Clotting Flashcards
Extrinsic system of clotting
TF > VII > VIIa > X > Xa > V Ca++ platelets > Prothrombin to Thrombin > Fibrinogen to Fibrin = clot
Intrinsic System of Clotting
Tissue Contact > XII > XIIa > XI > XIa > IX > IXa > X (VII) > Xa»_space; platelets/thrombin (IIa)/ Fibrin - clot
Where does Antithrombin III work?
Activated by heparin
Blocks XIIa, IXa, and Xa.
Allows TPA to convert plasminogen to plasmin = clot destruction
White thrombus formation and pathology
- Forms in high-pressure arteries, result of platelet binding to damaged endothelium and aggregation w/ little involvement of fibrin
- local ischemia due to arterial occlusion
* in coronary arteries: Myocardial infarction/angina pectoris
Red thrombus formation and pathology
- Forms in low-pressure veins and in the heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which red blood cells become enmeshed
- Emboli and distal pathology - DVT = pulmonary emboli; cardiogenic emboli = embolic stroke
Anticoagulants vs Antithrombics vs Thrombolytics
Anticoag: regulate fxn and synth of clotting factors
Antithrombic/antiplatelets: inhibit platelet fxn
Thrombolytics/fibrinolytics: destroy blood clot after it forms
When are anti-coags used?
primarily used to prevent clots from forming in the venous system and heart (red thrombi)
When are antithrombotics and antiplatelets used?
primarily used to prevent clots from forming in the arteries (white)
*Heart attacks/acute MI, arterial thrombosis of limbs, thrombotic/ischemic stroke, PCIs
When are thrombolytics/fibrinolytics used?
Re-estabilsh blood flow through vessel once clot has been formed
2 types of anticoagulants
- Parenteral
2. Oral
What 2 drugs are parenteral anti-coags?
- Heparins
2. Parenteral Direct Thrombin Inhibitors (DTIs)
How do heparins work
Indirectly inhibit thrombin via anti-thrombin III
Molecular weight determines activity: low = enoxaparin
How do DTIs work?
Peptide analogs of hirudin-purified from medicinal leeches.
Directly inhibit thrombin
What are the oral anti-coagulants?
- Warfarin
- Oral nonpeptide DTI : Dabigatran
- Factor Xa inhibitor : Rivaroxaban, Apixaban
Common uses of heparins?
Prevention of emboli during surgery or in hospitalized patients
SE of heparins
bleeding
Heparin-induced thrombocytopenia: immune response resulting in increased clotting
How does warfarin work?
Prevents vitamin K re-activation by inhibiting Vit K epoxide reductate
(Preventing Factors VII, IX, X)
SE and antidote to warfarin
SE: bleeding
tx: vit k
* many drug interactions
Common uses of warfarin?
Outpatient tx of DVT, cardiac conditions that generate emboli
What reduces warfarin metabolism and what does it do?
Genetic variation of CYP2C9 reduces metabolism, increased bleeding risk
What reduces warfarin sensitivity and what does it do?
variation of VKORC1 subunit reduces warfarin sensitivity = increased risk
How does Dabigatran etixilate work compared to warfarin?
Less bleeding risk
How do rivaroxaban and apixaban work compared to warfarin?
Reduced bleeding risk
t-PA drugs (2) and how they work?
- Alteplase : recombinant human t-PA
2. Urokinase: recombinant form of a non t-PA human protease
Clinical uses of fibrinolytic drugs and which drugs can be used
- Embolic/thrombotic stroke = alteplase
- Acute MI = urokinase
- Pulmonary emboli
What is the leading cause of adult disability?
Stroke
Embolic Stroke vs Thrombotic Stroke
Embolic emboli from red thrombi (cardiogenic)
Thrombotic results from white thrombus (atherosclerosis)
How to treat Stroke?
tPA
Alteplase - w/in 3 hours
*can worsen damage produced by hemorrhagic stroke
What do anti-thrombotics target?
- Thrombaxane A2: promos aggregation and vasoconstriction
- ADP: released from plateltes, binds purinergic receptors on other platelets, causes aggregation
- Thrombin: increases fibrin production, activated PAR-1 to promote platelet activation
What drug is PAR1 Antagonist?
Vorapaxar
What drugs are ADP receptor blockers?
- Clopidogrel
2. Prasugrel
How does aspirin work?
Irreversible COX1 inhibitor, decreased TXA2 production
What is aspirin used for?
- Analgesia - 325mg
- NSAID - 325mg
- Antipyretic - 325mg
- Antiplatelet - 81mg
What do we need to know about Clopidogrel?
- Prodrug (metabolized by CYP2C19)
- Polymorphisms = reduced metabolism = poor activators
- Many Drug interactions
What do we need to know about prasugrel (effient)
- Prodrug, metabolized by different enzymes than clopidogrel
- Consistent effects
PAR1 drug, and facts
Vorapaxar = PAR1 Antagonist (oral)
Long halflife + no antidote
Contraindicated for pt w/ history of stroke
How to platelet receptor antagonists work and how are they administered?
antagonize receptors on platlet cell membranes to prevent interaction of platelets w/ fibrinogen and prevent aggregation
- admin parenterally (effective) for Percutanous Coronary Interventions (PCIs - aka angioplasty) to prevent reocclussion
What drugs are platelet receptor antags and what to they antagonize?
Abciximab : anti-GPIIb/IIIa antibody
Tirofiban: GPIIbIIIa Antagonist
What are anti-platelet drugs primarily used for?
Prevent coronary occlussion/reocclussion due to clot formation
-protect against heart attack, protect against thrombotic stroke
Cox 1 vs selective Cox 2 inhibitors and CHD?
COX1 = platelet activation, promotes clotting, vasoconstriction
-inhibited by aspirin (reduced risk for CHD)
COX2: platelet inactivation, limits clotting, vasodilation
-inhibited by rofecoxib - promos platelet activation, increased risk for CHD
Anticoag antidotes
Vit K = warfarin
Protamine Sulfate = heparins
