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