This document discusses anticoagulation and neuraxial anesthesia/analgesia. It provides an overview of case reports of epidural hematomas occurring with the anticoagulant Lovenox. It then reviews indications for antithrombotic therapy and recommended prophylaxis for DVT/VTE. The properties and monitoring of various anticoagulants including heparin, warfarin, low molecular weight heparin, and antiplatelet medications are discussed. Guidelines for the use of neuraxial techniques in patients on different anticoagulation regimens are provided.

1. Anticoagulation andAnticoagulation and
NeuraxialNeuraxial
Anesthesia/AnalgesiaAnesthesia/Analgesia
Dr. Stelian SerbanDr. Stelian Serban

2. Case Reports of EpiduralCase Reports of Epidural
HematomasHematomas
on Lovenoxon Lovenox
 Prior to ‘94: Vandermuelen - 4/61Prior to ‘94: Vandermuelen - 4/61
casescases
 Since ‘94: >45 cases, (IncidenceSince ‘94: >45 cases, (Incidence
1:5000)1:5000)
 Dx:Dx:
 New onset of LE weakness/numbnessNew onset of LE weakness/numbness
 Only aOnly a minorityminority of cases have back painof cases have back pain
 Setting:Setting: Almost allAlmost all
THA/TKA/Hip fx’sTHA/TKA/Hip fx’s

3. Indications For Antithrombotic TherapyIndications For Antithrombotic Therapy
 Venous thromboembolic diseaseVenous thromboembolic disease
• Deep venous thrombosis (DVT)Deep venous thrombosis (DVT)
• Pulmonary embolism (PE)Pulmonary embolism (PE)
• Primary prophylaxis of DVT or PEPrimary prophylaxis of DVT or PE
 Arterial thromboembolic diseaseArterial thromboembolic disease
• Prosthetic heart valvesProsthetic heart valves
• Mitral valve disease, especially with atrial fibrillationMitral valve disease, especially with atrial fibrillation
• Congestive cardiomyopathies, especially with atrialCongestive cardiomyopathies, especially with atrial
fibrillatiofibrillatio
• Atrial fibrillationAtrial fibrillation
• Mural cardiac thrombiMural cardiac thrombi
• Transient ischemic attacksTransient ischemic attacks
• Stroke in evolutionStroke in evolution
 Disseminated intravascular coagulationDisseminated intravascular coagulation
 Maintenance of patency of vascular grafts, shunts, bypassesMaintenance of patency of vascular grafts, shunts, bypasses

4. Recommended DVT/VTE ProphylaxisRecommended DVT/VTE Prophylaxis
Hyers Am J Respir Crit Care 1999Hyers Am J Respir Crit Care 1999
Geerts et al Chest 2001, 2004 Bauer Blood 2002Geerts et al Chest 2001, 2004 Bauer Blood 2002
Risk groupRisk group Recommended prophylaxisRecommended prophylaxis
Hip replacementHip replacement Warfarin, LMWH, fondaparinuxWarfarin, LMWH, fondaparinux
Knee replacement Warfarin, LMWH, IPC,Knee replacement Warfarin, LMWH, IPC,
fondaparinux (Arixtra)fondaparinux (Arixtra)
Hip FractureHip Fracture Warfarin, LMWH, fondaparinuxWarfarin, LMWH, fondaparinux
Major traumaMajor trauma LMWH, IPCLMWH, IPC
Abdominal surgeryAbdominal surgery UFH, LMWH, IPC, warfarin, ESUFH, LMWH, IPC, warfarin, ES
Medical PatientsMedical Patients UFH, LMWH, ESUFH, LMWH, ES
IPC-Intermittent Pneumatic CompressionIPC-Intermittent Pneumatic Compression
ES-Elastic stockingES-Elastic stocking

7. Review of commonly usedReview of commonly used
anticoagulantsanticoagulants
 Antiplatelet drugs– inhibit plateletAntiplatelet drugs– inhibit platelet
functionfunction
1)1) Aspirin(ASA): irreversible inactivatesAspirin(ASA): irreversible inactivates
COX, even low-dose aspirin (81) mayCOX, even low-dose aspirin (81) may
suppress TXA2 synthesis & PLTsuppress TXA2 synthesis & PLT
aggregation, inhibiting 1 hr afteraggregation, inhibiting 1 hr after
ingestion, entire lifespan 10 daysingestion, entire lifespan 10 days
2)2) Newer generations: inhibiting ADP-Newer generations: inhibiting ADP-
induced PLT aggregation (entire lifespan)induced PLT aggregation (entire lifespan)
or PLT GPIIb/IIIa receptor (48 hrs)or PLT GPIIb/IIIa receptor (48 hrs)
3)3) NSAIDs: reversibly and competitivelyNSAIDs: reversibly and competitively
inhibit COX, duration is dose-dependentinhibit COX, duration is dose-dependent
and half-life of the NSAIDand half-life of the NSAID

10. Review of commonly usedReview of commonly used
anticoagulantsanticoagulants
 Oral anticoagulants (Warfarin)Oral anticoagulants (Warfarin)
 Interfering with the Vit. K-dependentInterfering with the Vit. K-dependent
coagulation protein, factorscoagulation protein, factors IIII (thrombin),(thrombin),
VIIVII,, IXIX, and, and XX
 Inhibiting Vit. K reductases, depletes Vit.Inhibiting Vit. K reductases, depletes Vit.
KHKH22, and limits carboxylation, and limits carboxylation
 PT and INR may not accurately measurePT and INR may not accurately measure
true antithrombotic activitytrue antithrombotic activity
 A decrease in factorsA decrease in factors IIII andand XX (longer half-(longer half-
life) is more important for thelife) is more important for the
antithrombotic efficacy of warfarinantithrombotic efficacy of warfarin

11. Review of commonly usedReview of commonly used
anticoagulantsanticoagulants
 HeparinHeparin
 Binding with antithrombinBinding with antithrombin IIIIII, which, which
accelerates inactivation of factorsaccelerates inactivation of factors IIII,, IXIX,, XX,,
XIXI andand XIIXII
 Mixture of polysaccharide chains, MWMixture of polysaccharide chains, MW
ranging from 5,000 to 30,000; the length ofranging from 5,000 to 30,000; the length of
the heparin chain determines which factorthe heparin chain determines which factor
will be inhibitedwill be inhibited
 Extensive binding to plasma proteinsExtensive binding to plasma proteins
complicated the pharmacokinetics of heparincomplicated the pharmacokinetics of heparin

12. Review of commonly usedReview of commonly used
anticoagulantsanticoagulants
 LMWH has relatively greater anti-LMWH has relatively greater anti-XaXa
activity, more predictableactivity, more predictable
bioavailability and longer half-lifebioavailability and longer half-life
 PTT doesn’t accurately reflect thePTT doesn’t accurately reflect the
degree of anticoagulation, factor Xdegree of anticoagulation, factor X
levels don’t correlate with potentiallevels don’t correlate with potential
for bleedingfor bleeding

15. Anticoagulant Properties of HeparinAnticoagulant Properties of Heparin
1.1. Inhibits the thrombin-mediatedInhibits the thrombin-mediated
conversion of fibrinogen to fibrinconversion of fibrinogen to fibrin
2.2. Inhibits the aggregation of plateletsInhibits the aggregation of platelets
by thrombinby thrombin
3.3. Inhibits activation of fibrinInhibits activation of fibrin
stabilizing enzymestabilizing enzyme
4.4. Inhibits activated factors XII, XI,Inhibits activated factors XII, XI,
IX, X and IIIX, X and II

16. Monitoring of AnticoagulantMonitoring of Anticoagulant
TherapyTherapy
HeparinHeparin
s.q. – no monitoring requireds.q. – no monitoring required
(q12H)(q12H)
i.v. - partial thromboplastin timei.v. - partial thromboplastin time
(P.T.T.)(P.T.T.)
*daily or more frequent if PTT*daily or more frequent if PTT
variesvaries
mechanismmechanism – measures intrinsic pathway– measures intrinsic pathway
therapeutic goaltherapeutic goal – 2-2.5 times normal– 2-2.5 times normal

17. Subcutaneous HeparinSubcutaneous Heparin
 During administration of subcutaneousDuring administration of subcutaneous
heparin, there is no contraindication toheparin, there is no contraindication to
neuroaxial techniquesneuroaxial techniques
 For patients receiving mini dose heparinFor patients receiving mini dose heparin
for ≥ 4 days, reassess platelet count priorfor ≥ 4 days, reassess platelet count prior
to neuraxial block or removal of catheterto neuraxial block or removal of catheter
 For patients with q8h heparin, PTT andFor patients with q8h heparin, PTT and
platelets requiredplatelets required

18. Intravenous HeparinIntravenous Heparin
 Indwelling neuraxial catheters should beIndwelling neuraxial catheters should be
removed 4 hours after the last heparinremoved 4 hours after the last heparin
dose and reevaluation of the patient'sdose and reevaluation of the patient's
coagulation status has occurredcoagulation status has occurred
 CHECK PTT!!CHECK PTT!!
 Re-heparinization should occur 1 h afterRe-heparinization should occur 1 h after
catheter removal.catheter removal.

22. Low-Molecular Weight Heparin (LMWH)Low-Molecular Weight Heparin (LMWH)
 Monitoring of anti-Xa level is notMonitoring of anti-Xa level is not
recommended as it is not predictive of therecommended as it is not predictive of the
risk of bleeding.risk of bleeding.
 Antiplatelet or oral anticoagulant medicationsAntiplatelet or oral anticoagulant medications
administered in combination with LMWH mayadministered in combination with LMWH may
increase the risk of spinal hematoma.increase the risk of spinal hematoma.
 Traumatic needle or catheter placement mayTraumatic needle or catheter placement may
signify an increased risk of spinal hematomasignify an increased risk of spinal hematoma
and initiation of LMWH therapy in this settingand initiation of LMWH therapy in this setting
should be delayed for 24 hours.should be delayed for 24 hours.

23. Low-Molecular Weight Heparin (LMWH)Low-Molecular Weight Heparin (LMWH)
Twice daily dosingTwice daily dosing
 The first dose of LMWH should be started noThe first dose of LMWH should be started no
earlier than 24 hours postoperatively andearlier than 24 hours postoperatively and
surgical hemostasis has been achieved.surgical hemostasis has been achieved.
 Indwelling catheters should be removed prior toIndwelling catheters should be removed prior to
initiation of LMWH thromboprophylaxis.initiation of LMWH thromboprophylaxis.
 If a continuous technique is selected, theIf a continuous technique is selected, the
epidural catheter may be left indwellingepidural catheter may be left indwelling
overnight and removed the following day, withovernight and removed the following day, with
initiation of LMWH occurring at least two hoursinitiation of LMWH occurring at least two hours
after catheter removal.after catheter removal.

32. WarfarinWarfarin
 In patient’s receiving chronicIn patient’s receiving chronic
anticoagulation, warfarin should beanticoagulation, warfarin should be
discontinued at least 4-5 days beforediscontinued at least 4-5 days before
procedure.procedure.
 The PT/INR should be evaluated prior toThe PT/INR should be evaluated prior to
any neuroaxial technique.any neuroaxial technique.
 In patients with an epidural receiving lowIn patients with an epidural receiving low
dose warfarin therapy, the PT/INR shoulddose warfarin therapy, the PT/INR should
be monitored on a daily basis, andbe monitored on a daily basis, and
checked before catheter removal.checked before catheter removal.

33. WarfarinWarfarin
 Indwelling catheters can be removed whenIndwelling catheters can be removed when
the INR is less 1.4the INR is less 1.4
 In patient’s with an INR >3, the warfarinIn patient’s with an INR >3, the warfarin
dose should be held or decreased.dose should be held or decreased.
• No removal of neuraxial catheters in patientsNo removal of neuraxial catheters in patients
with therapeutic levels of anticoagulation.with therapeutic levels of anticoagulation.
 Neurologic testing should be performedNeurologic testing should be performed
routinely during epidural analgesia androutinely during epidural analgesia and
should be continued after cathetershould be continued after catheter
removal for at least 24 hours.removal for at least 24 hours.

34. Antiplatelet MedicationsAntiplatelet Medications
 NSAIDs,NSAIDs,
 Thienopyridine derivativesThienopyridine derivatives
• Ticlopidine and ClopidogrelTiclopidine and Clopidogrel
 Platelet GP IIb/IIIa antagonistsPlatelet GP IIb/IIIa antagonists
• Abciximab, Eptifibatide and TirofibanAbciximab, Eptifibatide and Tirofiban

36. Antiplatelet MedicationsAntiplatelet Medications
 NSAIDs do not represent added significantNSAIDs do not represent added significant
risk for the development of spinalrisk for the development of spinal
hematoma in patients having epidural orhematoma in patients having epidural or
spinal anesthesia.spinal anesthesia.
 The actual risk of spinal hematoma withThe actual risk of spinal hematoma with
ticlopidine and clopidogrel and the GPticlopidine and clopidogrel and the GP
IIb/IIIa antagonists is unknownIIb/IIIa antagonists is unknown
• The suggested time interval betweenThe suggested time interval between
discontinuation of thienopyridine therapy anddiscontinuation of thienopyridine therapy and
neuraxial blockade is 14 days for ticlopidineneuraxial blockade is 14 days for ticlopidine
and 7 days for clopidogrel.and 7 days for clopidogrel.

37. Plavix/ClopidogrelPlavix/Clopidogrel
Ticlid/TiclopidineTiclid/Ticlopidine
 Plavix has fewer side effects thanPlavix has fewer side effects than
TiclidTiclid
 Inhibits platelets (via ADP binding)Inhibits platelets (via ADP binding)
 long t1/2long t1/2
 Plavix: wait 7d till CNBPlavix: wait 7d till CNB
 Ticlid: wait 14d(!) till CNBTiclid: wait 14d(!) till CNB

38. Plavix testPlavix test
Population Frequency of Cytochrome
P450 (CYP) 2C19 Metabolizer Types
Poor
(no or low
enzyme levels)
Intermediate
(reduced enzyme
levels)
Extensive
(normal enzyme
levels)
CYP2C19 3-21% 24-36% 43-73%

39. Arixtra/FondaparinuxArixtra/Fondaparinux
 Inhibits Xa via ATIIIInhibits Xa via ATIII
binding sitebinding site
 Inhibits plateletsInhibits platelets
 Long t1/2 (>20hrs)Long t1/2 (>20hrs)
 Avoid CNB!!!!!Avoid CNB!!!!!
 Actual risk unknownActual risk unknown
 Start 6-8 h afterStart 6-8 h after
surgerysurgery
 If given wait 36 h (2If given wait 36 h (2
T1/2s)T1/2s)

40. Direct Factor Xa inhibitorsDirect Factor Xa inhibitors
 DabigatranDabigatran
 RivaroxabanRivaroxaban
 ApixabanApixaban

41. Antithrombin medicationsAntithrombin medications
 ArgatrobanArgatroban
 LepirudinLepirudin
 DesirudinDesirudin
 BivalirudinBivalirudin
 All inhibit both free and clot-boundAll inhibit both free and clot-bound
thrombinthrombin
 No existing reversal agents available atNo existing reversal agents available at
this timethis time
 No neuraxial techniques advised!No neuraxial techniques advised!

42. Herbal medicationsHerbal medications
 No evidence re: direct relationship withNo evidence re: direct relationship with
neuraxial cathsneuraxial caths
 Caution with concomitant clot formingCaution with concomitant clot forming
inhibitorsinhibitors
 Gingko biloba associated withGingko biloba associated with
subdural/subarachnoid hemorrhagesubdural/subarachnoid hemorrhage
 Ginkgo, garlic, gingseng, cranberryGinkgo, garlic, gingseng, cranberry
decreases warfarin metab.decreases warfarin metab.
 St. John’s wort increases warfarin metab.St. John’s wort increases warfarin metab.

43. ““All areAll are
anticoagulatedanticoagulated
untiluntil
provenproven
otherwise”otherwise”