Antiplatelet, Anticoagulant, & Thrombolytic Pharmacology Flashcards
1
Q
Goal and Stages of Hemostasis
A
Keep the blood fluid and clot-free in normal/healthy vessels, but form a localized plug rapidly in injured vessels.
Stages:
- Vasoconstriction
- Occurs immediately after vascular injury
- Mediated by a poorly understood neurogenic reflex mechanism
- Local secretion of endothelin potentiates the reflex vasoconstriction
- Vasoconstriction is transient (bleeding would resume if primary hemostasis did not occur)
- Primary Hemostasis
- Secondary Hemostasis
2
Q
Primary Hemostasis
A
Stage of hemostasis during which platelets are activated and adhere to the subendothelial matrix. The goal is to form a plug that rapidly stabilizes vascular injury.
3
Q
Primary Hemostasis – Platelet Adhesion
A
- von Willebrand Factor (vWF) is secreted by activated platelets and the injured endothelial cells themselves (it is present in their Weibel-Palade bodies)
- vWF binds to GPIb on platelet surface and to exposed collagen
- it mediates the adhesion of platelets to collagen
- GPVI on the platelets interacts directly with collagen
- Both interactions (GPIb:vWF:collagen and GPVI:collagen) are required for initiation of primary hemostasis
4
Q
Primary Hemostasis – Platelet Activation & Granule Release
A
- Stimulation by ADP, Epi, and collagen → activation of platelet membrane phospholipase A2 (PLA2)
- PLA2 cleaves mb phospholipids → giving arachidonic acid → converted to cyclic endoperoxide by platelet COX → Thromboxane A2 (TxA2) by Tx synthase
- TxA2 stimulates the release of secretory granules within the platelets (also causes vasoconstriction of vascular smooth m. cells at site of injury via a GPCER → ⇣cAMP)
- Lots of ADP, Ca2+, ATP, serotonin, vWF, & platelet factor 4 are actively secreted from granules
5
Q
Primary Hemostasis – Platelet Aggegration & Formation of Hemostatic Plug
A
- TxA2, ADP, and collagen = potent mediators of platelet aggregation
- TxA2 binds to TxA2 GPCRs in platelet mb → activation of PLC → conversion of PIP2 into IP3 and DAG → ⇡Ca2+ (via IP3) and expression of GIIb/IIIa on platelet surface (via DAG → PKC → PLA2)
- ADP binds to ADP GPCRs on the platelet surface called P2Y1 and P2Y receptors
- P2Y1 (Gq) releases Ca2+ stores from cell
-
P2Y (Gi) inhibits adenylyl cyclase
- target of antiplatelet agents like clopidogrel (interacted w/ omeprazole)
- These receptors mediate platelet shape change and expression of GIIb/IIIa
- Collagen bind directly to GPVI
- promotes granule release reaction
- induces conformational changes in GPIIb/IIIa so that they can (directly or indirectly) bind to collagen
- Platelets aggregate with one another via the interaction between, fibrinogen, a bridging moledule, and GPIIb/IIIa (fibrinogen:GPIIb/IIIa)
- Aggregation → formation of reversible clot = primary hemostatic plug
6
Q
Secondary Hemostasis
A
- AKA The Coagulation Cascade
- Overlaps temporarily with the formation of the primary hemostatic plug; each process reinforces the other.
- Goal of the cascade is to form a stable fibrin clot at the site of vascular injury.
- Cascade generates thrombin, which is then cross-linked to yield the stable platelet plug
- General principles:
- It’s a sequence of enzymatic events. Activation reactions are catalytic, not stoichiometric (1 u factor X → 40 u thrombin)
- The major rxns occur at sites where phospholipid-based protein-protein complexes (composed of mb surface, enzyme, substrate, cofactor and sometimes calcium) have formed
- Intrinsic and extrinsic pathways = arbitrary division (results from in vitro study)
- Both intrinsic and extrinsic pathways lead to activation of factor X, which when coupled with factor V can cleave prothrombin into thrombin.
7
Q
Secondary Hemostasis: Intrinsic Pathway of the Coagulation Cascade
A
- In vitro
- Starts with activation of Factor XII → XIIa
- XIIa (plus calcium) converts XI →XIa
- XIa converts IX → IXa
- Thrombin converts VIII → VIIIa
- Factors VIIIa and IXa complex together (with calcium) and convert Factor X →Xa
8
Q
Secondary Hemostasis 2: Extrinsic Pathway of the Coagulation Cascade
A
- In vivo
- Starts with activation of tissue factor by tissue injury
- Thrombin activates factor VII → VIIa
- Activated tissue factor and VIIa (plus calcium) activate factor X → Xa
9
Q
Secondary Hemostasis: Common Pathway
A
- Xa complexed with Va cleaves prothrombin → thrombin
- Thrombin (with calcium) cleaves fibrinogen → fibrin
- Thrombin (with calcium) activates factor XIII → XIIIa
- XIIIa converts fibrin polymers → crosslinked fibrin polymers, a highly stable meshwork or clot
10
Q
Roles of Thrombin
A
- Converts fibrinogen (soluble) into fibrin (insoluble)
- Activates factor XIII, which cross-links insoluble fibrin polymers to make a stable meshwork or clot
- Amplifies the clotting cascade via feedback activation of factors V, VII, and VIII
- Activates platelets to cause granule release
- Regulates the coagulation response
- Binds to thrombin receptors on intact endothelial cells next to site of injury → stimulation of endothelial cells to release prostacyclin (PGI2), NO, tPA, and a tPA inhibitor (PAI-1)
11
Q
How does heparin aid in the restriction of hemostasis to the site of injury?
A
- Endogenous heparin-like molecules or exogenously administered heparin bind to Antithrombin III (ATIII) causing a conformational change in ATIII
- ATIII can then bind to thrombin or the coagulation factors IXa-XIIa and form a stoichiometric complex that inactivates them
***This is how hemostasis is restricted to the local site of injury, since it occurs at intact areas near the site of injury.
12
Q
How is the sized of the primary and secondary hemostatic plugs limited (as to not occlude the lumen)?
A
- Excess thrombin generation → activation of Protein C
- Activated Protein C and Protein S cleave and inactivate factors Va and VIIIa → slowing of the coagulation cascade → prevents enlarging fibrin clot from occluding the lumen
13
Q
Limiting Hemostatic Plug Size: Plasmin
A
- Tissue plasminogen activator (tPA) synthesized and secreted by the endothelium cleaves plasminogen → plasmin
- Plasmin cleaves cross-linked fibrin fibers into fibrin degradation products
- It also prevents the formation of additional clots by:
- Cleaving serum fibrinogen
- Destroying Coagulation factors
- Blocking platelet aggregation
- It also prevents the formation of additional clots by:
- Regulation of tPA and therefore plasmin:
- tPA most effective when bound to a fibrin meshwork
- tPA activity is inhibited by plasminogen activator inhibitor (PAI) [1 or 2]
- when local levels of thrombin are high, endothelial cells release more PAI to prevent tPA from activating plasmin and have a stable clot actually form
- tPA is neutralized by alpha2-antiplasmin (produced in the liver) to prevent degradation of fibrinogen so that primary hemostasis can occur.
14
Q
Pathogenesis of Thrombosis
A
- Thrombosis = pathologic extension of hemostasis
- Coagulation reactions are inappropriately regulated → clots enlarge uncontrollably → occlusion of lumen
- Three major factors predispose to thrombosis (Virchow’s triad):
- Endothelial injury (can cause the two below)
- Abnormal blood flow (STASIS or turbulence)
- Can cause both endothelial injury and hypercoagulability
- Hypercoagulability
15
Q
Antiplatelet agents
A
- Cyclooxygenase (COX) inhibitors
- Aspirin
- Indomethacin
- Other NSAIDs
- Phosphodiesterase inhibitors
- Dipyramidamole
- Cilostazol
- ADP Receptor Pathway Inhibitors
- Clopidogrel
- GPIIb/IIIa antagonists
- Abciximab
