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Phcol 401 > Quiz #3 Material > Flashcards

Quiz #3 Material Flashcards

1
Q

Hemostasis: four major events occur following a wound

A
  • VPCF
  • Vascular Constriction:
    • Limits the flow of blood to the injury
  • Platelet aggregation:
    • Blood platelets clump when binding to collagen that becomes exposed following rupture. Blood platelets become activated and aggregate at the site of injury
  • Clot formation:
    • To inure stability of the initially loose platelet plug, a fibrin mesh (aka clot) forms and entraps the plug
  • Fibrinolysis:
    • The clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin
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2
Q

Platelets

A
  • Platelets are NOT cells but really just a type of vesicle that pinches off of the megakaryocyte.
  • No nucleus
  • Hemopoetic stem cell→Promegakaryocyte→Megakaryocyte→Platelet
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3
Q

Major Drugs Acting on Platelets:

  • ADP antagonists
  • PDE Inhibitor
  • Platelet surface bind
  • COX inhibitor
  • (Multiple Mechanisms)
A
  • ADP antagonists
    • Clopidogrel (Plavix)
    • Ticlopidine (Ticlid)
    • Prasugrel (Ticagrelor)
  • PDE Inhibitor
    • Dipyridamole (Aggrenox)
  • Platelet surface bind
    • Abciximab (ReoPro)
    • Tirofiban (Aggrastat)
    • Eptifibatide (Integrelin)
  • COX inhibitor
    • Aspirin
  • (Multiple Mechanisms)
    • Thrombin
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4
Q

Three Steps of Clot Formation

A
  • Activation
    • Activation/Adhesion of platelets
  • Release
    • Release of factors to drive the activation and adhesion of platelets (ADP, thromboxane A2)
  • Recruitment
    • Recruitment of more platelets, aggregation and formation of a clot
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5
Q

Important Concept of Platelet Aggregation Mechanism

A
  • Works on a feed-forward mechanism
  • Is turned off by excretions from the endothelium
    • EDRF, PGI2, tPA, and heparin
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6
Q

Thrombin

A
  • Factor IIa
  • Cleaves N-terminus of PAR-1
    • Leaves behind a ‘tethered ligand’ that can provide continuous activity of the receptor until receptor recycling
    • Irreversible (actually slowly reversible)
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7
Q

Molecular Basis of Platelet Aggregation and Activation

A
  • Collagen/damaged endothelium bind Von Willebrand Factor which in turn has high affinity for GP1b/Gp IIb
  • Gp Ia: platelet receptor for collagen
  • Gp Ib: platelet receptor for VWF
  • Gp IIb-IIIa: integrin that binds fibrin
  • Antagonists to GpIIb/IIIa prevent binding to fibrin
    • Abciximab (Reopro): coronoary artery procedures to prevent platelet sticking
    • Tirofiban (RGD)
    • Eptifibatide (Integrilin, C-term of fibrinogen)
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8
Q

Synthesis and Effects of Arachadonic Acid Metabolites

A
  • COX Enzymes metabolize arachadonic acid, leading to the production of thromboxanes and prostacyclin
    • Thromboxanes: made in platelets and lead to increased platelet aggregration
    • Prostacylin: made in endothelial tissue and lead to decreased platelet aggregation
      • opposing factors
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9
Q

Action of Aspirin

A
  • Irreversibly inhibits COX to inhibit both:
    • Inhibits thrombaxane synthesis: decrease in platelet aggregation
      • Can’t be produced by COX enzmes until platelets are fully recycled
    • Inhibits prostacyclin synthesis
      • Can be recovered because endothelial cells have nuclei
  • Aspirin + PGHS2→Salicylic acid + acetylated PGHS2
  • Use low dose:
    • Platelet COX1 has highest affinity for aspirin
    • Aspirin doesn’t inhibit endothelium COX1
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10
Q

Ibuprofen and other NSAIDS

A
  • Other NSAIDs don’t work for clotting because they are reversible
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11
Q

Ticlid and Plavix

A
  • Thienopyridines
  • ADP receptor antagonists
  • Prevent recuring DVT, strokes and intermittent claudication
  • Plavix (clopidogrel)
    • Requires activation by CYP2C19
    • Low dose ASA + Plavix not more effective than ASA alone
    • Thrombocytic thrombocytopenia
  • Ticlid (ticlopidine)
    • Safety? bleeds and hemorraging
  • THM: Covalent/Irreversible
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12
Q

newer ADP receptor antagonists

A
  • Prasugrel (Effient)
    • Requires enzymatic activation
    • Noncompetitive antagonist at the P2Y12 purinergic receptor
  • Ticagrelor (Brilinta)
    • Reversible allosteric agonist
  • Better safety and efficacy when used in combo with ASA?
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13
Q

Dipyridamole

A
  • Dipyridamole (Persantin)
  • Cilostazol, PDE3 inihibitor, approved for intermittent claudication
  • Aggrenox
    • Dipyridamole with tartaric acid to solubilize
    • Sustained release pellets with ASA
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14
Q

Factors on platelet surface involed in clot formation

A
  • GpIa: receptor for collagen
  • GpIb: receptor of VWF
  • GpIIb-GpIIIa: integrin that binds fibrin
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15
Q

ADP Receptor Antagonists: MOA and Example

A
  • Block the ADP receptor from being activated by ADP→block platelet adhesion
    • Plavix (clopidegrel) falls into this category
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16
Q

Clotting Cascade: Key Players

A
  • Xa: converts prothrombin→thrombin
  • IIa: thrombin; converts fibrinogen→fibrin
  • XIIIa: transglutaminase enzyme that converts soluble fibrin to insoluable fibrin, the final step of the clotting cascade
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17
Q

Direct vs. Indirect clotting cascade effectors: General MOA and examples

A
  • Indirect Effectors:
    • Doesn’t directly effect coagulation cascade factors
    • Warfarin
  • Direct Effectors:
    • Directly effects coagulation cascade factors
    • Antibodies
    • Heparin
18
Q

Warfarin Mechanism

A
  • Indirect effector
  • Vitamin K analog→binds and inhibits the recycling of factors that drive the ‘active’ prothrombin
  • Very NTI
  • Easily reversible with vitamin K
19
Q

Antibody Anticoagulants Mechanism

A
  • Direct effectors
  • Inhibit the enzymes in the cascade by preventing their action
  • Ex: dabigatran blocks IIa in converting fibrin→fibrinogen
  • Do not require a cofactor
20
Q

Heparin Mechansim

A
  • Direct Effector
  • Endogenous
  • Form a complex with antithrombin III
  • Act quickly
  • Inhibts the actions of factor Xa and IIa (thrombin)
  • LMW heparins can be more specific
  • Reversal with protamine sulfate
21
Q

What is coagulation controlled physiologically by?

A
  • Plasma Protease Inhibitors
    • inhibit many of the coagulation factors
  • Protein C
    • active protease which drives fibrinolytic action
    • This is often a cause of bleeding following warfarin withdrawal
22
Q

How to dissolve a clot

A
  • Thrombolytics/fibrinolytics
  • Tissue plasminogen activator (tPA)
  • Streptokinase
  • Urokinase
23
Q

tPA Mechansim

A
  • Is made by healthy endothelial tissues and converts plasminogen to plasmin (an active protease which drives the breakdown of insoluable fibrin clots)
    • Acts by having an increased affinity for fibrin-bound plasminogen (to activate it to fibrin)
  • protease
24
Q

Streptokinase MOA

A
  • Binds to plasminogen and the complex activates a second plasminogen molecule to active plasmin
  • Direct binding activator
25
Q

Urokinase MOA

A
  • Proteolytically activates plasminogen directly
  • A protease
26
Q

Apixaban and Rivaroxaban

27
Q

Lepirudin

A
  • Recombinant form of hirudin
  • From leach
  • Direct thrombin inhibitor
28
Q

Heparin and Fondaparinux

A
  • Heparin pentasaccharide binds to anti-thrombin III
    • Accelerates interaction with Xa
    • When thrombin binds complex, needs tail to loop around to inhibit
      • Need to be at least 18 saccharide units (5400 Da)
  • Fondapurinux (1500 Da): LMWH heparin less likely to bind to ATIII:IIa and inhibit it
  • If only have the pentasaccharide, only acceleratie ATIII:Xa inhibition
29
Q

How are coagulation reaction limited?

A
  • Endothelial health
    • PGI2, EDRF
  • Plasma protease inhibitors:
    • Excess (anti-thrombin III)
    • Remember endothelium makes heparin
  • Thrombomodulin/Protein C:
    • Another endothelial/thrombin dependent pathway
30
Q

Thrombin/Thrombomodulin Model of Protein C Action

A
  • Thrombin bound to thrombomodulin
    • endothelial surface
    • cleaves protein C to activated protein C
    • Cleaves factors Va and VIIIa to give inactive products→Anticoagulant activity
  • process is accelerated in the presence of protein S and platelets
  • Both protein C and protein S are GLA-containing proteins, are vitamin K-dependent, and are affected by warfarin.
    • Inactivates tPA inhibitor→increases tPA activity→fibrinolytic action
  • Protein C has most rapid turn over of any Ca2+ dependent proteases
31
Q

Clinical Significance of Thrombolytic Therapy

A
  • 80% of MI never get thrombolytic treatment
  • Delivery is a big problem
  • Time to treatment is cruical for stroke
    • is it a hemorrhagic stroke?
    • needs to be within 3+ hours
32
Q

Lipoproteins: Why do we need to be concerned?

A
  • High LDL cholestrol is poitvely associated with increased risk of coronary artery disease and death
  • Clog, break off, exposed phospholipid surface that starts coagulation rxn
33
Q

The order of cholesterol transport

A
  • Gut: chylomicron→VLDL→LDL→IDL→HDL: Liver
  • Needed to transport and store chlesterol around the body
  • Very hydrophobic and wouldn’t be able to move freely in body’s water-based environment
34
Q

Chylomicrons

A
  • Deliver triglycerides derived from dietary fat to non-hepatic tissues
    • Apolipoproteins: B48, CII and CIII
      • Act as cofactors for lipoprotein lipase and allow interaction with downstream molecules for dilevery to fat cells
35
Q

VLDL

A
  • Deliver triglycerides derived from liver synthesis to non-hepatic tissues
  • Apolipoproteins: C, E, B100
    • B100 is same gene as B48, but longer→allows for binding to LDL receptor
36
Q

LDL

A
  • Derived from VLDL and deliver cholesterol derived from liver synthesis to various tissues
  • Apoliprotein B:
    • Has same B100 protein to bind LDL receptor
37
Q

HDL

A
  • Collect (scavenge) cholesterol from non-hepatic tissues and deliver to the liver
  • ApoA-I and ApoA-II
    • Remove excess cholesterol from foam cells and transport to where they may be less toxic
    • Role is to remove ‘free cholesterol’ and convert to cholesterol esters and deliver to liver or steroidogenic tissue (uses SR-B1)
    • Cholesterol can be transferred to other lipoproteins by CETP
  • ApoC: cofactor with lipase to break down triglycerides
38
Q

What must be true about B100 for it to bind LDL receptor

A
  • Must be oxidized
39
Q

Lp(A)

A
  • Very artherogenic form of lipoprotein
  • More/longer coiled “pringles” make them more artherogenic
  • Form disulfide bond with B100
  • Plaque promoting
  • Things that lower LDL also lower Lp(A) because half of Lp(A) is LDL
40
Q

Framingham Study

A
  • High ration of HDL to total cholesterol is often protective
    • We now know not ALL forms of HDL are ‘good’
    • We particularly want HDL3

Phcol 401 (10 decks)

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