1. Thin Blood Department of Clinical Toxicology and Pharmacology Newcastle Mater Hospital

2. 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

3. Background Precipitating incident : –Brother suicided recently –Planned overdose for 2 days Psychiatric background : –No previous deliberate self harm –Amphetamine dependence

4. 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

5. 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

6. Initial Management INR 2.0 Appropriate Management ? –FFP –Vitamin K

7. Initial Management Haematology consult –4 units FFP –10 mg vitamin K IVI Neurological observation 2-3 daily INR

8. INR Results Vitamin K 10 mg IVI 4 Units FFP

9. INR Results Heparin 5,000 U Infusion 1000 U/hr

10. INR Results Heparin ceased Warfarin recommenced, normal dose 5 mg/d

11. Time course of INR FFP Vit K HeparinHeparin Ceased Warfarin Restarted

12. Optimal Management - Issues Perfect dose of vitamin K ! Normalised INR with FFP; then therapeutic Required heparinisation for 2 days No active bleeding

13. 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

14. Background Precipitating incident : –Argument with wife, asked to leave Psychiatric background : –Narcotic dependence; 7 year history –No previous deliberate self harm

15. Medical History Thromboembolic disease –Pulmonary embolus (definite diagnosis) –Recurrent DVTs, mainly on symptoms –Not thrombophilic ; testing negative Chronic back pain Gastro-oesophageal reflux Hypertension

16. 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

17. Initial Management Response to naloxone; infusion commenced (2mg/50 mL) at 15 mL/hr Lacerations sutured Bloods sent including Group + Save

18. Initial Management 2 INR 3.7 Appropriate management ? –FFP –Vitamin K

19. Initial Management 2 Haematology consult –6 units FFP –10 mg vitamin K IVI Neurological observation 2-3 daily INR

20. Progress - Day 2 Clinical : no bleeding complications Naloxone infusion continued INR Results

21. 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

22. Progress - Day 2 - 6 Day 4 : Warfarin recommenced 14 mg daily (normal dose) Day 5 : Enoxaparin increased to twice daily Warfarin recommenced

23. Progress - Day 5 - 12 Transferred to inpatient psychiatric unit Normal warfarin dose Continue enoxaparin until therapeutic INR

24. Time course of INR Warfarin Vitamin K

25. Comments / Problems What dose of vitamin K is appropriate ? Patient still has a non-therapeutic INR two weeks after vitamin K

26. 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

27. Initial Assessment Drowsy but easily roused Normal observations No active bleeding or bruising INR 1.9

28. Plan No haematology consult Q3H INR Research: –Intermittent factor levels –Serial warfarin determination Vitamin K 1 mg if INR > 5.0

29. 100%

30. Excessive Anticoagulation Situation : –Therapeutic dose : drug interaction, other –Acute Overdose Thromboembolic Risk –None –Low-medium : previous DVT/PE/thrombophilia –High : mechanical heart valve

31. 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

32. 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

33. 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

34. 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

36. 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

37. 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

38. 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

39. 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

41. Therapeutic Options Fresh frozen plasma Vitamin K –oral –intravenous Heparinisation –intravenous unfractionated –low molecular weight

42. Fresh Frozen Plasma Major bleeding Minor bleeding; risk groups eg. age Guidelines Br J Haematol 1998

43. 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

44. 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

48. 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

49. Vitamin K