Lecture 14: Hemostasis Flashcards
How does cAMP levels affect platelet aggregation?
increase in cAMP
decrease Ca2+
decrease platelet aggregation
PDE breaks down cAMP, therefore PDE inhibitor decrease platelet aggregation
Partial Thromboplastin Time (PTT)
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
Prothrombin Time (PT) or INR
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
Thrombin Time (TT)
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
Aspirin as anti-platelet drug
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
Dipyridamole
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
Thienopyridines (Ticlopidine)
irreversible inhibition of ADP induced platelet aggregation
prevents expression of glycoprotein 2B/3A receptor
Clopidogrel (Plavix)
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
Abciximab
GP 2b/3a receptor inhibitor
monoclonal antibody
irreversibly bind to receptor
used in angioplasty
Vitamin K antagonist (Warfarin)
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
Adverse effect of warfarin
bleeding - treat by infusing vitamin K or fresh frozen plasma
drug interactions with ASA (aspirin)
Heparin
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
Adverse effect of heparin
bleeding
thrombocytopenia - low level of platelets concentration
Protamine
antidote to heparin
basic protein strongly binds to heparin and inactivates heparin
adverse effect: dyspnea, flushing, hypotension, intrinsic anticoagulant effect
Heparin resistance
- congenital anti thrombin III deficiency
- acquired anti thrombin III deficiency via previous consumption of anti-thrombin III
treat with fresh frozen plasma, anti-thrombin III concentrate
Low molecular weight heparin (LMWH), Enoxaparin and Dalteparin
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
Fondaparinux
specific factor 10a inhibitor
long half time 30-35 hours
100% bioavailability
wont induce thrombocytopenia
CAUSE SIGNIFICANT BLEEDING
Apixaban and Rivaroxaban
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
Dabigatran
direct thrombin inhibitor
binds directly to free and clot bound thrombin
substitute for heparin with thrombocytopenia or heparin resistance
replacing warfarin in some cases
Streptokinase
binds with plasminogen and expose active site to increase plasmin formation
bolus and infusion
monitored by thrombin time (TT)
bleeding and allergic reactions
Tissue plasminogen activator (tPA)
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
Tenecteplase
newer fibrinolytic drug
genetic variant of tPA
lower incidence of bleeding
single bolus administration
Aprotinin
anti fibrinolytic
inhibits plasmin
2.5 hours half time
Lysine derivatives
binds and inhibits plasminogen and plasmin
reduce pre-op bleeding
Factor 7a
Anti fibrinolytic
induce thrombin generation by both tissue factor-dependent and independent pathways
