Anticoagulation / Antiplatelets Flashcards
Hemostasis
Arrest of bleeding from a damaged blood vessel
Coagulation
Multi-step process to plug leaking vessel
Phases of hemostasis
Injury –> bleeding
Vasospasm
Platelet plug form –> adherence / aggregation
Fibrin clot form –> prothrombin -> thrombin
Fibrinolysis –> plasminogen -> plasmin
Deadly duo
Atherosclerosis plaque and thrombosis –>
coronary plaque rupture
Platelet composition
Presence of organelles and secretory granules, but no nucleus
Contact with ECM initiates platelet reactions
Adhesion and shape change
Secretion reaction
Aggregation
First step of platelet activation
Platelet adhesion and shape change
Platelet adhesion mediated by
GP Ia binding to collagen
GP Ib binding to von Willebrand factor
Shape changes facilitate receptor binding
Intact endothelial cells secret PGI2 to inhibit thrombogenesis
Second step of platelet activation
Platelet secretion
Secretion / release reaction
Degranulation ->
Platelet granules release ADP, TXA2, serotonin (5-HT) ->
ADP, 5-HT, TXA2 activate and recruit other platelets ->
TXA2 and 5-HT are potent vasoconstrictors
Third step of platelet activation
Platelet aggregation
Conformation of GP receptors to bind fibrinogen ->
Platelets are cross-linked ->
Form temporary hemostatic plug ->
Platelets contract ->
Form irreversibly fused mass ->
Fibrin stabilizes to anchor aggregated platelets ->
Forms surface clot
Antiplatelet drugs
COX-1 Inhibitors (aspirin)
ADP receptor inhibitors
BP IIb / IIIa receptor blockers
PDE-3 inhibitors
PAR inhibitors
COX-1 inhibitor (aspirin)
Inhibition of TXA2 synthesis -> anti-platelet activity
Irreversibly COX-1 inhibition by acetylation
Prolongs bleeding time
Aspirin indications
Prophylaxis and treatment of arterial thromboembolic disorders
Aspirin SEs
Upper GI bleeding
Acute aspirin overdose
Increased CVD risk
ADP receptors involved in activating platelets
P2Y1 and P2Y12
Activation of both is required for platelet activation by ADP
Direct acting P2Y12 antagonists
Cliostazol, ticagrelor, cangrelor
Pro-drug P2Y12 antagonists
Prasugrel, clopidogrel
ADP receptor inhibitor MOA
Irreversibly block ADP receptor on platelet and activates of GP IIb / IIIa complex
ADP receptor inhibitor administration
Taken orally
Clopidogrel has a lower toxicity profile
Action lasts for several days after dose
ADP receptor inhibitor uses
Recent MI, stroke, acute coronary syndrome
Thrombotic thrombocytopenic purpura
Spurious and excessive platelet aggregation
Can be fatal
Prasugrel
Used for: acute coronary syndrome
Taken orally
Prodrug: req esterases + CYP2A4 / 2B6
Irreversibly bind P2Y12 receptor
High bleeding risk
Ticagrelor
Used for: acute coronary syndrome, PCI
Taken orally
Binds to allosteric site, reversible
Faster onset of action
High bleeding risk
Cangrelor
Used adjunct for: PCI
Given IV
Binds reversibly
Fast onset of action
PDE-3 Inhibitors MOA
Platelet aggregation inhibitor
Action related to cAMP PDE inhibition and inhibiting adenosine uptake
Dipyridamole use
Adjunct with warfarin to prevent embolization from prosthetic heart valves
Adjunct with ASA to prevet cerebrovascular ischemia
Cilostazol use
Intermittent claudication (muscle cramps)
GP IIb / IIIa receptor inhibitors MOA
Inhibits fibrinogen crosslinking of platelets to decrease aggregation
Eptifibatide
Given IV bolus followed by infusion up to 72 hours
Short duration of action
Used: prevent thromboembolism
Tirofiban
Reversible inhibition
Given IV in dilute solution
Combined with heparin for acute coronary syndrome
Abciximab
Given IV bolus followed by infusion
Long duration of action -> high bleeding risk
Adjunct with t-PA for early tx of acute MI
PAR inhibitors
Thrombin activates platelets
GPCRs coupled to release Ca
PAR inhibitors MOA
Proteolytic cleavage of PAR-1 receptors
Vorapaxar
Oral administration
Used with aspirin or clopidogrel
Effects continue for days
Contra: history of stroke, TIAs, hemorrhage
Vorapaxar use
Prevent thrombosis if previous MI or peripheral artery disease
Clotting factors
Serine proteases:
- Factors XII, XI, X, IX, VII, II -> cleave and activate down-stream factors
- Protein C -> cleave factors Va, VIIIa to inactivate them
Glycoproteins:
- Factors VIII, V, III, Protein S -> cofactors for protease activation
- Anti-thrombin III -> binds and inhibits thrombin
Fibrinogen/fibrin
Substrate protein for F IIa (thrombin)
Polymerizes to form clot
Hemophilia A
Deficiency in factor VIII
Hemophilia B
Deficiency in factor IX
Clotting factor production
All produced in liver
Except von Willebrand factor is produced in endothelium
Liver disease can have unpredictable effects on coagulation
Coagulation via extrinsic pathway
Requires tissue facto
Used when vessel is damaged and blood leaks out (thromboplastin)
Rapid clot formation ~15 seconds
Thrombin in clotting pathways
Convergence point of intrinsic and extrinsic pathways at thrombin activation
Converts fibrinogen -> fibrin
Coagulation via intrinsic pathway
Triggered when neg charged collagen is exposed on the wall of the blood vessel
Ex. blood in test tubes clotting
Feedback mechs increase coagulation
Thrombin
- Activates factor V, VIII
- Enhances platelet activation
Platelet activation
- Increases factor VII, X activation
- Cleaves prothrombin
Feedback mechs decrease coagulation
Antithrombin
- Neutralizes thrombin, factor Xa, IXa
- Accelerated by heparin
Protein C system
- Inactivates factor Va, VIIIa
Factor Xa
- Blocks initial activation of factor VII
Platelet Count test
Too high: thrombocytopenia -> bone marrow malfunctions or nutritional deficiencies
Prothrombin time (PT/INR) test
Plasma + thromboplastin + Ca
Clots in 12-14 seconds
aPTT test
Plasma + phospholipid + activating agent
Clots in 26-33 seconds
Used to monitor heparin therapy
Fibrinogen test
Less common
200-400 mg/dL
D-dimer test
Product of fibrin breakdown
INR ranges
Normal: 0.8-1.2
Therapeutic: 2-3
Risk of hemorrhage: >3
Uses for anticoagulants
Prevent excessive clotting -> causes other issues if untreated
- Stroke
- Post-MI
- DVT
- PE
Oral anticoagulant drugs
Coumarin anticoags
- All derivatives are water soluble lactones
- Warfarin is most common
Warfarin MOA
Inhibits Vit K-epoxide reductase -> blocks reduction of Vit K epoxide back to active form
Inhibits synthesis of clotting factor II, VII, IX, X
Warfarin OD
Discontinue warfarin
Administer Vit K
If serious can admin plasma instead
Warfarin necrosis
Deficiency in protein C
Warfarin further decreases protein C levels so can cause initial incr in blood coag at start of therapy
Often common to start pts on heparin w warfarin in parallel
Drug’s decr warfarin’s effects
Rifampin
Vitamin K
Pregnancy
Drugs incr warfarin’s effects
SSRI’s
Broad spectrum antibiotics
Anabolic steroids
Indirect factor IIa, Xa inhibitors
Heparin
- UFH
- LMWH (enoxaparin, daltaparin)
Non-heparinoids
- Fondaparinux
Heparin MOA
Accelerated AT reactions -> inactivates thrombin and factor Xa
Heparin clinical use
Admin IV -> immediate effect
Adjust dosing based on coag tests
Effects stop within hours of ending therapy
Heparin AEs
Latrogenic hemorrhage
- Tx: protamino sulfate
HIT
- Type 1 and 2
Osteoporosis
- Associated with extended therapy
HIT risk ranking
UFH > LMWH > fondaparinux
Fondaparinux MOA
Indirectly inhibits factor Xa by selectively binding AT
DOACs
Direct Xa inhibitors
- Rivoroxaban
- Apixaban
- Edoxaban
- Betrixaban
Direct thrombin inhibitors (DTI)
- Dabigatran
Factor Xa inhibitor antidote
Andexanet - approved with apixaban and rivoroxaban
DTI actions
Non-heparinoid parenteral agents
Inhibit free and fibrin-bound thrombin