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 9/122030

10/120000

10/120400

10/121300

INR 2.0 1.9 1.4 1.2

Vitamin K 10 mg IVI

4 Units FFP

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

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

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

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 23/021930

24/020325

24/021105

24/022030

INR 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

0

1

2

3

4

0 2 4 6 8 10 12 14

Time (days)

INR

WarfarinVitamin K

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

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

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 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

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

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 (3.68-9.67, 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