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Pharm 22- Hemostasis and Thrombosis
1. How do platelets adhere to injured endothelium? How is TxA2 made and what are 3
stimuli?
a. vWF from platelet/injured endothelial cell links collagen to gpIb of platlet
b. stimulated by ADP, epinephrine, and collagen; PLA2 activated to cleave
arachidonic acid--> converted to cyclic endoperoxidase (via cyclooxygenase)-->
convert to TxA2 (thromboxane synthase)
2. How does TxA2 cause vasoconstriction? Important mediator for platelet aggregation
released from platelet granules? How can TxA2 lead to platelet aggregation?
a. binds Gi receptor reducing cAMP and hence smooth m. activation= constrict
b. ADP- makes platelets sticky (see next)
c. TxA2 activates Gq causing PLC activation--> increased Ca++ and activated PKC
(via DAG)--> PKC activates PLA2 leading to expression of GPIIb-IIIa on
platelets so they can aggregate
3. 2 G-protein receptors for ADP? 3 drugs that target P2Y(ADP)? GPIIb-IIIa w/ what is
critical for aggregation?
a. P2Y1 (Gq coupled- increases Ca++ and PKC like TxA2) and P2Y(ADP) (Gidecreases cAMP)
b. Clopidogrel, ticlopidine, and prasugrel (anything with a -clop- or -grel)
c. fibrinogen
4. Appart from the enzyme/substrate, what 2 things are needed for most coagulation cascade
reactions? How can the intrinsic pathway be activated by the extrinsic pathway?
a. neg charged phospholipid surface (gen phosphotidylserine transferred to platelet
surface) and Ca++
b. VIIa can activate factor IX (also X common to both and IIa can go back and turn
on intrinsic)
5. TxA2=> PLC; ADP=> adenylyl cyclase; Thrombin=> PLC
6. 4 ways IIa further activates clotting?
a. converts fibrinogen to fibrin, activates XIII so 'firm' clot can be formed, activates
V and VIII, activates platelets to aggregate and degranulate
7. Where are procoag factors generally found? Anticoag? 5 mechanisms that limit the
propagation of the hemostatic processes to the immediate area of concern?
a. pro-coag generally membrane bound and localized; anticoag- secreted and soluble
b. prostacyclin (PGI2) (increases cAMP-vasodilation and prevents platelet
activation), antithrombin III (inactivates IIa, IXa, Xa, XIa, XIIa; heparin
enhanced), protein C+S (vit K dep. inactivate Va, VIIIa via thrombomodulin),
Tissue factor pathway inhibitor (TFPI)- forms Xa:TFPI:VIIa:TF complex, plasmin
8. 3 ways plasmin actin restricted to clot area? Virchow's triad?
a. t-PA most effective bound to fibrin meshwork (clot), t-PA is inhibited by PAI
(thrombin/inflammatory cells secrete IL-1 and TNF-a increase PAI, alpha2antiplasmin in plasma neutralizes circulating plasma
b. endothelial injury (arterial), abnormal blood flow (stasis-venous thrombi), and
hypercoagulability
9. Most prevalent mutation for hyper coagulation? 2nd most common? Clinical
consequences?
a. factor V Leiden mutation (can't be inactivated by protein C)
b. prothrombin G20210A (adenine sub. for guanine)= 30% increase in plasma
prothrombin levels
c. both significantly increase risk of venous thrombosis; modest increase in risk of
arterial ththrombosis
10. What are the 3 classes of anti-thrombus agents?
a. anti platelet agents, anticoagulants, and thrombolytic agents
11. What are anti-platelet agents useful for (2)? 4 classes of drugs in this category?
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12.
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a. prophylactic and therapeutic treatment against MI and stroke
b. the cyclooxygenase (COX) inhibitor, the phosphodiesterase inhibitor, P2Y ADP
receptor inhibitors, and GPIIb-IIIa antagonists
When is aspirin most effective (dosing)? Why isn't prostacyclin (PGI2) affected as much
as TxA2?
a. low doses and/or at infrequent intervals (81 mg 1x daily)
b. b/c TxA2 is made by platelets and they don't have DNA or RNA to make new
cyclooxygenases once theirs are inactivated; prostacyclin is made by endothelial
cells, so they can make more if blocked
What drug inhibits phosphodiesterase-3, hence increasing cAMP and decreasing platelet
aggregation? Uses? What is its danger?
a. dipyridamole (weak so use in combo)
b. prophylaxis against thromboembolic disorders and as an alt to exercise for
myocardial perfusion imaging
c. coronary steal phenomenon in people with coronary artery disease
2 approved uses for ticlopidine in US? Why less safe than clopidogrel? What is
clopidogrel approved for?
a. secondary prevention against throbotic strokes in ppl intolerant to aspirin and in
combo w/ aspirin to prevent stent thrombosis
i. loading dose is helpful for thienopyridine drugs
b. ticlodipine is less safe b/c it causes bone marrow toxicity and TTP; clopidogrel’s
adverse effects are mostly GI-related
[TICkles your bone marrow]
c. secondary prevention in ppl w/ recent MI, stroke, periph vasc disease, acute
coronary syndromes, prevention of stent thrombosis (same type of stuff)
What is another use of clopidogrel—what is it used in combination with? Adverse effects
(2)?
a. Also used with aspirin for percutaneous coronary intervention
b. Can interact with P450 drugs: statins, proton pump inhibitors, etc.
c. Also GI effects
Drawbacks of prasugrel?
a. High bleeding risk in patients over 75 years or under 60 kg
3 antagonists of GP IIb-IIIa? What is their common, clinically serious side effect? Why is
abciximab unique and what are the clinical implications?
a. eptifibatide, abciximab, and tirofiban
[don’t FIB about being sick]
i. used for ischemic events and during/after coronary intervention
b. major bleeding
c. abciximab binds GPIIb-IIIa site irreversibly (other 2 don't) so it can be reversed
w/ admin of fresh platelets; with eptifibatide and tirofiban just have to wait it out
4 classes of anticoagulants from least selective to most selective? What makes warfarin
different from all others in this class? What factors does it work on?
a. Warfarin, unfractioned heparins, selective factor Xa inhibitors, and direct
thrombin inhibitors
b. delayed action (18-24 hrs) b/c warfarin only affects vit. K regeneration by
epoxide reductase, not active factors; stays elevated b/c it binds to albumin
c. 2, 7, 9, 10, C, S are dependent on this regeneration
How is warfarin administered? Carried in blood? What must be carefully considered w/
therapy? What are adverse effects?! How is therapy monitored?
a. orally (100% bioavailable); carried by albumin in blood
i. fibrates [chapter 19] and chloral hydrate displaces warfarin from albumin
b. drug interactions must be considered (CYP450 metabolized)
c. pregnancy category X; rarely can cause crazy skin necrosis due to concommitant
inhibition of proteins C and S, especially people with protein C mutations
d. via INR (PT) every 2-4 wks
[factor VII]
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20. What is difference in size, preparation, and target of unfractioned vs LMW heparins?
a. Unfractioned=> from bovine lung or porcine intestinal mucosa; effectively
inactivates both Xa and thrombin via antithrombin III
b. LMW=> inactivates Xa but less effective against thrombin
21. What are heparins used for clinically? How administered and monitored? What are
unfractioned used for? LMW examples and uses?
a. In general, for prophylaxis and treatment of thromboembolic diseases, unstable
angina
i. e.g. DVT and pulmonary embolism
b. admin parenterally; monitor only unfractioned heparin w/ aPTT
(factors II, IX, X, XI, XII)
c. unfractioned heparin is used in combo w/ anti platelet for acute coronary
syndrome; higher risk of HIT!
d. LMWs: enoxaparin, dalteparin, tinzaparin; prevention/treatment of DVT, acute
MI (enoxa and dalte)
22. What is a selective factor Xa inhibitor (negligible II inactivation)? Indication? Who
shouldn't have it?
a. fondaparinux; for prevention/treatment DVT
b. NOT for ppl w/ renal insufficiency
23. 5 direct thrombin inhibitors? What is each approved for? Which 2 bind only the active site
of thrombin? Which is not excreted via the kidney (safe for use in renal failure)?
a. lepirudin: heparin induced thrombocytopenia
i. rare antibody reaction
b. desirudin: prophylaxis against DVT (hip replacements)
[I DESIRe to walk]
c. bivalirudin: anticoag in coronary angiography/angioplasty
[VALve]
d. argatroban: HIT, prophylaxis in percutaneous coronary intervention, coronary
artery thrombosis
[ARG i HIT the LEPeR]
i. does not use kidney
e. dagitroban: non-valvular atrial fibrillation
24. What is recombinant activated protein C (r-APC) indicated for? 4 thrombolytic agents?
a. septic shock w/ evidence of organ dysfxn, shock, acidosis, etc
b. streptokinase, recombinant t-PA, tenecteplase, reteplase
25. 2 limitations of streptokinase? What is it approved for? What is alteplase approved for?
a. it is foreign and can produce antigenic response (esp. if it has been used before)
and it can cause systemic fibrinolysis b/ not specific
b. approved for ST elevated MI and life-threatening pulmonary embolism
c. for STEMI, life threatening pulmonary embolism, and acute ishemic stroke (not
hemorrhagic)
26. What are the benefits of tenecteplase and reteplase over alteplase?
a. they have longer 1/2 lives, increased fibrin specificity, resistance to PAI-1
(tenecteplase)
b. tenecteplase is administered as a single bolus, reteplase as a “double bolus”
27. What is used against heparin excess? What is it ineffective against? What is aprotinin
used for? What makes lysine analogues better for this purpose and what are 2?
a. protamine (highly cationic protein that binds heparin); not effective against
fondaparinux
b. aprotinin (inhibitor of serpins like plasmin, thrombin,and t-PA) used to decrease
bleeding during cardiac surgery
i. Adverse fx = acute renal failure
c. Better b/c much less risk of acute renal failure: aminocaproic acid and
tranexamic acid
i. bind plasminogen and plasmin
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