Anticoagulants

Question 1

what are the 4 phases of hemostasis

Answer 1

• vascular spasm
• platelet plug formation (primary hemostasis)
• blood coagulation (2ndary hemostasis)
• dissolution of fibrin clot (tertiary hemostasis)

Question 2

what is Virchow’s triad and what is its importance

Answer 2

endothelial injury, abnormal flow of blood, and hypercoagulability

they predispose one to formation of a thrombus

Question 3

classes of drugs that are used to reduce clotting

Answer 3

• platelet aggregation inhibitors
• anticoagulants
• thrombolytics

Question 4

classes of drugs that are used to treat bleeding

Answer 4

• plasminogen activation inhibitors
• protamine sulfate
• vitamin K
• plasma fractions

Question 5

platelet aggregation inhibitor are useful in the prevention and treatment of

Answer 5

cardiovascular diseases
maintenance of vascular grafts and arterial patency
adjuncts in treatment of MI

Question 6

what are the platelet aggregation inhibitors

Answer 6

GAAP

• GP IIb/IIIa inhibitors: abciximab, eptifibatide, tirofiban
• Aspirin
• ADP receptor inhibitors: Clopidogrel, ticlopidine
• Phosphodiesterase inhibitor: Cilostazol, Dipyridamole

Question 7

mechanism of aspirin

Answer 7

it inhibits thromboxane synthesis by irreversible acetylation of enzyme COX hence it is a COX inhibitor

Question 8

why is aspirin better than other NSAIDs

Answer 8

it can acetylate COX and is irreversible hence its action lasts longer than the reversible action of other NSAIDs

Question 9

what is aspirin used for

Answer 9

• prophylactic tx of transient cerebral ischemia
• reduce incident of recurrent MI
• reduce mortality in post MI patient

Question 10

name the ADP receptor blockers and their mechanism

Answer 10

clopidogrel and ticlopidine

inhibit P2Y12 irreversibly (ADP receptor on platelet surface) –> reduced platelet aggregation

Question 11

adverse effects of ADP receptor blockers (name the drugs again)

Answer 11

clopidogrel and ticlopidine

thrombocytopenia pupura

but ticlopidine can cause neutropenia

Question 12

how is clopidogrel activated and what are conditions that can cause it not to be activated

Answer 12

• it is a prodrug that is activated by CYP2C19
• if someone is a poor metabolizer of CYP2C19 or takes omeprazole (CYP2C19 inhibitor), then they would have less of the active metabolite in their plasma

Question 13

uses of clopidogrel and ticlopidine (more clopidogrel though)

Answer 13

reduce the rate of stroke, MI, death in pts with recent MI or stroke, established peripheral artery disease, or acute coronary syndrome

Question 14

mechanism of dipyridamole

Answer 14

inhibits phosphodiesterase and/or blocks adenosine uptake –> increase in cAMP –> activates adenylyl cyclase –> coronary vasodilation

Question 15

uses of dipyridamole

Answer 15

• little to no benefit if taken alone
• with warfarin it prevents post op thromboembolic complication of cardiac valve replacement
• with aspirin it’s a prophylaxis for cerebrovascular disease

Question 16

mechanism of cilostazol

Answer 16

inhibits phosphodiesterase –> vasodilation and inhibition of platelet aggregation

Question 17

what is cilostazol used for

Answer 17

intermittent claudication

Question 18

uses of platelet GP IIb/IIIa receptor blocker (name drugs agin)

Answer 18

tirofiban, eptifibatide, abciximab,

• reduce the rate of thrombotic cardiovascular event in non-ST elevation acute coronary syndrome (NSTE-ACS)
• adjunct to percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic complications

Question 19

how does the IIb/IIIa complex function

Answer 19

• receptor for fibrinogen and vitronectin but also for fibronectin and von willebrand factor
• activation of this complex is the final common pathway for platelet aggregation

Question 20

condition called in those lacking the IIb/IIIa receptor

Answer 20

bleeding disorder called Glanzmann’s thrombasthenia

Question 21

direct mechanism of the IIb/IIIa drugs

Answer 21

• tirofiban: nonpeptide tyrosine analogue that is a reversible antagonist of the complex
• eptifibatide: cyclic peptide reversible antagonist of the receptor
• abciximab: chimeric mouse human monoclonal antibody against the receptor

Question 22

anticoagulants can be classified into what four groups

Answer 22

• indirect thrombin and factor X inhibitor: unfractioned standard heparin, low molecular weight heparin (Enoxaparin, Dalteparin, Tinzaparin) and fondaparinux
• direct thrombin inhibitors: lepirudin, bivalirudin, argatroban, dabigatran
• direct factor Xa inhibitor: apixaban and rivaroxaban
• couramin anticoagulants: warfarin

Question 23

why are low molecular weight heparin (name them) the replacement for unfractioned heparin

Answer 23

Enoxaparin, Dalteparin, Tinzaparin

they have fewer drawback than UFH, have equal efficacy, superior bioavailability, longer half lives, less frequent dosing requirements

Question 24

mechanism of action of heparin

Answer 24

binds to anti thrombin III –> inhibits clotting factor proteases especially thrombin, IXa, Xa

Question 25

difference in mechanism of UFH and LMWH

Answer 25

- to most efficiently inactivate thrombin by antithrombin III, heparin has to bind to both antithrombin and thrombin simultaneously - to inactivate factor Xa by antithrombin III, heparin only needs to bind to antithrombin III - LMWH inhibits Xa but not long enough to form ternary complex so no effect on thrombin but UFH efficiently inactivates Xa and thrombin

Question 26

what test is used to monitor heparin levels and prevent bleeding and what does the test check

Answer 26

aPTT | test for the integrity of the intrinsic and common pathway of coagulation

Question 27

when taking LMWH why is it not necessary to monitor blood level

Answer 27

it's weight dosing causes predictable plasma levels with normal renal function

Question 28

when do you have to monitor LMWH

Answer 28

in those with renal insufficiency, pregnancy, and obesity

Question 29

uses of heparin

Answer 29

- initiate tx of venous thrombosis and pulmonary embolism (warfarin started at same time then heparin discontinued after 5 days when warfarin reaches its full therapeutic effect) - initial management of pts with unstable angina of acute MI - coronary balloon angioplasty to prevent thrombosis - drug of choice for preggos because does not cross the placenta

Question 30

adverse effects of heparin

Answer 30

- bleeding - hypersensitivity reactions - heparin induced thrombocytopenia (two types) - elevation of liver transaminases - osteoporosis

Question 31

how is type II heparin induced thrombocytopenia work (mechanism)

Answer 31

- seen more commonly in UFH - antibodies recognize heparin and a platelet protein, platelet factor 4 - IgG binds both heparin and PF4 forming an immune complex then binds to Fc receptor on platelets - Fc activation lead to platelet degranulation and aggregation - activated platelets release more PF4 and more immune complexes form - leads to thrombocytopenia and thrombosis - hence leading to DVT, heart attack, stroke, PE

Question 32

what is next step if excessive anticoagulant action with heparin

Answer 32

stop heparin and give direct thrombin inhibitor or fondaparinux if bleeding give protamine sulfate though it does not reverse action of fondaparinux

Question 33

mechanism of fondaparinux and what it is mainly used for

Answer 33

selective, indirect, inhibitor of factor Xa with negligible antithrombin activity mainly used for DVTs

Question 34

what are the direct thrombin inhibitors and how do they work which ones are parenteral and which oral how are they monitored

Answer 34

BALD Bivalirudin, Argatroban, Lepirudin, Dabigatran they directly bind to the active site of thrombin all parenteral except for dabigatran monitored by aPTT

Question 35

what types of patients should lepirudin be given cautiously to and why

Answer 35

those with renal insufficiency because no antidote exists

Question 36

what are the direct factor Xa inhibitors and how are they monitored

Answer 36

apixaban and rivaroxaban like dabigatran, they do not require monitoring