HOW TO HOW TO

ANTICOAGULATEANTICOAGULATE

Dr Andrew MumfordDepartment of HaematologyBristol Royal Infirmary

• 3 established drugs……

All used to treat/prevent arterial or venous thrombosis ‘Anti-thrombotics’

Unfractionated heparinLow molecular weight heparinWarfarin

LECTURE PLAN

For each agent…

i. Description and mode of action

ii. Pharmacology

iii. Presentation

iv. Indications

v. Interactions/adverse effects

vi. Laboratory monitoring

vii. Administration and dose

viii. Management of over-anticoagulation

Unfractionated and low molecular weight

HEPARIN

HEPARIN manufacture

Description & action- HEPARIN

• Parenteral anticoagulant

• Naturally occurring glycosaminoglycan

• Mixture of different length molecules

(UFH av. 50 LMWH av. 15-20)

How it works• Increases activity of plasma Antithrombin

• Inhibits active clotting factors esp. factors IIa and Xa

(LMWH inhibits Xa better)

PHARMACOLOGY OF HEPARINS

UF HEPARIN LMW HEPARIN

RouteRoute IV SC

BioavailabilitBioavailabilityy

Variable, poor

Predictable, good

MetabolismMetabolism Complex, mostly renal

Predictable renal

TT1/2 1/2 (hours)(hours) 1-2 4-6

Presentation- UF Heparin

• Vials containing..

25,000 IU/ml (sc)5,000 IU/ml1,000 IU/ml (flush)10 IU/ml (flush)

Typical dose5000 IU loading then 30,000 IU by iv

infusion / 24 hrs

Presentation- LMW heparin

• 4 generic preparations

eg Tinzaparin (Innohep)

Enoxaparin (Clexane)

• Pre-filled syringes

Clexane 100 mg/ml; 20, 40, 60, 80, 100, 120, 150 mg syringes

Typical doses

40mg sc once daily ‘prophylactic’

100 mg sc once daily ‘treatment’

HEPARINS- Indications

Anti-thrombotic activity with rapid onset /offset

• Initial treatment of DVT or PE LMWH

• Acute coronary syndromes LMWH

• Cardiothoracic surgery UFH

• Other extra-corporeal circuits UFH

• Warfarin unsuitable esp pregnancy LMWH

• Prophylaxis against venous thrombosis LMWH

HEPARINS- Adverse effects1. Bleeding Heparins are contraindicated in

individuals at high risk of bleeding Caution and dose reduction in renal impairment

2. Heparin-induced thrombocytopenia Associated with

thrombosis

3. Skin reactions Local bleeding and hypersensitivity

4. Hyperkalaemia Inhibits aldosterone secretion

5. Osteoporosis

UF heparin>>> LMW heparin

Laboratory monitoring- UF heparin

• Inhibition of thrombin (IIa) causes aPTT and PT

• aPTT is best measure of heparin in ‘therapeutic’ anti-thrombotic activity range

• Expressed as aPTT ratio

• aPTT ratio= Patient’s aPTT÷Normal aPTT

• Inhibition of factor Xa (common pathway) will also cause aPTT and PT

• But……at therapeutic anti-thrombotic levels there is insufficient anti-coagulant effect to cause long clotting times

• Activity can be measured with anti-Xa assay

Laboratory monitoring- LMW heparin

Administration– UF heparin1. iv bolus 5,000 IU

2. iv infusion 15,000 IU over 12 hours

3. Check aPTT ratio – 4 hours after start and after every dose change

– Daily if infusion rate stable

– Check platelet count 4 days after start

Therapeutic target range• Treatment of venous thrombosis 1.5- 2.5• Arterial thrombosis/Extracorp. circuits Usually

Administration– LMW heparin• Empiric ‘prophylaxis’ and weight

adjusted ‘treatment’ regimes

eg Enoxaparin (Clexane)• 40 mg sc once daily – Venous thrombosis

prophylaxis

• 1.5 mg/Kg sc once daily – Venous thrombosis treatment (1 mg/Kg bd in pregnancy)

• Monitoring with anti-Xa assay only if long-term treatment or renal failure

Over-anticoagulation with heparinsMILD OR MODERATE BLEEDING

• STOP UF heparin or LMW heparin

LIFE THREATENING BLEEDING

• STOP UF heparin or LMW heparin

• Protamine iv

1mg/100 IU heparin given in last hr (max 40mg)

Expect repeat treatment to be needed

WARFARIN

Warfrain developed as a rodenticide

Description & action-WARFARIN

• Oral anticoagulant

• A coumarin derivative

How it works

• Inhibits recycling of vitamin K

• Vitamin K is needed for synthesis of clotting factors II, VII, IX and X

Pharmacology- WARFARIN

• Orally active

• Near 100% bio-availability

• Variation in pharmacokinetics and

pharmacodynamics

• Half life ~36 hours

• Metabolised by liver

WARFARIN- PresentationWARFARIN- Presentation

• 1mg, 3mg, 5mg tablets

• Colour coded packaging

Typical dose

1 -10 mg po once daily

WARFARIN- Indications

Long-term anti-thrombotic treatment

• Treatment of DVT or PE

• Prevention of arterial thrombosis in……– Atrial fibrillation– Mechanical or bio-prosthetic valves– Peripheral vascular disease– Cerebrovascular disease– Ischaemic heart disease

WARFARIN- Important interactions• Assume all co-prescriptions will alter

warfarin dose responseCause over-anticoagulation

AmiodaronePPI’sStatinsFluconazoleErythromycin

Cause under-anticoagulation

BarbituratesCarbemazepineRifampicinCholestyramine

•Anti-platelet agents increase bleeding risk

WARFARIN-Adverse effects

1. Bleeding Usually associated with over

anticoagulation

2. Skin necrosis/thrombosis Associated with protein C or S deficiencies

esp. if rapid loading or withdrawal

3. Fetal warfarin syndrome Bleeding and fetal abnormalities

Cautions Previous coagulopathy incl. liver disease

Renal failure

Laboratory monitoring-WARFARIN• Depletion of factors II, VII, IX and X affects

extrinsic, intrinsic and common pathways

• PT and aPTT will both be prolonged

• PT is used to monitor warfarin dose response but expressed as INR

• INR= (Patient’s PT ÷ Normal PT)c

(‘C’ is a correction factor ~1)

Administration-WARFARIN

1. Loading dose 5-10 mg PO day 1

2. Measure INR next day

3. Subsequent daily doses determined from ‘dosing schedule’

4. Monitor INR daily until stable

5. For treatment of venous or arterial thrombosis DO NOT discontinue heparin until >48 hrs after reaching therapeutic INR

Example warfarin dosing schedule

Day INR Dose (mg)

1 <1.4 10

2 <1.8 101.8 1

>1.8 0.5

3 <2.0 10

2.0-2.1 5

2.2-2.3 4.5

Continued ……………….

WARFARIN- How much and how long?Determined by indication and circumstances

Target INR Duration(months)

Below knee DVT 2 -3 3

Above knee DVT 2 -3 6

PE 2 -3 6-12

Atrial fibrillation 2 -3 longterm

Mechanical heart valve 3 -4 longterm

DVT/PE during anticoagulation

3 -4 longterm

WARFARIN- Long-term supervision

• Warfarin has narrow therapeutic index with life-threatening toxicity

• Responsibility of prescribing clinician to ensure safe and effective on-going anticoagulation

• Refer to specialist anticoagulation clinic

WARFARIN- Over-anticoagulation•Common scenario following

– Poor patient understanding

– Failure of monitoring/communication

– Drift in dose response or drug interaction

•Significant source of morbidity and mortality

WARFARIN- over-anticoagulation

1. Life threatening bleeding

• STOP warfarin

• 5mg vitamin K1 (slow IVI)

• Beriplex 50 iu/Kg or FFP 15 ml/Kg

2. Mild bleeding or asymptomatic INR>8

• STOP warfarin and restart when INR<5.0

• 1mg vitamin K1 (slow IVI)

WARFARIN- over-anticoagulation

3. INR 3-8 no bleeding

– Stop warfarin/omit 1or 2 days/dose reduction

4. Bleeding at therapeutic INR

– Investigate underlying cause

Warfarin in surgical patientsPrinciples…

• Therapeutic anticoagulation may cause serious surgical bleeding

• Risk is depends on INR and procedure

• Short term cessation of warfarin has very low risk of thrombosis

Warfarin in surgical patients

1. Routine INR check ~1 week before surgery

2. Omit warfarin for 3-4 days

3. Check INR evening before surgery

4. Consider 1 mg oral Vit K1 if INR still >2.5

5. Most procedure can proceed with INR<2.0

6. Restart warfarin 2-3 days after surgery

Warfarin in surgical patients

High thrombosis risk patients» Thrombotic event within last 4 weeks

» Severe heritable pro-thrombotic disorder

1. Admit at least 3 days before surgery

2. Stop warfarin and start UF heparin infusion

3. Stop UF heparin 3 hours before surgery

4. Restart UF heparin 12-24 hrs after surgery

5. Restart warfarin 2-3 days after surgery but continue

UF heparin for 48 hrs after achieving therapeutic INR

Above all………

Please discus

anticoagulation problems

with liaison haematology

team