Hematological agents I Flashcards
What are the three chemokines released from platelets at the site of injury, that cause vasoconstriction?
Thromboxane A2
5HT
ADP
Thrombin causes endothelial cells to secrete what chemokine? What does this do?
endothelin 1
Vasoconstricts
What is the protein on blood vessels that is exposed and allows for the attachment of GP Ib?
von Willebrand factor
What is the protein on platelets that attachs to vWF?
GP Ib
What are the proteins on platelets that interact with ADP?
P2Y1 and P2Y12 GPCRs
What does the glycoprotein GPIIb/IIIa on platelets bind to?
fibrinogen in the plasma, which binds other platelets
What does the coagulation cascade utimately produce? What does that cause?
thrombin, which activates fibrinogen into fibrin
Thrombin activates protease-coupled receptors (PARs). What is the function of this?
further activation of platelets
What mineral increases with platelet activation, and activates phospholipase A2?
Ca
What is the role of phospholipase A2, after activation by Ca?
cleaves phospholipids to create arachiodonic acid
What is the MOA by which ASA decreases platelet activation?
Prevents formation of thromboxane A2 by inhibiting cox enzymes
What organ synthesizes most of the coagulation factors?
Liver
What are the components of the prothrombin activator complex?
Xa, Va, Ca2+
What activates factor 12 in the intrinsic pathway?
negative surface of a damaged blood vessel
What is the order of the intrinsic pathway?
12, 11, 9, 10
What are the components of the tenase complex? What is the role of the tenase complex?
factors 8 and 9significantly accelerates the catalytic activity of IXa
What is the cause of hemophilia A?
reduced levels of factor VIII
What allows the initial small amounts of thrombin to lead to an explosive burst of thrombin production?
Positive feedback of thrombin mediated Factor VIII and V activation
What factor is an intregral membrane protein, that binds to , and proteolytcally activates facot VII?
Factor 3
What is the order of the extrinsic pathway of coagulation
3, 7, 10
What does the factor 3 and 7 complex do?
activates factor X
What is the protein that initially tethers platelets to the site of injury?
GP 1b
What are the two mechanisms by which the anticoagulation system prevent aberrent clot formation?
Prevent thrombin mediated fibrin clot formationDestroying thrombin
What is thrombomodulin?
integral membrane protein on vasculature endothelial cells that can bind thrombin and protein C
What is protein C? What role does it play in it’s complexed form?
Protein that is activated by thrombomodulin, and activates protsin SProteolytically activates factors V and VIII
What is the role of tissue factor pathway inhibitor?
Circulating protein that inhibits tissue factor/ VII complex and factor X
What is the role of antithrombin?
Circulating protease inhibitor that inactivates thrombin when bound to heparin
What is the key protein involved in the fibrinolytic system?
Plasminogen / plasmin
What activates plasminogen, and turns it into plasmin? What cells express this activator?
tPA which is expressed by endothelial cells
How is it that not all clots are dissolved if tPA is expressed by endothelial tissue?
tPA removed by plasminogen activator inhibitorthrombin-activatable fibrinolysis inhibitor
What is the role of alpha2 antiplasmin?
Inhibits unbound plasmin
What is the role of factor XIII?
Stabilizes the fibrin clot
What organ produces antithrombin?
Liver
What is the complex that activates protein C?
Thrombin+ thrombomodulin
What does the E1 site on thrombin bind?
Fibrin
How is thrombin prevented from forming clots throughout the body? What stops antithrombin from stopping it?
Has to bind to fibrinBinding site is not exposed to antithrombin
True or false: the antithrombin/heparin complex does not inhibit thrombin bound to fibrin
True
Why are venous thromboses referred to as “red clots”?
Platelet poor, filled with RBCs
Why are arterial thrombi white?
Full of platelets
Where do venous thrombi usually form?
Vavle cusps
Why aren’t antiplatelet therapies not very useful for veinous thromboses?
Not a lot of platelets in the clot
Prothrombitic or antithrombic: factor V leidin
Prothrombotic
Prothrombitic or antithrombic: Protein C mutation
Prothrombotic
What is the MOA of ASA?
Irreversibly blocks COX-1 in plateletsReduces thromboxane A2 production
Why don’t other NSAIDs reduce platelet aggregation?
Do not irreversibly bind cox enzyme
What are the adverse effects of ASA?
Gastric bleeding and inducing bronchospasms
What activates phospholipase A2? What does it produce?
Ca levelsProduces arachiodonic acid
Why is blocking of the Cox enzyme so effective in antiplatelet therapy?
Platelets do not have the machienery to make more
What is the MOA of dipyridamole?
Phosphodiesterase inhibitor that prevents conversion of cAMP to AMP, which lowers Ca levelsAlso increases cAMP uptake
True or false: dipyramidole has little effect without ASA
True
What is the role of P2Y12?
Protein on platelets that increases clotting when bound by Ca
What is the MOA of clopidogrel?
Prevents P2Y12 activation, which decreases {Ca] within platlets
True or false: clopidogrel is administered orally in the active form
False-prodrug form
What is one major issue that decreases the effectivness of clopidogrel?
Some pts have polymorphims that detract from effectiveness
What is the MOA of prasugrel?
Irreversible P2Y12 inhibitor
What is the major difference between clopidegreal and prasugrel?
Prasugrel is more activated, but higher rates of bleeding
What is the MOA of ticagrelor?
Reversible P2Y12 inhibitor
True or false: ticagrelor is administered as a prodrug
False
Why is it that ticagrelor’s effect are more easily reversed than clopidogrel or prasugrel?
Others are irreversible inhibitors of P2Y12
What is the MOA of cangrelor?
Reversible P2Y12 inhibitor
What is the major difference between cangrelor and other P2Y12 antagonists like clopidogrel or prasugrel?
Administered IV
Why is ticagrelor more potent than other P2Y12 inhibitors?
Administered in the active state
What is the enzyme that clopidogrel needs to be activated? What drugs inhibit this enzyme?
CYP2C19Omeprazole
What is the major contraindication to using prasugrel or ticagrelor? Why?
h/o intracrainal bleeding because causes bleeding
What is the MOA of abciximab?
Glycoprotein IIb/IIIa receptor antagonist, preventing crosslinking of platelets
How is abciximab administered?
IV bolus
What are the major adverse effects of abciximab?
Bleeding and thrombocytopenia
What is the MOA of Eptifbatide?
Peptide that prevents GP IIb/IIIa from binding other platelets
What is the major difference between abciximab and Eptifbatide?
Eptifbatide has a longer half life, with lower adverse effects
What is the MOA or tirofiban?
Inhibitor of GP IIa/IIIb
What is the MOA of vorapaxar?
Protease activated receptor (PAR) antagonist
What are the indications for vorapaxar use?
Reduction in thrombotic cardiovascular events in pts with a h/o MI
What do protease activated receptors do?
Thrombin binds to PARs and cause an increase in platelet activation
What are the adverse effects of Vorapaxar?
Intracrainal bleeding
True or false: antiplatelet therapy usually involves multiple drugs being used at once
True
What are the three drugs that are indirect inhibitors of thrombin and/or factor X?
HeparinEnoxaparinFondaparinux
What are the four direct thrombin inhibitors?
LepirudinBivalirudinArgatrobanDabigatran
What are the direct factor X inhibitors?
RivaroxabanApixaban
What is the vit K antagonist?
Warfarin
What are the diseases that anticoagulants are generally used?
Treatment/prevention of venous thromboses
What exactly is heparin?
family of sulfated polysaccharides found on mast cells
Is heparin usually found in the plasma?
No
What does it mean when heparin is unfractionated?
contains many different sizes of polysaccharide chains
What is the MOA of heparine?
binds to antithrombin, which inactivates coagulation factor Xa
How must heparin be administered?
IV or SQ (but must be parenterally)
What are the two ways that heparin is cleared?
Kidneys and liverEndothelial cells take it up
Why is it that uptake of heparin by endothelial cells is saturatable?
Limited space on endothelial cells
What is the equation for half life?
0.693 x Vd/CL
What is the lab test that is used to monitor heparin?
aPTT
Heparin clear is so variable, that it is often given in amounts greater than therapeutic range, causing bleeding. Why is this not such a big deal?
Short half life, so just tone back
What is the drug that can be given to inhibit heparin? MOA?
Protaminebinds and inactivates larger heparin molecules
What disease can be caused by long term heparin use?
Osteoporosis
