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Clinical Toxicology Case Presentation. Dr.K.Go UCH 16/2/2005. A Bleeding Case. F/73 Known CRHD with valvular replacement/AF On warfarin 4mg/4.5mg alt day History of GIB a month ago OGD – gastritis / Colonoscopy - NAD c/o PRB once P/E

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a bleeding case
A Bleeding Case
  • F/73
  • Known CRHD with valvular replacement/AF
  • On warfarin 4mg/4.5mg alt day
  • History of GIB a month ago
  • OGD – gastritis / Colonoscopy - NAD
  • c/o PRB once
  • P/E
    • Proctoscopy – piles, no active bleeding, no melena
    • Bruise over L scapula
a bleeding case con t
BP 123/68, Pulse 79

Hb 9.8 g/dl, similar to CBP a month ago

INR 5.9

Haemodynamically stable during AED stay and no evidence of further PRB

What is your management ?

A Bleeding Case – Con’t
the consideration
Mx in the AED

Withhold Warfarin

Consider Vit K 1-2.5mg orally if bleeding .

If con’t bleeding , consider FFP & Vit K 10mg SC

Admit Medical

The consideration
  • Indications for anticoagulants
  • Presence of severe/life threatening bleeding
  • INR
  • +/- causes of over-anticoagulation.
slide5

Progress

All along – no more PRBHb - stable

warfarin
Warfarin
  • An anticoagulant .
  • A racemic mixture of S and R enantiomers.
  • S racemer is 1.5-2X more potent than R racemer
    • But faster clearance.
inactive factor 2 7 9 10 protein c s
Inactive Factor 2,7,9,10Protein C,S

Vitamin K Quinol

Vitamin K 2,3 epoxide

Action of warfarin

Metabolism by 2C9, 1A2, 3A4, 2C19High Protein Bound

Active Factor 2,7,9,10Protein C,S

Vitamin K Quinone

Vitamin K supply

Warfarin inhibition

pharmacokinetics of warfarin
Pharmacokinetics of warfarin.
  • Absorption: completely absorbed orally
  • Distribution:
    • Vd 0.14L/kg
    • 99% protein bound.
  • Metabolism:
    • P450 to inactive hydroxylated metabolites
    • Reductase to warfarin alcohols (minimal anticoagulant activity).
  • Excretion :
    • Most metabolite excreted into urine .
    • Some into the bile.
    • Little excreted unchanged in the urine.
  • Effective t½ =20-60 hrs (mean 40 hrs)
  • Onset of action :delayed , At least 15 hrs.
slide10
% of clotting factor loss

INR

25%

Shortest T1/2 –Factor VII ~ 5 hrs

About 3 T1/2 to see effect of ↓INR

100%

75%

50%

1

5

10

15

major causes
Major causes
  • Overdose
  • Drug interaction:
    • Inhibition of warfarin metabolism (P450) in the liver.
    • Displacement of warfarin from protein binding.
  • Vit K deficiency :
    • Malnutrition
    • Malabsorption (recent diarrhea)
    • Change in gut flora (e.g antibiotic uses)
other causes
Other causes
  • Hypoalbuminaemia
    • Increase free fraction of drug.
  • Concomitant disease
    • Malignancy ,CHF, etc.
    • Hepatic dysfunction
  • Aging
synergistic drug combination
Synergistic drug combination
  • NSAID + Warfarin
  • 13x increase in hemorrhagic ulcer disease.

Shorr R I. Arch Intern.Med, 1993 ;153 (14)

over warfarinisation
Over-warfarinisation
  • Known Cx of warfarin therapy
    • Rate of major bleeding in elderly (age >80) discharged with OAT = 2.4 per 1000 patients month.
    • Risk factors :
      • Insufficent patient education (OR= 8.83)
      • Polypharmacy (OR=6.14)
      • Use of INR above therapeutic range (OR=1.08)

Kagansky N Arch. Intern.Med ,2004 Oct;164(18)

slide17
In a surveillance of outpatient adverse drug events treated in hospital ED
  • Warfarin and insulin
    • Most common drugs encountered
    • (16% and 33% respectively) in patients of age >50.

Budnitz DS. Annals of Emerg Med ,Feb 2005 ;45

management of warfarin overdose
Management of warfarin overdose
  • Stop warfarin
  • If life threatening hemorrhage
    • FFP
      • 10ml/kg IVI
    • Vit K
      • 10mg SC/slow IV
    • Switch to heparin if necessary
slide19
For non-life threatening hemorrhage
    • No need for long term anticoagulation
      • Vit K1
    • Need for chronic anticoagulation:
      • Stop warfarin and observe.
      • Try avoid giving Vit K ( complete reversal will occur, difficult to reanticoagulate in future).
      • If vit K is to be given, give a low dose e.g 2.5mg orally.
      • If significant bleeding, give FFP.
slide20
Management of supra-therapeutic INR6th ACCP Consensus Conference on Antithrombotic Therapy; CHEST 2001:119:22S-38S
summary learning points
Summary/Learning Points
  • Warfarin PK & PD
  • Supra-therapeutic INR is common
  • Causes of over-warfarinisation
  • Management options for over-warfarinisation
  • Aware the drug interactions of warfarin and try to avoid it
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