Clinical Toxicology Case Presentation

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Clinical Toxicology Case Presentation

• Dr.K.Go UCH 16/2/2005

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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

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A Bleeding Case Cont

• 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 ?

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The consideration

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

• Mx in the AED
• Withhold Warfarin
• Consider Vit K 1-2.5mg orally if bleeding .
• If cont bleeding , consider FFP Vit K 10mg SC
• Admit Medical

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Progress
All along no more PRBHb - stable
30/12 31/12 1/1 2/1 3/1 4/1 5/1 6/1 7/1
FFP 4u
Vit K1 10mg IV 10mg IV
Heparin on on on on on on off
Warfarin 3mg 3mg 3mg 3mg 3mg
APTT 35.9 43.6 61.2 51.1 40.2 55.5 69.3 65.8
INR 5.9 1.3 1.2 1.3 1.2 1.2 1.4 1.6 1.9
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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.

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How warfarin works ?
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Inactive Factor 2,7,9,10Protein C,S
Action of warfarin
Metabolism by 2C9, 1A2, 3A4, 2C19High Protein
Bound
Active Factor 2,7,9,10Protein C,S

• Vitamin K Quinol

• Vitamin K 2,3 epoxide

Vitamin K Quinone
Vitamin K supply
Warfarin inhibition
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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.

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Shortest T1/2 Factor VII 5 hrs About 3 T1/2 to
see effect of ?INR

• of clotting factor loss

100
75
50

• INR

1
5
10
15
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Why our patient got supra-therapeutic INR ?
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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)

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Other causes

• Hypoalbuminaemia
• Increase free fraction of drug.
• Concomitant disease
• Malignancy ,CHF, etc.
• Hepatic dysfunction
• Aging

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(No Transcript)
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Synergistic drug combination

• NSAID Warfarin
• 13x increase in hemorrhagic ulcer disease.
• Shorr R I. Arch Intern.Med, 1993 153 (14)

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Over-warfarinisation

• Known Cx of warfarin therapy
• Rate of major bleeding in elderly (age gt80)
  discharged with OAT 2.4 per 1000 patients
  month.
• Risk factors
• Insufficent patient education (OR 8.83)
• Polypharmacy (OR6.14)
• Use of INR above therapeutic range (OR1.08)
• Kagansky N Arch. Intern.Med ,2004 Oct164(18)

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• 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
  gt50.
• Budnitz DS. Annals of Emerg Med ,Feb 2005 45

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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

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• 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.

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Management of supra-therapeutic INR6th ACCP
Consensus Conference on Antithrombotic Therapy
CHEST 200111922S-38S
INR Bleeding Recommendations
lt5 No Omit 1 dose Resume at lower dose
5-9 No Omit 1 to 2 dose, monitor INR more frequently Consider Vit K1 1-2.5mg PO Resume a lower dose.
9-20 No Withhold, frequent INR monitoring Consider Vit K1 3-5mg PO Resume a lower dose .
gt20 Severe Withhold Vit K1 10mg slow IV /- FFP
Any Abnormal INR Life Threatening Withhold. Give FFP Vitamin K1 10mg slow IV
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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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Thank you