Armelle de Laforcade DVM DACVECC
Anticoagulation Update
Where Do We Stand?HeparinClopidogrelAspirinWarfarinRivaroxaban
When to initiate anticoagulationWhich one?DoseMonitoringWhen to discontinueHow to discontinue
Anticoagulation in peopleAtrial fibrillation (5x greater risk of stroke)
Vitamin K antagonistsDecreased risk of stroke by 64% compared to 22% with
platelet blockersNovel anticoagulants
DVT, PEHeparin therapy short termVitamin K antagonists
Coronary artery disease, aortic thrombosisPlatelet blockers
Combination therapy?
Anticoagulation in People
Venous Thrombosis
Heparins: UnfractionatedDiscovered in 1916
Second year medical student in a research laboratory
Found in high concentration in the liverMix of variably sized glycosaminoglycan moleculesIncreases inhibitory effect of antithrombin
Minimal length required to bind both antithrombin and thrombin
18 monosaccharide units Does not occur on every heparin molecule
Heparin:antithrombin complexInhibits coagulation factors (thrombin, IXa, Xa, XIa,
XIIa) Inhibits thrombin induced platelet activationPrevents factors V & VIII upregulation
Heparins: Unfractionated
Administered 3-4 times daily or as continuous infusion75-250U SQ TID-QID 10u/kg/hr
Unpredictable clearanceLarge molecules bind plasma proteins, macrophages,
endothelial cellsSmaller molecules cleared more slowly via kidneysMonitoring and titration required
aPTTProlong to target 1.5-2.5 mean of reference rangeMeasure q 6 hours until stable at target range (initiation phase)Measure once daily thereafter (stable phase)
Same time Avoid limb with IV catheter and limb receiving infusion
aPTT Target
Studies: Up to 20% not achieving target ranges within 24 hours
People: reference range for aPTT determined with each lot change (yearly)
Anti-Xa methodMost specific and is least affected by other
variables Blood is collected from patients on
unfractionated heparin. aPTT and anti-Xa assays performedLinear regression performed to determine the
range of aPTT values that correlate to anti-Xa levels in a range of 0.3 – 0.7 U/mL of heparin.
Used as target aPTT range
aPTT: Why We Like ItEase and speed of performanceWidespread availability of the testTechnically easyLow costLack of a suitable alternative
Just know…Doubts relative to the aPTT persistConsider anti Xa test if
Unable to achieve target aPTT (heparin resistance)Acute phase proteins?
Other DisadvantagesParenteral route of administrationFrequent laboratory monitoringRisk of heparin induced thrombocytopenia
Indirect inhibitors of coagulationEffect mediated by plasma cofactors
(antithrombin)
Heparins: Low Molecular Weight
Derived from UFH by depolymerizationMean MW 4,000-5,000d (1/3 that of UFH), 15
monosaccharide unitsHigh ratio anti-Xa activity : anti-IIa activity
Factor Xa inhibition occurs with very low MW fragments
LMWH Average MW Ratio anti-Xa/anti-IIa
Enoxaparin 4500 3.9
Dalteparin 6000 2.5
Tinzaparin 6500 1.6
Parnaparin 5000 2.3
Low Molecular Weight Heparin
Largely replaced UFHLonger half life, renal clearance100% bioavailability after SQ injection
Peak activity consistently 3-5 hours after injectionPredictable dose response and clearanceReduced binding to plasma proteins and
endothelium
Fixed dose, no monitoring in people (in routine cases)
Animal use: Marketed for SID dosing (100U/kg SQ)Limited pharmacokinetic studiesLikely needed 2-3x/day
MonitoringLMWH: minimal change in aPTT
Factor Xa inhibition has little effect on the aPTT
Plasma anti Xa activityMore accurate for assessment of
anticoagulationInversely related to thrombus formation and
propagationUseful for both UFH and LMWH monitoring
Timing: Peak kevels (2-4 hours after LMWH)Condition being treated (not yet studied in
animals)
Anti-Xa AssayChromogenic assay
Heparin + free AT AT-HeparinAT-Heparin + FXa (in excess) AT-Heparin-FXa +
FXa (residual)FXa (residual) + Substrate Signal
Signal generated proportional to residual FXa remaining after neutralization by the AT-Heparin complexInversely proportional to the concentration of heparin
Interpreting Anti Xa Levels
Unfractionated heparin 0.3-0.7 U/mlDalteparin 0.5-1.0 U/mlEnoxaparin 0.5-1.0 U/ml If anti Xa activity is within the therapeutic range
and the patient is doing well clinically (not clotting, bleeding excessively, or having complications), then dose is considered appropriate
If the anti-Xa activity is high, either too high of a dose or poor clearance , at increased risk for excessive bleeding
If the anti-Xa activity is below the therapeutic range, dose may need to be increased
Anti-Xa Assay: When?Renal disease
Reduced clearanceLong term heparin use
Prevent over/under anticoagulationShort term heparin use
High risk of bleeding (post-operative) High likelihood of thrombotic recurrence
Obese/low body weight
Arch Pathol Lab Med 1998
Our Experience with Anti-Xa
35 dogs 25 serial measurements
Hypercoagulability19 dogs
Prophylactic vs. therapeuticTarget 0.5-1 U/ml
7 dogs in range10 above range6 below range
As G increased, greater odds of being out of range
GENERAL CATEGORY
SPECIFIC DISEASES
Septic process
Infective endocarditis (2)Abdominal sepsis (1)Pyothorax (1)
Hematological disease
IMHA (9)PRCA (1)
Neoplastic process
Splenic masses (2)Myeloid leukemia (1)
Protein losing disease
PLN (3)PLE (2)
Miscellaneous
Chylothorax (1)Gall bladder mucocoele (1)
Warfarin (Coumadin)1939 - Dicumerol compound identified
Sweet clover diseaseFirst used as anthrombotic at Mayo Clinic in 1941
1940s - Warfarin sodium synthesizedWisconsin Alumni Research Foundation held initial
patentBetter pharmacological properties‘Ideal’ rodenticide
1950s – First use as antithrombotic in peopleUsed to treat President Eisenhower following heart
attackQuickly grew to be major anticoagulant in US & NA14th largest selling prescription drug
Mechanism of Action (1974)Prevents gamma carboxylation of coagulation
factorsII, VII, IX, X, Proteins C,S
Narrow therapeutic windowFood-drug & drug-drug interactions
Protein binding, cytochrome p450Slow onset of action
Requires 2-7 days to reach therapeutic levelsStart therapy with heparin
Unpredictable / variable dose responseInternational normalized ratio (INR)
INR = (Patient PT/Normal PT)ISI
ISI – International sensitivity index
Warfarin: MontioringTarget INR – Generally 2.0-3.0
2.5-3.5 with mechanical heart valvesDaily until INR is therapeutic twice at least
24 hours apartTwice a week for 2 weeks, then once a
month until therapy is complete
IssuesExpenseComplianceDrug interactionsComplications
Intracranial hemorrhage most feared
Warfarin in Dogs
0.05-0.2mg/kg PO/dayAdjusted periodicallyTarget INR 2-3“Total weekly dose”Some had concurrent aspirin or clopidogrel
Warfarin in DogsHeparin administered 24-48 hrs after surgery, for 2-4 days
Warfarin 0.08-1.2mg/kg/day3months durationTarget INR 2.52-10% changes in TWD
Aspirin started 1-2 weeks postop and continued >1year
Dabigatran Etexilate
Direct thrombin inhibitor Converted to active form (Dabigatran)Bind active site of thrombinBlock free and fibrin bound thrombinMinimally protein boundRequires acidic environment for absorptionRapid onsetPredictable anticoagulant response (no
monitoring) Twice daily
Compared favorably to warfarin therapy (18,000 people)RE-LY trial
Factor XaCatalyzes production of thrombin
Marked suppression without suppressing hemostasis6-10% considered mild deficiency
Potential as anticoagulation Reduced risk of bleeding complications
First Xa inhibitorsAntistasin
Salivary glands of a mexican leech (Haementaria officinalis)
Tick anticoagulant peptide (TAP)Extracts of Ornithodoros moubata
Factor Xa InhibitionClot bound Xa: enzymatically active
Resistant to inactivation by antithrombinFactor Xa inhibition
Decrease new thrombin generationFree and clot bound Xa
Existing thrombin sufficient to maintain adequate hemostasis
Poor oral absorption
Rivaroxaban (Xarelto)>10,000x affinity for Xa compared to other factorsBind directly and reversibly to active Fxa
Inhibits prothrombinase complexBlock thrombin generation (amplification)
Animal models: effective against venous & arterial thrombosis
Rapidly absorbed (peak plasma concentrations in 2-4 hrs)
Short half life Markers of thrombin generation inhibited for up to 24 hrsSID dosing may be ok
Predictable anticoagulant response No monitoring
RivaroxabanPartially metabolized by CYT p450Partial renal elimination
Rocket AF trialRIVA non inferior to warfarin in preventing
stroke or systemic embolismLess intracranial hemorrhage, more GI
hemorrhage than warfarinCombination with aspirin increases
intracranial hemorrhage
IndicationsVTE prophylaxis (total hip)
5-20mg/day effective, 10mg safestTreatment of VTE
15mg BID for 3 weeks then 20mg/dayEinstein PE study “non inferior to
enoxaparin/VKA course)Thrombophylaxis in medically ill patientsStroke prevention, a-fib
Reduced risk of stroke compared to warfarin20mg/day, 15mg/day with mild renal
impairmentStroke prevention, acute coronary syndrome
5-10mg/day
Practical ApplicationLiver and renal impairment? Excluded from trials
Dose adjustmentsIncluded in most common recommendations
ACCP, AHA/Am College of Cardiology Foundation/ Canadian guidelines
Discontinue 3-5 days prior to surgery procedureNo bridging strategy needed
Lack of reversibilityEncouraging data from trialsReports of major bleeding in populations excluded from
trialsDabigatran: #1 medication for direct reports of serious
drug events to FDA in 2011 – labeling updateOverdose vs. trauma/emergent sx, compliance issues
Veterinary UseTheoretical application in cats with ATELimited to in vitro studies
Brainard, “In vitro effects of Rivaroxaban on feline coag indices”
Rapidly absorbed after oral dosing0.3mg/kg, 1mg/kg, 3mg/kgProtein bound, safeShort half life
Xenobiotics 2005
Clopidogrel• Hepatic transformation to active metabolite
• Variable effects, cytochrome p450• Irreversible binding to P2Y12 receptor• Decreases platelet activation and
aggregation• Combination therapy
• Other platelet inhibitors• Other anticoagulants
Platelets and Inflammation
Platelets and Cancer30% of dogs with PTE, 27% of dogs with
PVTPotential role for platelets
MetastasisTumor cell growthTumor associated thrombotic disease
Potential mechanismsThrombin, ADP production by tumorsDirect interaction with plateletsAggregates may promote metastasis
Enhance tumor cell adhesion to vessel wallsRelease mediators that facilitate extravasationEnhance survival of tumor cells at distant sites
Platelets hyper-responsive to added agonists
59 dogs with malignancies, 24 controlsSarcomas, carcinomas, hematopoietic
neoplasmsIncreased aggregation and rate of aggregation
Vet J 2011
Platelet Activation in Critical Illness82 dogs admitted to ICU
P selectinexpression
ResultsNo significant difference in P-selectin
expression at restIncreased P-selectin response with agonists
addedIncreased platelet aggregation in critically
ill dogsP-selectin expression correlated with TEG
values (MA)No correlation with severity of illness, SIRS,
MODS
Hypercoagulabilitiy in 50% of dogs with malignanciesvs. 31% with benign neoplasia
High MA, thrombocytosis, elevated fibrinogenGreater speed of clot formation
Hypercoagulability in 50% of dogs with malignanciesVs. 31% of dogs with benign neoplasia
High MA, thrombocytosis, elevated fibrinogen
Greater speed of thrombus generation
Vet J 2011
Induced coronary thrombosis in 32 dogs
1 of 4 treatmentst-PA + heparin 5/5 re-occludedt-PA + heparin + aspirin 7/7 re-
occludedt-PA + heparin + clopidogrel 2/7 re-occludedt-PA + heparin + clopidogrel (higher dose) 0/7
re-occluded
As adjunctive treatment to t-PA, clopidogrel prevents or delays coronary artery re-occlusion more effectively than aspirin
Am J Phys 1994
Aspirin / Clopidogrel ResistanceFailure to prevent the clinical condition for
which it was intendedFailure of drug to achieve pharmacological
effect**Variability in response to drug
<30% reduction in platelet function
Does this occur in dogs and cats?
Causes of Resistance: PeopleAspirin
Environmental factorsInadequate dosingDrug-drug interactionsVariations in cox-1 structure, Thromboxane production elsewhere
Link to adverse events
ClopidogrelInappropriate dosingUnder dosingDrug-drug interactionsVariable conversion to active metabolite
Link to adverse events