Block 2-Reymann (Coag)

Question 1

Hemostatis

Answer 1

• Is cessation of blood loss from a DAMAGED vessel

1. Vascular spasm
2. Platelet plug formation (primary)
3. Blood coag (secondary)
4. Dissolution of fibrin clot (tertiary)

• _2 major systems down reg coag _
• Firbrin inhibition (limit coag)
• Plasma has protease inhibitors that inactivate coag proteins
• Fibrinolysis (antagonize coag)
• Inactive plasminogen is converted to proteolytic plasmin ^{<u><strong>(DIGESTS fibrin)</strong></u>}

Question 2

Drugs for disorders in Coag

Answer 2

• Inhibit coag (-):
• Platelet aggregation inhibitors
• Anticoag
• Thrombolytics
• Restore or promote coag (+):
• Plasminogen activation inhibitors
• Protamine sulfate
• VIt k
• serine protease inhibitors
• Plasma fractions

Question 3

Platelet aggregation inhibitors (Aspirin)

Answer 3

• Decrease synthesis/action of mols that promote aggregation
• Cyclooxigenase inhibitor
• Thromboxane A2=Platelet degranulate & aggregate
• Aspirin antagonize ^{<u><strong>(inhibits)</strong></u>} this pathway=PROLONGED BLEEDING TIME
• Mech-Inhibits TXA2 synthesis by irrever acetylation of enzyme COX
• Takes 10 days for new COX synthesize
• 81Mg = Anti-platelet (no SEs)
• Preventive treatment-cerebral ischemia & POST MI (ischemic coronary)
• 600-1000Mg-Analgesic/anti-inflammatory/Anti-fever
• CI: before surgery due to ^{<u><strong>INCREASE BLEEDING TIME</strong></u>}

Question 4

Platelet aggregation inhibitors (ADP receptor blockers)

Answer 4

• 1st gen=^Ticlopidine
• 2nd gen=^Clopidogrel
• 3rd gen=^Prausgral
• PK:
• All above are PRODRUGS
• Slow onset of action - LOADING dose may be required
• PD:
• Irreversible inhibitors of P2Y12 (ADP receptor on platelet surface)
• Use:
• Pts intolerant to aspirin

Question 5

Platelet aggregation inhibitors (Phosphodiesterase inhibitors)

Answer 5

• Dipyridamole
• PD:
• Elevation of cAMP lvls by inhibition of phosphodiesterase
• Blockade of adenosine uptake-ACTS on A2 receptors ACTIVATES platelet adenylyl cyclase
• Use:
• Preventive combo antiplatelet w/aspirin or warfarin
• “prosthetic heart valve”
• Test coronary reserve (opens coronary arteries)
• NO USE as anti-anginal drug - can PROVOKE coronary steal

Question 6

Platelet aggregation inhibitors (Phosphodiesterase inhibitors)

Answer 6

• Cilostazol
• Newer drug
• Promotes vasodialation & inhibition of platelet aggregation
• Use:
• Primarily in treatment of ^{<u><strong>INTERMITTENT CLAUDICATION </strong></u>}or “window shopping disease”
• Signs of artheroscelrosis in lower extermities

Question 7

Platelet aggregation inhibitors (Block G2B/3A)

Answer 7

• Use in pts w/acute coronary syndromes
• The 2B/3A complex receptor for fibronogen, vitronectin, firbonectin, & VWF
• Activation of this receptor is Final part of Common pathway ^{<u><strong>(Factor 7)</strong></u>}
• AbcixMAB: monoclonal Ab against human G2b/3a receptor. Reversible w/thrombo-infusion ONLY = Restore coag cascade
• Eptifibatide: Peptide reversible antagonist of GP2B/3A receptor
• Tirofiban: Non-peptide reversible antagonist of GP2B/3A receptor
• Uses:
• Unstable angina
• High-risk percutaneous coronary interventions ^{<u><strong>(Treating stenosis)</strong></u>}

Question 8

Anticoags (Heparin)

Answer 8

• Water sol Injectible RAPID acting anti-coag & ^{<u><strong>SAFE IN PREGERS</strong></u>}
• Used to acutely interfere w/formation of THROMBI
• Mixture of straight chain anionic glycosaminoglycans w/a MEAN MW=15,000
• PD:
• Anti-throm 3 is Alpha-glob that inhibits ^{<u><strong>(serine proteases &amp; several clotting factors-thrombin)</strong></u>}
• Absence of heparin=Anti-throm 3 interacts w/thrombin VERY SLOWLY
• Heparin allows Antithrombin 3 to RAPIDLY inhibit thrombin ^{<u><strong>(DOES NOT EFFECT ALREADY BOUND FIBRIN)</strong></u>}

Question 9

Anticoags (LMWH)

Answer 9

• Low-Mol weight Heparin
• Heterogeneous compounds produced by chemical or enzymatic depolymerization of unfractionated heparin ^{<u><strong>(UFH)</strong></u>}
• LWMH inhibit activated factor 10 BUT has less effect on thrombin than regular Heparin
• Has LITTLE acceleration & less likely to ^{<u><strong>INDUCE HYPERSENSITIVITY</strong></u>}
• Danaparoid: LMWP from pork gut
• Contains Hep sulfate, dermatan sulfate, chondroitin sulfate
• Mainly inhibits Factor 10 w/LESS EFFECT on thrombin
• Use:
• For DVTs in hip replacement surgeries
• Treatment of HIT ^{<u>(Type 2 Hypersen)</u>}

Question 10

Anticoags (Heparin)

Answer 10

• Monitoring effects:
• Preformed by **PTT of activated factors **
• aPTT test integrity of ^{<u><strong>INTRINSIC &amp; COMMON </strong></u>}pathways
• LMW Hep:
• Has higher therapeutic index that its Big brother - in Prevention care
• NOT necessary to monitor LMW Hep
• SE:
• Bleeding-USE of protamine sulphate acts as antagonism of Hep
• Hypersensivity Rxn ^{<u><strong>(HIT type 2)</strong></u>}
• Thrombosis-w/long term admin of hep=reduction of Anti-thrombin 3 activity
• This decrease of coag factors=^{<u><strong>HIGHER risk of thrombosis</strong></u>}
• Minimize risk w/Low doses

Question 11

Heparin-induced Thrombocytopenia (HIT)

Answer 11

• Ab recognize complexes of heparin & platelet factor 4 on platelet membrane
• through IgG binds to PF4/Hep complex = ^{<u><strong>IMMUNE COMPLEX</strong></u>}
• Leads to to platelet aggregation & release of platelet contents
• Result is thrombocytopenia & thrombosis
• Treatment: Sub Hep w/a DTI or Fondaparinux (LMW HeP)
• DTIs=exert anticoag effect by direct binding to active site of thrombin

Question 12

Anticoags (Factor X active inhibitors)

Answer 12

• Fondaparinux-Synthetic pentasaccharide
• Sequence of 5 carbs necessary for BINDING to anti-thrombin 3
• Binding induces conformational change in anti-thrombin required for Factor 10
• SPECIFIC inhibitor of 10A
• Negligible ANTI-thrombin activity
• Approved for prevention treatment of DVTs
• Use as INJECTION once a day

Question 13

Anticoags (DTIs)

Answer 13

• Exert anti-coag effect directly binding to active site on thrombin
• Lepirudin, Desirudin, Bivalrudin, Argatroban
• Hirudin powerful & specific thrombin inhibitor from leech
• Recombinant form peptide =^{<u><strong> LEPIRUDIN</strong></u>}
• Action independent from Anti-thrombin 3=reach inactivate fibrin bound thrombin in ^{<u><strong>THROMBI</strong></u>}
• Given parenterally
• Monitor by aPTT
• Bivalirdin=Thrombotic Anticoag
• Argatroban=Small mol thrombin activator

Question 14

Anticoag (Coumarin)

Answer 14

• Warfarin & Dicumarol
• Unlike Hep they are Lipid sol and given ^{<u><strong>ORAL</strong></u>}
• _PD: _
• Inhibit VIT K **epoxide reductase **
• Use:
• Treating inactive clotting factors DUE to LACK of gamma-carboxyglutamyl side chains
• Take 8-12 hours for onset
• Anticoag effects can be overcome with VitK ^{<u><strong>TAKES 24 HRS</strong></u>}

Question 15

Anticoag (warfarin)

Answer 15

• Monitoring LVLS:
• Has narrow TI & participates in MANY drug to drug interactions
• Effects must be monitored ^{<u><strong>every 2-4 weeks</strong></u>}
• Preformed by PT ^{<u><strong>(extrinsic &amp; common)</strong></u>}
• Prolongs PT decreases amount of functional Factor 7
• SE:
• Hemmorrhage
• Skin necrosis related w/reduced activity of protein C ^{<u><strong>(Occurs 1st weeks of therapy)</strong></u>}
• Crosses placenta ^{<u><strong>(lipid sol)</strong></u>} can cause ^{<u><strong>hemorrhagic disorder in fetus (ANACEPHALY)</strong></u>}
• Antibiotics mess w/flora = LOW VIT K
• Anti-bile reabsorb-Mess with Vit K

Question 16

Anticoag (Fibrinolytics)

Answer 16

• Lyse thrombi by catalyzing conversion of plasminogen into PLASMIN
• Reduce mortality of ACUTE MI ^{<u><strong>(dissolve thrombus to save Myocaridal tissue)</strong></u>}
• Used in situations where angoplasty(balloon catheter) ^{<u><strong>NOT AVAILABLE</strong></u>}
• Streptokinase
• Urokinase
• Anistrepeplase
• Alteplase

Question 17

Drugs for bleeding disorders

Answer 17

1. Plasminogen activation inhibitors ^{<u><strong>(OPPOSITE of THROMBOLYSIS)</strong></u>}
2. Protamine sulfate
3. VIT K
4. Plasma factors

Question 18

Drugs for bleeding disorders (Plasminogen A Inhibitors)

Answer 18

• Aminocaporic acid & tranexamic acid
• Inhibit plasminogen activation
• Decrease plasmin LVLS
• Down-reg of fibrinolysis
• Down Reg of fibronogen breakdown

Question 19

Drugs for bleeding disorders (Protamine sulfate)

Answer 19

• Antagonizes ^{<u><strong>(inhibits)</strong></u>} Heparin
• HIGH in arginine-Cationic protein interacts w/anionic Hep
• Forms complex w/^{<u><strong>NO ANTICOAG activity</strong></u>}
• Dose dep has immediate effect

Question 20

Drugs for bleeding disorders (VIT K)

Answer 20

• Stop bleeding due to oral-anticoag ^{<u><strong>(warfarin)</strong></u>}
• Effect delayed 6-12 hours w/complete penetrance by 24hours
• NOT for use in ACUTE bleeds ^{<u><strong>(USE FROZEN FRESH PLASMA or BLOOD TRANSFUSION)</strong></u>}

Question 21

Plasma Fractions Def.

Answer 21

• Def in plasma coag factors can cause bleeding
• Spont bleeding occurs when factor activity is less 5-10% of normal
• Factor 8 (Hemo A)
• Factor 9 (Hemo B or Christmas)