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HOW TOHOW TO
ANTICOAGULATEANTICOAGULATE
Dr Andrew Mumford
Department of Haematology
Bristol Royal Infirmary
• 3 established drugs……
All used to treat/prevent arterial or venous
thrombosis ‘Anti-thrombotics’
Unfractionated heparin
...
For each agent…
i. Description and mode of action
ii. Pharmacology
iii. Presentation
iv. Indications
v. Interactions/adver...
Unfractionated
and low
molecular weight
HEPARIN
HEPARIN manufacture
Description & action- HEPARIN
• Parenteral anticoagulant
• Naturally occurring glycosaminoglycan
• Mixture of different le...
PHARMACOLOGY OF HEPARINS
UF HEPARIN LMW
HEPARIN
RouteRoute IV SC
BioavailabilityBioavailability Variable,
poor
Predictable...
Presentation- UF Heparin
• Vials containing..
25,000 IU/ml (sc)
5,000 IU/ml
1,000 IU/ml (flush)
10 IU/ml (flush)
Typical d...
Presentation- LMW heparin
• 4 generic preparations
eg Tinzaparin (Innohep)
Enoxaparin (Clexane)
• Pre-filled syringes
Clex...
HEPARINS- Indications
Anti-thrombotic activity with rapid onset /offset
• Initial treatment of DVT or PE LMWH
• Acute coro...
HEPARINS- Adverse effects
1. Bleeding Heparins are contraindicated in
individuals at high risk of bleeding
Caution and dos...
Laboratory monitoring- UF heparin
• Inhibition of thrombin (IIa) causes ↑aPTT
and ↑PT
• aPTT is best measure of heparin in...
• Inhibition of factor Xa (common pathway)
will also cause ↑aPTT and ↑PT
• But……at therapeutic anti-thrombotic levels
ther...
Administration– UF heparin
1. iv bolus 5,000 IU
2. iv infusion 15,000 IU over 12 hours
3. Check aPTT ratio
– 4 hours after...
Administration– LMW heparin
• Empiric ‘prophylaxis’ and weight adjusted
‘treatment’ regimes
eg Enoxaparin (Clexane)
• 40 m...
Over-anticoagulation with heparins
MILD OR MODERATE BLEEDING
• STOP UF heparin or LMW heparin
LIFE THREATENING BLEEDING
• ...
WARFARIN
Warfrain
developed as a
rodenticide
Description & action-WARFARIN
• Oral anticoagulant
• A coumarin derivative
How it works
• Inhibits recycling of vitamin K
...
Pharmacology- WARFARIN
• Orally active
• Near 100% bio-availability
• Variation in pharmacokinetics and
pharmacodynamics
•...
WARFARIN- PresentationWARFARIN- Presentation
• 1mg, 3mg, 5mg tablets
• Colour coded packaging
Typical dose
1 -10 mg po onc...
WARFARIN- Indications
Long-term anti-thrombotic treatment
• Treatment of DVT or PE
• Prevention of arterial thrombosis in…...
WARFARIN- Important interactions
• Assume all co-prescriptions will alter warfarin
dose response
Cause
over-anticoagulatio...
WARFARIN-Adverse effects
1. Bleeding Usually associated with over anticoagulation
2. Skin necrosis/thrombosis
Associated w...
Laboratory monitoring-WARFARIN
• Depletion of factors II, VII, IX and X affects
extrinsic, intrinsic and common pathways
•...
Administration-WARFARIN
1. Loading dose 5-10 mg PO day 1
2. Measure INR next day
3. Subsequent daily doses determined from...
Example warfarin dosing schedule
Day INR Dose (mg)
1 <1.4 10
2 <1.8 10
1.8 1
>1.8 0.5
3 <2.0 10
2.0-2.1 5
2.2-2.3 4.5
Cont...
WARFARIN- How much and how long?
Determined by indication and circumstances
Target INR Duration
(months)
Below knee DVT 2 ...
WARFARIN- Long-term supervision
• Warfarin has narrow therapeutic index with
life-threatening toxicity
• Responsibility of...
WARFARIN- Over-
anticoagulation
• Common scenario following
– Poor patient understanding
– Failure of monitoring/communica...
WARFARIN- over-anticoagulation
1. Life threatening bleeding
• STOP warfarin
• 5mg vitamin K1 (slow IVI)
• Beriplex 50 iu/K...
WARFARIN- over-anticoagulation
3. INR 3-8 no bleeding
– Stop warfarin/omit 1or 2 days/dose
reduction
4. Bleeding at therap...
Warfarin in surgical patients
Principles…
• Therapeutic anticoagulation may cause
serious surgical bleeding
• Risk is depe...
Warfarin in surgical patients
1. Routine INR check ~1 week before surgery
2. Omit warfarin for 3-4 days
3. Check INR eveni...
Warfarin in surgical patients
High thrombosis risk patients
» Thrombotic event within last 4 weeks
» Severe heritable pro-...
Above all………
Please discus anticoagulation
problems with liaison
haematology team
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HOW TO ANTICOAGULATE ! Dr Andrew Mumford Department of Haematology ...

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HOW TO ANTICOAGULATE ! Dr Andrew Mumford Department of Haematology ...

  1. 1. HOW TOHOW TO ANTICOAGULATEANTICOAGULATE Dr Andrew Mumford Department of Haematology Bristol Royal Infirmary
  2. 2. • 3 established drugs…… All used to treat/prevent arterial or venous thrombosis ‘Anti-thrombotics’ Unfractionated heparin Low molecular weight heparin Warfarin LECTURE PLAN
  3. 3. 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
  4. 4. Unfractionated and low molecular weight HEPARIN
  5. 5. HEPARIN manufacture
  6. 6. 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)
  7. 7. PHARMACOLOGY OF HEPARINS UF HEPARIN LMW HEPARIN RouteRoute IV SC BioavailabilityBioavailability Variable, poor Predictable, good MetabolismMetabolism Complex, mostly renal Predictable renal TT1/21/2 (hours)(hours) 1-2 4-6
  8. 8. Presentation- UF Heparin • Vials containing.. 25,000 IU/ml (sc) 5,000 IU/ml 1,000 IU/ml (flush) 10 IU/ml (flush) Typical dose 5000 IU loading then 30,000 IU by iv infusion / 24 hrs
  9. 9. 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’
  10. 10. 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
  11. 11. HEPARINS- Adverse effects 1. 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
  12. 12. 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
  13. 13. • 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
  14. 14. Administration– UF heparin 1. 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 ↑
  15. 15. 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
  16. 16. Over-anticoagulation with heparins MILD 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
  17. 17. WARFARIN
  18. 18. Warfrain developed as a rodenticide
  19. 19. 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
  20. 20. Pharmacology- WARFARIN • Orally active • Near 100% bio-availability • Variation in pharmacokinetics and pharmacodynamics • Half life ~36 hours • Metabolised by liver
  21. 21. WARFARIN- PresentationWARFARIN- Presentation • 1mg, 3mg, 5mg tablets • Colour coded packaging Typical dose 1 -10 mg po once daily
  22. 22. 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
  23. 23. WARFARIN- Important interactions • Assume all co-prescriptions will alter warfarin dose response Cause over-anticoagulation Amiodarone PPI’s Statins Fluconazole Erythromycin Cause under-anticoagulation Barbiturates Carbemazepine Rifampicin Cholestyramine •Anti-platelet agents increase bleeding risk
  24. 24. 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
  25. 25. 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)
  26. 26. 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
  27. 27. Example warfarin dosing schedule Day INR Dose (mg) 1 <1.4 10 2 <1.8 10 1.8 1 >1.8 0.5 3 <2.0 10 2.0-2.1 5 2.2-2.3 4.5 Continued
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. 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)
  32. 32. 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
  33. 33. Warfarin in surgical patients Principles… • 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
  34. 34. 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
  35. 35. 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
  36. 36. Above all……… Please discus anticoagulation problems with liaison haematology team

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