Chapter 39 - Anticoagulants Flashcards
Arterial thrombi vs venous thrombi
Arterial = rich in platelets because of high shear Venous = low shear - few platelet mostly fibrin and trapped RBC
Antithrombotic drugs classes
1) Antiplatelet 2) anticoagulant 3) thrombolytic
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
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
Antithrombin key points
1) serine protease inhibitor 2) made from liver 3) concentration 2.6 +/- 0.4 mcM 4) suicide substrate for target enzyme
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
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
Molecular weight of heparin
15000 (range 5000-30000)
Size of heparin needed to bridge thrombin and antithrombin
5400 Da
Half life phenomenon of heparin
low dose binds endothelium - short half life higher doses - saturate endothelium - longer half life range from 30-60 minutes
Clearance of heparin
1) binds to macrophages 2) internalizes and depolymerizes the long heparin chain 3) shorter chain secreted back to circulation
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
Heparin rebound
Slow release of protein-bound heparin back into circulation after heparin reverse
Therapeutic heparin level define
2-3x prolongation of aPTT
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
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
Pharmacokinetic and biophysical limitations of heparin
TABLE 39.1
Protamine sulfate origin
Salmon sperm binds heparin then clears it
HIT features
TABLE 39.2
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
Risk of osteoporosis with long term heparin therapy
30% 2-3% have vertebral fracture
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
Advantages of LMWH over heparin
TABLE 39.4
LMWH MOA
1) activate antithrombin 2) half too short to bridge thrombin
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
