Thin Blood

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Thin Blood

• Department of Clinical Toxicology and
  Pharmacology
• Newcastle Mater Hospital

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Case 1

• 37 year old male
• Presented to JHH Emergency Department
• Drug overdose
• 120 mg warfarin
• Activated charcoal
• Bloods sent
• Transfer to MMH after d/w Toxicology

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Background

• Precipitating incident
• Brother suicided recently
• Planned overdose for 2 days
• Psychiatric background
• No previous deliberate self harm
• Amphetamine dependence

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Medical History

• Endocarditis 2º to IVDU
• Valve replacement x 2
• mitral and aortic valve replacements
• St. Judes bileaflet
• Complicated by AMI and CVA
• Lifelong anticoagulation
• Nil attendance with cardiology follow up

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On arrival

• HR 80 BP 144/88 Temp 36.2
• Alert and Cooperative
• No bruising or evidence of bleeding
• Dysarthric with mild cognitive impairment
• HSD, metallic sounds
• No signs of cardiac failure

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Initial Management

• INR 2.0
• Appropriate Management ?
• FFP
• Vitamin K

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Initial Management

• Haematology consult
• 4 units FFP
• 10 mg vitamin K IVI
• Neurological observation
• 2-3 daily INR

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INR Results
Vitamin K 10 mg IVI 4 Units FFP
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INR Results
Heparin 5,000 U Infusion 1000 U/hr
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INR Results
Heparin ceased
Warfarin recommenced, normal dose 5 mg/d
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Time course of INR
Warfarin Restarted
FFP Vit K
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Optimal Management - Issues

• Perfect dose of vitamin K !
• Normalised INR with FFP then therapeutic
• Required heparinisation for 2 days
• No active bleeding

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Case 2

• 43 year old male
• Drug overdose 1 hour previously
• 25 x 5 mg warfarin
• 40 x 5 mg oxycodone
• Multiple lacerations to left forearm
• Vomited in transit to MMH

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Background

• Precipitating incident
• Argument with wife, asked to leave
• Psychiatric background
• Narcotic dependence 7 year history
• No previous deliberate self harm

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Medical History

• Thromboembolic disease
• Pulmonary embolus (definite diagnosis)
• Recurrent DVTs, mainly on symptoms
• Not thrombophilic testing negative
• Chronic back pain
• Gastro-oesophageal reflux
• Hypertension

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On arrival

• HR 66 BP 155/91 RR 14
• Decreased LOC, just rousable
• Small and sluggish pupils
• Multiple lacerations on left forearm
• Nil else on examination

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Initial Management

• Response to naloxone infusion commenced (2mg/50
  mL) at 15 mL/hr
• Lacerations sutured
• Bloods sent including Group Save

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Initial Management 2

• INR 3.7
• Appropriate management ?
• FFP
• Vitamin K

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Initial Management 2

• Haematology consult
• 6 units FFP
• 10 mg vitamin K IVI
• Neurological observation
• 2-3 daily INR

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Progress - Day 2

• Clinical no bleeding complications
• Naloxone infusion continued
• INR Results

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Progress - Day 3

• Haematology review
• commenced on daily enoxaparine 1 mg/kg
• TED stockings
• Daily INR
• Naloxone infusion ceased
• Psychiatric assessment
• Drug and Alcohol review

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Progress - Day 2 - 6

• Day 4 Warfarin recommenced 14 mg daily (normal
  dose)
• Day 5 Enoxaparin increased to twice daily

Warfarin recommenced
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Progress - Day 5 - 12

• Transferred to inpatient psychiatric unit
• Normal warfarin dose
• Continue enoxaparin until therapeutic INR

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Time course of INR
Vitamin K
Warfarin
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Comments / Problems

• What dose of vitamin K is appropriate ?
• Patient still has a non-therapeutic INR two weeks
  after vitamin K

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Case 3

• 44 year old male
• Drug overdose 3 hours previously
• 150 mg warfarin
• 2 g chlorpromazine
• Aortic valve replacement 8 years previously
• Asthma, OCD, pathological gambling

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Initial Assessment

• Drowsy but easily roused
• Normal observations
• No active bleeding or bruising
• INR 1.9

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Plan

• No haematology consult
• Q3H INR
• Research
• Intermittent factor levels
• Serial warfarin determination
• Vitamin K 1 mg if INR gt 5.0

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Excessive Anticoagulation

• Situation
• Therapeutic dose drug interaction, other
• Acute Overdose
• Thromboembolic Risk
• None
• Low-medium previous DVT/PE/thrombophilia
• High mechanical heart valve

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Acute Overdose - not own

• No thromboembolic risk
• Treatment
• vitamin K 5 - 10 mg IVI or oral
• FFP if actively bleeding
• Monitor INR
• Straight-forward
• Complicated in cases of long-acting agents

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Overdose or TherapeuticLow-Medium Risk of
Thromboembolism

• Requirements
• decrease INR to prevent bleeding complications
• can tolerate normalisation of INR for a period
• need to be restarted and reach therapeutic INR
• Issues
• Use of FFP
• Use of vitamin K and dose
• requirement for heparin and hospital stay

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Overdose or TherapeuticHigh Risk of
Thromboembolism

• Requirements
• decrease INR to prevent bleeding complications
• risk of thromboembolic complications with
  normalisation of INR for any period of time
• Issues
• Use of FFP
• Use of vitamin K and dose
• requirement for heparin and hospital stay

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Increased INR Risk of bleeding

• INR gt 4.5, 5.0 and 6.0
• Exponential increase in bleeding
• Br J. Haem 1998 (Guidelines)
• Cannegieter NEJM 1995
• Pal

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Increased INR and Risk of bleeding

• Palareti et al.
• Prospective cohort study
• 2745 patients on anticoagulants
• F/U for a mean of 267 days
• temporally related INRs
• Multivariate analysis patients with an INR gt 4.5
  had an increased risk of bleeding, RR 5.96
  (3.68-9.67, plt0.0001), compared to INR lt 4.5

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Increased INR and Risk of bleeding

• INR gt 6.0 Hylek Arch Intern Med 2000
• Abnormal bleeding 8.8
• Major bleeding 4.4 cf. 0 INR lt 6.0 (Plt0.001)
• INR gt 7.0 Panneerselvam Br J Haem 1998
• Total bleeding 12/31 vs. 13/100 O.R. 5.4
• 5 major bleeds vs. none

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Increased INR and Risk of bleeding

• INR gt 8.0 Baglin Blood Rev 1998
• 12.9 major bleeding Murphy Clin Lab Haematol
  1998
• Severe anticoagulation Hung Br J Haematol 2000
• INR gt 9.5
• APTT ratio gt 2.0
• Required additional vitamin K doses

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Low INR and Risk of Embolism for High risk
patients

• Patients with mechanical heart valves
• Risk of embolism rises with INR lt 2.5
• Sub-groups with higher risk
• gt 70 years age
• Both gt mitral gt aortic
• Caged ball/disk gt tilting disk gt bileaflet

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Therapeutic Options

• Fresh frozen plasma
• Vitamin K
• oral
• intravenous
• Heparinisation
• intravenous unfractionated
• low molecular weight

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Fresh Frozen Plasma

• Major bleeding
• Minor bleeding risk groups eg. age
• Guidelines Br J Haematol 1998

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Vitamin K ? Appropriate dose

• Oral vitamin K
• RCT Vit K, 1 mg vs. placebo (INR 4.5 - 10)
• more rapid decrease in INR 56 vs. 20 with INR
  between 1.8 - 3.2 after 24 hrs (plt 0.001)
• fewer patients had bleeding episodes during
  follow up 4 vs. 17 p 0.05 ( 3 months)
• Crowther Lancet 2000

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Vitamin K ? Appropriate dose

• Intravenous vitamin K RCT INR gt 6.0
• asymptomatic 0.5 mg vs. 1 mg
• symptomatic 1 mg vs. 2 mg
• INR fallen to 5 - 5.5 in all 3 groups by 6 hrs
• Optimal INR (2-4) in 67 receiving 0.5 mg, but
  only in 33 receiving 1 or 2 mg
• Over-correction in 16 (0.5 mg) 50 (1-2 mg)
• no adverse effects
• Hung. Br J Haematol 2000

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Vitamin K - Suggested dosing

• INR gt 5.0 asymptomatic, mild bleeding
• 0.5 mg IV
• repeat INR 6 - 12 hours
• titrate as required
• INR gt 9.5 APTT ratio gt 2.0
• 1 mg IV
• repeat 6 hours
• more likely to require repeat doses

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Vitamin K