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Thin Blood
Department of Clinical Toxicology
and Pharmacology
Newcastle Mater Hospital
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
Background
• Precipitating incident :
– Brother suicided recently
– Planned overdose for 2 days
• Psychiatric background :
– No previous deliberate self harm
– Amphetamine dependence
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
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
Initial Management
• INR 2.0
• Appropriate Management ?
– FFP
– Vitamin K
Initial Management
• Haematology consult
– 4 units FFP
– 10 mg vitamin K IVI
• Neurological observation
• 2-3 daily INR
INR Results
Date/Time
9/12
2030
10/12
0000
10/12
0400
10/12
1300
INR
2.0
1.9
1.4
1.2
Vitamin K 10 mg IVI
4 Units FFP
INR Results
Date/Time 10/12
INR
APTT
2015
11/12
0745
11/12
1540
12/12
0805
1.3
1.9
2.2
2.6
63
63
60
Heparin 5,000 U
Infusion 1000 U/hr
INR Results
Date/Time 12/12
0805
13/12
0740
1412
0805
15/12
1035
INR
2.6
2.2
2.1
2.4
APTT
60
45
46
Heparin
ceased
Warfarin recommenced,
normal dose 5 mg/d
Time course of INR
3
INR
2
Heparin
Ceased
1
Warfarin
Restarted
FFP
Heparin
Vit K
0
0
1
2
3
Time (days)
4
5
6
Optimal Management - Issues
•
•
•
•
Perfect dose of vitamin K !
Normalised INR with FFP; then therapeutic
Required heparinisation for 2 days
No active bleeding
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
Background
• Precipitating incident :
– Argument with wife, asked to leave
• Psychiatric background :
– Narcotic dependence; 7 year history
– No previous deliberate self harm
Medical History
• Thromboembolic disease
– Pulmonary embolus (definite diagnosis)
– Recurrent DVTs, mainly on symptoms
– Not thrombophilic ; testing negative
• Chronic back pain
• Gastro-oesophageal reflux
• Hypertension
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
Initial Management
• Response to naloxone; infusion commenced
(2mg/50 mL) at 15 mL/hr
• Lacerations sutured
• Bloods sent including Group + Save
Initial Management 2
• INR 3.7
• Appropriate management ?
– FFP
– Vitamin K
Initial Management 2
• Haematology consult
– 6 units FFP
– 10 mg vitamin K IVI
• Neurological observation
• 2-3 daily INR
Progress - Day 2
• Clinical : no bleeding complications
• Naloxone infusion continued
• INR Results
Date/Time 23/02
INR
1930
24/02
0325
24/02
1105
24/02
2030
3.7
1.3
1.3
1.2
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
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
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
Time course of INR
4
INR
3
2
1
Vitamin K
Warfarin
0
0
2
4
6
8
Time (days)
10
12
14
Comments / Problems
• What dose of vitamin K is
appropriate ?
• Patient still has a non-therapeutic
INR two weeks after vitamin K
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
Initial Assessment
•
•
•
•
Drowsy but easily roused
Normal observations
No active bleeding or bruising
INR 1.9
Plan
• No haematology consult
• Q3H INR
• Research:
– Intermittent factor levels
– Serial warfarin determination
• Vitamin K 1 mg if INR > 5.0
30
Warfarin
INR
INR or Warfarin Concentration (mg/L)
Vitamin K
25
20
100%
15
Factor II
Factor VII
Factor IX
10
5
0
0
1
2
3
4
Time (days)
5
6
7
8
Excessive Anticoagulation
• Situation :
– Therapeutic dose : drug interaction, other
– Acute Overdose
• Thromboembolic Risk
– None
– Low-medium : previous DVT/PE/thrombophilia
– High : mechanical heart valve
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
Overdose or Therapeutic
Low-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
Overdose or Therapeutic
High 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
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
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 (3.689.67, p<0.0001), compared to INR < 4.5
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
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
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
Therapeutic Options
• Fresh frozen plasma
• Vitamin K
– oral
– intravenous
• Heparinisation
– intravenous unfractionated
– low molecular weight
Fresh Frozen Plasma
• Major bleeding
• Minor bleeding; risk groups eg. age
• Guidelines Br J Haematol 1998
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
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
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
Vitamin K