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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
Date/Time 9/122030
10/120000
10/120400
10/121300
INR 2.0 1.9 1.4 1.2
Vitamin K 10 mg IVI
4 Units FFP
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INR Results
Date/Time 10/122015
11/120745
11/121540
12/120805
INR 1.3 1.9 2.2 2.6
APTT 63 63 60
Heparin 5,000 U
Infusion 1000 U/hr
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INR Results
Date/Time 12/120805
13/120740
14120805
15/121035
INR 2.6 2.2 2.1 2.4
APTT 60 45 46
Heparin ceased
Warfarin recommenced, normal dose 5 mg/d
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Time course of INR
0
1
2
3
0 1 2 3 4 5 6
Time (days)
INR
FFP
Vit K Heparin
Heparin Ceased
Warfarin Restarted
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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
Date/Time 23/021930
24/020325
24/021105
24/022030
INR 3.7 1.3 1.3 1.2
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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
Date/Time D2 D3 D5 D6
INR 1.3 1.1 1.0 1.1
Warfarin recommenced
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Progress - Day 5 - 12
• Transferred to inpatient psychiatric unit
• Normal warfarin dose
• Continue enoxaparin until therapeutic INR
Date/Time D8 D10 D11 D12
INR 1.2 1.5 1.5 1.6
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Time course of INR
0
1
2
3
4
0 2 4 6 8 10 12 14
Time (days)
INR
WarfarinVitamin K
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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 > 5.0
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0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8
Time (days)
INR
or
Wa
rfa
rin
Co
nc
en
tra
tio
n (
mg
/L)
Warfarin
INR
Vitamin K
100%
Factor II
Factor VII
Factor IX
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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 > 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 > 4.5 had an increased risk of bleeding, RR 5.96 (3.68-9.67, p<0.0001), compared to INR < 4.5
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Increased INR and Risk of bleeding
• INR > 6.0 : Hylek Arch Intern Med 2000
– Abnormal bleeding 8.8% – Major bleeding 4.4% cf. 0% INR < 6.0 (P<0.001)
• INR > 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 > 8.0 Baglin Blood Rev 1998;
– 12.9% major bleeding Murphy Clin Lab Haematol 1998
• Severe anticoagulation : Hung Br J Haematol 2000
– INR > 9.5– APTT ratio > 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 < 2.5
• Sub-groups with higher risk :– > 70 years age– Both > mitral > aortic– Caged ball/disk > tilting disk > 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 (p< 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 > 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 > 5.0 ; asymptomatic, mild bleeding– 0.5 mg IV– repeat INR 6 - 12 hours– titrate as required
• INR > 9.5; APTT ratio > 2.0– 1 mg IV – repeat 6 hours– more likely to require repeat doses
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Vitamin K