
What is hemostasis?
The arrest of bleeding from a damaged blood vessel
What are the five stages of hemostasis?
- Injury to blood vessel
- Vasospasm
(blood vessel constricts to reduce blood flow through vessel which minimizes bleeding) - Platelet Plug Formation
(platelets form temporary plug, platelet adherence and aggregation) - Fibrin clot formation
(reinforced by fibrin) - Fibrinolysis
(pathway clears away the clot/plug)
What molecules are involved in the creation of fibrin during clot formation?
Prothrombin -> Thrombin
Thrombin then cleaves Fibrinogen -> Fibrin
What molecules are involved in the break down of fibrin during fibrinolysis?
Plasminogen -> Plasmin
Plasmin then splits Fibrin -> Split Products
What cells are platelets derived from?
Megakaryocytes
True or False: Platelets do not have a nucleus
TRUE
They have organelles and secretory granules but no nucleus
How to platelets replicate?
Platelets do not divide
-they just get bigger until they send out processes that pinch off into pre-platelets
-these are then broken down into small platelets
How does not having a nucleus affect platelet’s ability to fix themselves?
Platelets do not have DNA or RNA and therefore cannot make proteins
-Because of this, they are unable to replace proteins that have been inhibited
What initiates platelet reactions?
Contact with the extracellular matrix
After injury to a blood vessel occurs and platelets come into contact with the extracellular matrix, what are the 3 processes that mediate platelet adhesion to the extracellular membrane?
(First Step of Platelet Activation)
-GP la on the platelet binding to collagen
-GP lb on the platelet binding to von Willebrand Factor bridged to collagen
-Shape changes that facilitate receptor binding
When platelets aggregate to the extracellular matrix after injury occurs, GP la (on the platelet) mediates adhesion by binding to what?
collagen
When platelets aggregate to the extracellular matrix after injury occurs, GP lb (on the platelet) mediates adhesion by binding to what?
von Willebrand Factor bridged to collagen
How do intact endothelial cells inhibit thrombogenesis (blood clot formation)?
They secrete PGI2 (prostacyclin)
-prostacyclin inhibits platelet aggregation and increases vasodilation
What occurs during the second step of platelet activation?
Secretion
-Degranulation
-Platelet granules are released:
—ADP
—Thromboxane A2 (TXA2)
—Serotonin (5-HT)
*These granules are released from platelets and activate + recruit other platelets
Besides recruiting other platelets during platelet activation, what is the other function of Thromboxane A2 (TXA2) and Serotonin (5-HT)?
Vasoconstrictors
What happens during the third step of platelet activation?
-The actual aggregation itself
-ADP, 5-HT, and TXA2 granules induce a conformational change of GPIIb/IIIa receptors (on platelets) which causes them to bind fibrinogen
-The fibrinogen cross-links the platelets to form a temporary hemostatic plug
-The platelets contract and form a mass (irreversible)
-Fibrin stabilizes and anchors the mass to form a surface for clot formation
What is the role of fibrinogen in clot formation?
Cross-links platelets into a temporary hemostatic plug that eventually fuses into a mass
What is the role of fibrin in clot formation?
Fibrin stabilizes and anchors the mass of platelets formed by fibrinogen to form a surface for clot formation
What molecule is responsible for changing fibrinogen into fibrin?
Thrombin
What molecule is responsible for changing prothrombin into thrombin?
Factor Xa
What are the 5 kinds of antiplatelet drugs?
COX-1 Inhibitors
ADP Receptor Inhibitors
Blockers of GPIIb/IIIa receptors
Phosphodiesterase-3 Inhibitors
Protease-Activated Receptor Inhibitors
What is the main COX-1 inhibitor used?
Aspirin (ASA)
How do COX-1inhibitors work? (Aspirin)
-Inhibits platelet COX-1 irreversibly through acetylation
(platelets cannot fix this without a nucleus)
-Interferes with platelet aggregation
-Prolongs bleeding time
Prevents arterial thrombi from forming
What is key to the anti-platelet activity of aspirin?
Inhibition of TXA2 granule (Thromboxane A2)
*interferes with platelet aggregation and loss of vasoconstriction effect
How does aspirin (COX-1 Inhibitor) inhibit the TXA2 granule?
The permanent loss of platelet COX-1 activity caused by aspirin results in decreased TXA2 levels
What dosing of aspirin gives its maximal effect?
50-320mg per day
What is prostacyclin (PGI2) and how can it be affected by aspirin?
Prostacyclin (PGI2) is produced by COX-2 in endothelial cells and secreted to inhibit thrombogenesis (see other card)
-Production of prostacyclin in tissues can be inhibited with high doses of aspirin
**We do not want this because prostacyclin helps with anti-coagulation
What are the indications for use of aspirin (COX-1 Inhibitor)?
Prophylaxis and treatment of arterial thromboembolic disorders:
-Prevent coronary thrombosis in unstable angina (restricted blood flow to heart)
-Adjunct to thrombolytic therapy
-Reduce recurrence of thrombotic stroke
What are the clinical actions of aspirin (COX-1 Inhibitor)?
-Prolongs bleeding time
*No change in prothrombin time (PT) (how long it takes for a clot to form)
How long after the last dose of aspirin is given does it take for hemostasis (body’s natural way of stopping bleeding) to return to normal?
36 hours
What are the side effects of aspirin?
-Upper GI Bleeding
(due to inhibition of COX1 produced prostaglandins in the GI tract that protect the stomach from acid)
*risk increases with age, NSAID use, and alcohol
-Acute Aspirin Overdose
(Symptoms: nausea, vomiting, diarrhea, fever, coma, death)
What doses of aspirin can induce Acute Aspirin Overdose?
Doses above 150 mg/kg
**Doses above 500 mg/kg can be fatal
Why did selective COX-2 inhibitors not work?
COX-2 makes prostacyclin in endothelial cells which leads to vasodilation and inhibition of platelet aggregation
COX-1 produces thromboxane A2 in platelets which lead to vasoconstriction and platelet aggregation (what we want to block)
Selective COX-2 inhibitors were blocking prostacyclin synthesis (blocking the anti-coagulation effects) and not preventing TXA2 synthesis
**This increased the cardiovascular risk!
What are the two ADP receptors involved in platelet activation?
P2Y1
P2Y12
**Both of these must be activated to activate platelets, so you can inhibit just one!
What are the 4 ADP receptor inhibitors?
Pro-Drug:
-Clopidogrel
-Prasugrel
Direct Acting:
-Ticagrelor
-Cangrelor
What is the mechanism of action of Clopidogrel (Plavix)?
P2Y12 ADP receptor inhibitor (on platelet surface)
—irreversibly blocks the ADP receptor and subsequent activation of the GPIIb/IIa complex
*reduces platelet aggregation