Anticoag

Front 1

Coagulation overview

Back 1

-Hemostasis -->vasospasm --> formation of platelet plug --> coagulation factors activated on platelets--> prothrombin to thrombin and thrombin activates fibrinogen --> fibrin forming a fibrin clot

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platelet adhesion

Back 2

-platelets stick to vessel wall
(aggregation- they stick to each other)

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Clot dissolution controlled by...

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-thrombin -->
protein C, protein S (anticoag) -->
inactivate coag factors and inc tissue plasminogen activators -->
which activate plasminogen -->
plasmin (destroyer) which digests fibrin strands -->
fibrinogen degradation products increase and inhibit thrombin

Front 4

antithrombin III

Back 4

-inhibits thrombin and factors IX and X, and intrinsic factors
-Target for heparin; protease inhibitor

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Heparins inhibit

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intrinsic and common pathway

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coumadin inhibits

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extrinsic and common pathway

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common pathway

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-Activated X converts prothrombin --> thrombin--> fibrinogen to fibrin (clot)

Front 8

Vitamin K

Back 8

-necessary for enzymatic activation of factors X, IX, VII, and II (1972)
(these factors inhibited by coumadin)
-also needed for coagulation factor inhibitors, prot C and S

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protein C and protein S

Back 9

inhibits factors V and VIIIA

Front 10

PT (prothrombin time) (INR)

Back 10

measures extrinsic and common pathway function (vit K dependent factors) (used to measure pts on coumadin_

Front 11

Activated partial thromboplastin time (aPTT)

Back 11

-measures intrinsic and common pathways
(heparin)
-measure baseline then 6 hours after initiation or change in dosage
adjust heparin up or down according to aPTT

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mechanism of action of heparin

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-pentasaccaride sequence binds to antithrombin III and forms a complex 100-1000x more potent anticoagulant -->
-result prevents growth and formation of formed thrombus and facilitates fibrinolysis
-it prevents thrombus propagation but does not lyse existing thrombi (clot)

Front 13

how is heparin given

Back 13

-IV (for rapid anticoag) or subcutaneously)
-1/2 life is 30-90 min (short) (dosed often)
-hepatic and renal elimination
-use aPTT to manage pts on this (therapeutic range is 1.5-2.5 times normal control)

Front 14

what is heparin (UFH) used for?

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1. tx of DVT/PE
2. Acute coronary syndrome
3. Prophylaxis for VTE (venous thromboemolism)

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adverse effects of unfractionated heparin (UFH)

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1. Bleeding**
-more commonly in elderly W
-GI, urinary and soft tissue
-mgmt of major bleeds (D/C and give IV protamine sulfate**)
2. Thrombocytopenia (check CBC)
3. Hypersensitivity

Front 16

Protamine sulfate

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-binds heparin into a complex and forms a complex in a blood which is filtered out in the urine; works within 5 min and effect is up to 2 hours

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Heparin induced thrombocytopenia

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-rare
-more common in pts who have been on heparin for a week or so
-heparin molecule starts binding to platelets and the bodies immune system starts to attack the platelets
-can see clots forming
-once this happens, pt CANNOT HAVE IT AGAIN

Front 18

Low molecular wt heparin (LMWH) -fragments of UFH

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1. Predictable dose response
2. Improved subcutaneous 3. 3. bioavailability
3. Longer half life (4-6 hours) (dosing evert 12-24 hrs in fixed or wt based)
4. Less thrombocytopenia
5. Reduced need for lab monitoring

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Types of LMWH

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1. Dalteparin (Fragmin)
2. Enoxaparin (Lovenox)
3. Tinzaparin (Innohep)
use for: prophylaxis for DVT and PE, tx of DVT/ PE, ACS
-routine lab tests are unnescessary

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adverse effects of LMWH

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1. bleeding (gingival, noes, GI tract)
2. Thrombocytopenia but rarely HIT

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pregnancy and anticoags

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-heparin can be used coumadin cannot (category x)

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Direct Thrombin inhibitors

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MOA: bind to and inactivate circulating clot bound thrombin
-used for pts who had HIT
-Hirudin derived from medicinal leech salivary secretions
1. Argatroban
2. Lipirudin (Refludan)
3. Desirudin (IV, SC)
4. Bivalirudin (angiomax) (also for unstable angina undergoing PTCA)

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indications and monitoring-direct thrombin inhibitors

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1. mgmt of pts with HIT
2. new drug called ximelagation with good oral bioavailability? FDA said no
3. Monitoring with aPTT

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averse effects of Direct Thrombin inhibitors

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1. Bleeding!
-13-17% major bleeding with lepirudin
-no fatal or intracranial hemorrhage
-no known agents to reverse thrombin inhibitors

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oral anticoag close to market

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1. Rivaroxaban (Xarelto)- direct factor Xa inhibitor
2. Dabigatran (Pradaxa) direct thrombin inihibtor
-fast onset, no need to monitor
-may replace coumadin

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Warfarin (coumadin)

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- most widely prescribed oral anticoag (brand)
MOA: inhibits enzymes necessary for Vit K activation (need for activation of Vit K dependent factors prothrombin, VII, IX, and X (and prot C and S) which are formed in the liver)

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what is Warfarin used for?`

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1. Prevention and tx of VTE
2. Prvention of emoblic complications of:
-a fib (can get clots in atria which can lead to strokes)
-heart valve replacement
-MI

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Pharmacology of Warfarin

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-extensive binding to albumin
-CATEGORY X
-effects depend on 1/2 life of coagulation factors that is affects
(prothrombin 2-4 days so full effects takes 8 days or more; actual 1/3 life of warfarin is 3-5 days but variable)
-hepatic metabolism via CYP450 (drug interactions are numerous)

Front 29

coumadin: dosing and administration

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1. most start w/ 5 mg/day (dosed once a day) and adjust according to PT/INR levels (should be b/t 2-3)
2. Initial dose changes should not be made more frequently than every 3 days and based on INR, oncei ts stable, less freq monitoring

Front 30

dosing of coumadin and INR

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1. measure INR days 5-7
2. If INR < 1.5 inc weekly dose by 10-25%
3. if INR is 1.5-1.9 inc weekly dose by 0-25%
4. If INR is 2-3 than no change and repeat in 1 wk
5. if INR > 3.0 hold one daily dose and dec by 10-25%

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Adverse effects of coumadin

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1. Bleeding (1-10% major episode- need a transfusion)
-monitor INR, ask pts about bleeding, tx
2. Purple toe syndrome (rare)
3. Skin-necrosis in areas os subcutaneous fat and M/C in women
4. GI

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mgmt of elevated INR and bleeding complication of coumadin

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1. mild inc in INR 3/5-5 (hold dose & recheck in 3-7 days; restart dose 10-25% < initial weekly dose)
2. INR 5-9- ask about bleeding
-omit next 1-3 doses; Pro Vit K & recheck INR q24-48 hrs; reduce dose
3. INR > 9 (prob need to be hospitalizeD)
-omit next 3 doses
-VIt K (reverse coumadin) po nor IV depending on severity of bleeding
-FFP (fresh frozen plasma) for severe bleeds

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pt with active bleeding

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-hospitalize and give IV Vit K infusion with FFP as needed
-repeat VIt K in 12 hours and repeat Vit K as needed until INR is in therapeutic range

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Drug and Food interactions with coumadin

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1. Vit K rich foods reduce effects (broccoli, lettuce, spinach)
2. Drugs that increase bleeding risks:
a. ASA and NSAIDS
b. Triclopidine
c. Heparins, other anticoags (plavix)
d. drugs that inc INR (MANY)

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Glycoprotein IIb/ IIIa inhibitors

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-antiplatelets
-given IV, work by blocking interaction between platelets via the glycoprot IIB/IIa inhibitors
1. Abciximab (REOPRO)
2. Epitifibatide (Integilin)
3. Tirofiban (AGGRASTAT)

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platelet GP IIb/IIIA receptor blockers

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Uses:
-w/heparin for PTCA and medical mgmt of ACS
Toxicity:
-major andm inor bleeding events inc with heparin + GP IIb/IIIa blockers (most common bleeding site was in arterial acces in the groin)

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Aspirin

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MOA: In plts. blocks cyclooxygenase which synthesizes thromboxane A2, a platelet aggregator --> Action is permanent for life of platelet (7-10 days)
(irreversible effect on the platelet)
Uses:
-strokes, heart attacks

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aspirin clinical uses

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-other coronary conditions:
1. tx pts who have had certain revascularization procedures such as angioplasty, and cornoary bypass operations

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AE/Toxicity of aspirin

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1. GI upset- bleeds
2. Higher doses --> salicylism w/ vomiting, tinnitus, decreasing hearing and vertigo
3. UGI bleed and inc incidence of gastric and duodenal ulcers
4. dec in renal blood flow

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Clopidogrel (Plavix)

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MOA: blocks platelets ADP receptor --> and blocks platelet activation and degranulation
Uses:
1. prevention of thrombosis in PTCA
2. reduces atherosclerotic events in pts w/recent MI, CVA, PAD
-oral med

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AE of plavix

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1. purpura (Thrombotic thrombocytopenic pupura)
2. GI upset
-issues with genetic differences and drug interactions which can lead to decreased efficacy

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Effient (prasugrel)

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-new plavix competitor
-antiplatelet for use in pts who undergo angioplasty
-oral
-MOA similar to plavix (ADP receptor blocker)
-black box warning of bleeding
-contraindications: stroke, active bleed, age >74

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Nplate & Promacta

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-used to increase the number of platelets

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Anemias

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1. oral iron therapy for iron deficiency anemia
-ferrous salts given orally after meals (Feosol)
AE: GI, constipation, black stools
2. Vit B12
-Cyanobalamin IM every mo for life
-rapid recovery of bone marrow and red cells
3. Folic acid for megaloblastic anemia
-oral supplementation