Lecture 14: Hemostasis

Question 1

How does cAMP levels affect platelet aggregation?

Answer 1

increase in cAMP
decrease Ca2+
decrease platelet aggregation

PDE breaks down cAMP, therefore PDE inhibitor decrease platelet aggregation

Question 2

Partial Thromboplastin Time (PTT)

Answer 2

Heparin/ direct thrombin inhibitor

detects significant deficiencies in all plasma coagulation factors except 7 and platelets (extrinsic pathway)

measure efficacy of INTRINSIC & common coagulation pathways

Question 3

Prothrombin Time (PT) or INR

Answer 3

determine warfarin efficacy/safety

determine liver damage and Vit K status

measures rate of conversion of prothrombin to thrombin

Vit K dependent factors: 1,2,7,9,10

Question 4

Thrombin Time (TT)

Answer 4

time for clot to form via conversion of fibrinogen to fibrin

diagnose blood coagulation disorders and assess the effectiveness of fibrinolytic therapy

time increase if takes longer to clot

Question 5

Aspirin as anti-platelet drug

Answer 5

inhibit platelet and cox enzyme

decrease thromboxane A2

irreversible inhibition because platelet does not have nucleus

GASTROINTESTINAL BLEEDING

black box warning: selective COX2-inhibitor inhibit PGI2, leads to constricted blood vessel, TXA2 clumped vessels

Question 6

Dipyridamole

Answer 6

inhibits PDE-3
increase cAMP leads to decrease Calcium leads to decrease platelet aggregation
decrease ADP and block adenosine reuptake

little effect on its own, combined with ASA and warfarin

Adverse effect: headache and vasodilation due to decrease plasma cAMP

Question 7

Thienopyridines (Ticlopidine)

Answer 7

irreversible inhibition of ADP induced platelet aggregation

prevents expression of glycoprotein 2B/3A receptor

Question 8

Clopidogrel (Plavix)

Answer 8

irreversible ADP antagonist
inhibit ADP platelet aggregation
prevent expression of glycoprotein 2b/3a

prevention of ischemic stroke, myocardial infarction and progressive peripheral vascular disease
common used in stenting and angioplasty

PRODRUG
more potent than ASA
safer profile than Ticlopidine

Question 9

Abciximab

Answer 9

GP 2b/3a receptor inhibitor
monoclonal antibody
irreversibly bind to receptor

used in angioplasty

Question 10

Vitamin K antagonist (Warfarin)

Answer 10

inhibit synthesis of vitamin K dependent factors (2,7,9,10) by inhibiting VKOR
VKOR = vitamin K epoxide reductase, recycles vitamin K
decrease coagulation factors by 30%-50%

indicated for atrial fibrillation
prosthetic heart valves recurrent thromboembolus (DVT)

very narrow therapeutic index used PT to monitor

Question 11

Adverse effect of warfarin

Answer 11

bleeding - treat by infusing vitamin K or fresh frozen plasma

drug interactions with ASA (aspirin)

Question 12

Heparin

Answer 12

fast onset
enhance the activity of anti thrombin III

anti thrombin III binds to thrombin and inactivates it

anti thrombin III also inhibits factor Xa

Question 13

Adverse effect of heparin

Answer 13

bleeding

thrombocytopenia - low level of platelets concentration

Question 14

Protamine

Answer 14

antidote to heparin
basic protein strongly binds to heparin and inactivates heparin

adverse effect: dyspnea, flushing, hypotension, intrinsic anticoagulant effect

Question 15

Heparin resistance

Answer 15

1. congenital anti thrombin III deficiency
2. acquired anti thrombin III deficiency via previous consumption of anti-thrombin III

treat with fresh frozen plasma, anti-thrombin III concentrate

Question 16

Low molecular weight heparin (LMWH), Enoxaparin and Dalteparin

Answer 16

very high affinity for anti-thrombin III, inactivates thrombin

inhibits Factor 10a through anti-thrombin

high anti-10a activity and minimal anti-3a activity

more predictable pharmacokinetics

2-3 hours onset of action

STILL HAVE SIGNIFICANT BLEEDING RISK

Question 17

Fondaparinux

Answer 17

specific factor 10a inhibitor

long half time 30-35 hours
100% bioavailability

wont induce thrombocytopenia

CAUSE SIGNIFICANT BLEEDING

Question 18

Apixaban and Rivaroxaban

Answer 18

Direct factor 10a inhibitor

no reversal of anticoagulant effect unlike warfarin

better than LMW heparin and may replace warfarin

1st oral anticoagulant, decrease all risk mortality

Question 19

Dabigatran

Answer 19

direct thrombin inhibitor

binds directly to free and clot bound thrombin

substitute for heparin with thrombocytopenia or heparin resistance

replacing warfarin in some cases

Question 20

Streptokinase

Answer 20

binds with plasminogen and expose active site to increase plasmin formation

bolus and infusion

monitored by thrombin time (TT)

bleeding and allergic reactions

Question 21

Tissue plasminogen activator (tPA)

Answer 21

synthesized by recombinant DNA

more specific for fibrin bound plasminogen (only activated at clot site)

very short half time 3-4min

GREAT EFFICACY for myocardial infarction

Question 22

Tenecteplase

Answer 22

newer fibrinolytic drug

genetic variant of tPA

lower incidence of bleeding

single bolus administration

Question 23

Aprotinin

Answer 23

anti fibrinolytic

inhibits plasmin

2.5 hours half time

Question 24

Lysine derivatives

Answer 24

binds and inhibits plasminogen and plasmin

reduce pre-op bleeding

Question 25

Factor 7a

Answer 25

Anti fibrinolytic

induce thrombin generation by both tissue factor-dependent and independent pathways