Chapter 39 - Anticoagulants Flashcards by Gary Yang

Arterial thrombi vs venous thrombi

Arterial = rich in platelets because of high shear Venous = low shear - few platelet mostly fibrin and trapped RBC

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Antithrombotic drugs classes

1) Antiplatelet 2) anticoagulant 3) thrombolytic

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Heparin molecule

1) Sulfated polysaccharide 2) isolated from mammalian tissue rich in mast cells 3) commercially derived from porcine intestinal mucosa 4) polymer of alternating D-glucoronic acid and N-acetyl-D-glucosamine residues

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Effect of heparin

1) activate antithrombin 2) antithrombin inhibits thrombin and Factor 10a 3) heparin causes release of TFPI = factor Xa dependent inhibitor of factor 8a

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Antithrombin key points

1) serine protease inhibitor 2) made from liver 3) concentration 2.6 +/- 0.4 mcM 4) suicide substrate for target enzyme

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Steps of heparin to activate antithrombin

1) pentasaccharide on heparin binds antithrombin 2) conformational change to antithrombin 3) enhances rate of antithrombin to inhibit factor Xa 4) heparin act as template to bind thrombin as well bringing the two together 5) form thrombin-antithrombin complex

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Heparin, LMWH and fondaparinox activity ratio for anti factor Xa and IIa

heparin 1:1 LMWH 2:1 to 4:1 fondaparinox only Xa inhibition

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Molecular weight of heparin

15000 (range 5000-30000)

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Size of heparin needed to bridge thrombin and antithrombin

5400 Da

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Half life phenomenon of heparin

low dose binds endothelium - short half life higher doses - saturate endothelium - longer half life range from 30-60 minutes

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Clearance of heparin

1) binds to macrophages 2) internalizes and depolymerizes the long heparin chain 3) shorter chain secreted back to circulation

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Heparin binding proteins in circulation

The more there are, the lower activity of heparin (less available to bind antithrombin) Acute phase reactants multimers of vWF during platelet activation PF4

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Heparin rebound

Slow release of protein-bound heparin back into circulation after heparin reverse

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Therapeutic heparin level define

2-3x prolongation of aPTT

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Key points about heparin resistant patients based on aPTT

need to check anti-factor Xa level Possible that high protein binding heparin reduces aPTT but does not affect factor Xa level

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Heparin titration bolus and maintenance regimens

1) IV 70 U/kg then infusion 12-15 U/kg/hr if ACS 2) IV 80 U/kg then infusion 18 U/kg/hr if VTE

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Pharmacokinetic and biophysical limitations of heparin

TABLE 39.1

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Protamine sulfate origin

Salmon sperm binds heparin then clears it

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HIT features

TABLE 39.2

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HIT test

1) ELISA against antibodies against heparin-PF4 2) serotonin release assay - platelet with labelled serotonin exposed to serum in absence or presence of heparin

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Risk of osteoporosis with long term heparin therapy

30% 2-3% have vertebral fracture

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Perioperative heparin management

1) stop 2 hours before surgery if prophylaxis 2) stop full dose IV heparin 4-6 hours before 3) low dose heparin restart 12-24 hours after surgery

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Advantages of LMWH over heparin

TABLE 39.4

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LMWH MOA

1) activate antithrombin 2) half too short to bridge thrombin

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half life of LMWH

4-6 hours

clearance of LMWH

kidney

LMWH binding in plasma

90% bioavailable after sc doesn't bind protein as much

monitoring effect of LMWH

only anti-factor Xa level little effect on aPTT

VTE treatment dose of LMWH

150-200 U/kg daily or 100 U/kg BID

protamine on LMWH

only partial effect on anti-Xa completely block anti-factor IIa activity

LMWH on HIT

less likely to bind PF4 but still can

LMWH perioperative holding

prophylaxis 12 hours before surgery treatment dose 24 hour before surgery restart 12-24 hr postop start with half dose

Comparison of heparin, LMWH and fondaparinux

TABLE 39.5

Bioavailability of fondaparinux after sc injection

100%

half life of fondaparinux

17 hours

Clearance of fondaparinux

renal only

Dose of fondaparinux for VTE

2.5 mg prophylaxis 5-10 mg treatment

Risk of fondaparinux in PCI

catheter thrombosis need to give heparin as well

fondaparinux with HIT

unlikely

Reversal of fondaparinux

Recombinant activated factor 7

Preoperative fondaparinux

36 hours before surgery

Comparison of direct thrombin inhibitors

TABLE 39.6

Hirudins

Lepirudin and desirudin Act on active site and exosite 1 of thrombin

Dose of desirudin

15 mg BID

Monitoring of lepirudin

aPTT to maintain 1.5-2.5 of control ecarin clotting time also usable

Argatroban

Acts on the active site of thrombin

Clearance of argatroban

liver

Monitoring argatroban

aPTT 1.5-3x baseline but less than 100 seconds INR also elevated

Bivalirudin

divalent thrombin inhibitor

Monitor bivalirudin

ACT

Vitamin K cycle and inhibition by warfarin

FIGURE 39.2

Factor X half life

24 hr

Prothrombin half life

72 hours

Warfarin pharmacology key points

1) 90 min to peak concentration 2) half life 36-42 hours 3) 97% bound to albumin 4) free is biologically active 5) S-isomer (more active) metabolized by CYP2C9

Monitoring of warfarin effect

Prothrombin time converted to INR

Treatment for supratherapeutic INR

4.5-9 asymptomatic = withhold warfarin until therapeutic again INR \> 9 = vitamin K 2-5 mg bleeding = prothrombin complex concentrate and vitamin K

Prothrombin complex concentrate types

3 factor or 4 factor 4 adds factor 7 to 7, 9 and 10

Warfarin necrosis skin biopsies

thrombi in microvasculature

Warfarin in fetus

1) crosses placenta 2) embryopathy, nasal hypoplasia, stippled epiphyses 3) avoid in 1st and 3rd trimester 4) does not pass to breast milk

DOAC comparisons

TABLE 39.7

DOAC uses in afib

all except 1) mechanical heart valve 2) severe rheumatic valvular disease

DOAC use in VTE

all except active cancer

Dosing of DOAC in AFIB

Dabigatran 150 mg BID (renal adjust 75 mg if \< 30) Rivaroxaban 20 mg daily (renal 15 mg \< 49) Apixaban 5 mg BID (2.5 renal) Edoxaban 60 mg daily (30 if \< 50 gfr)

Dosing of DOAC in VTE

Dabigatran 150 mg BID Rivaroxaban 15 mg BID x 21 days then 20 daily Apixaban 10 mg BID x 7 days then 5 mg BID Edoxaban 60 mg daily (30 if gfr \<50)

Reasons to reduce DOAC doses

Renal failure weight \< 60 kg age \> 80 also receiving P-glycoprotein inhibitors (amiodarone, verapamil)

Monitoring DOAC effects

prothrombin time for Xa inhibitors aPTT for dabigatran

Side effects of oral anticoagulation

Warfarin - intracranial bleed (factor 7 reduction) DOAC - GI bleed (active drug stuck there) Dabigatran - dyspepsia 10%

Flow diagram for bleeding in DOAC treatment

FIGURE 39.3

Reversal for DOAC

Idarucizumab 5g IV for dabigatran - bind 1:1 renal clear Andexanet alfa and ciraparantag - Xa inhibitor not yet approved IV PCC 25-50 U/kg

DOAC in pregnancy

not to be used also cannot use if breastfeeding

DOAC in mechanical heart valves

cause more stroke and bleeding cannot be used

Chapter 39 - Anticoagulants Flashcards

(71 cards)