1. Anticoagulation 101 Neil A. Lachant, MD Chief, Section of Hematology Director, Thrombosis Program Cooper Cancer Institute Professor of Medicine UMDNJ Robert Wood Johnson Medical School

2. Venous Thrombosis Magnitude of the Problem No national data Incidence –1- 2/1,000 –300,000 - 600,000 new cases per year –increasing as population ages life expectancy 78 years

3. Incidence of VTE AgeIncidence <101:100,000 201:10,000 501:1,000 801:100

4. Manifestations 2/3 DVT –50- 80% post-phlebitic syndrome 1/3 pulmonary emboli –30% mortality –30,000 – 60,000 deaths per year

5. Mechanisms of Anticoagulation 1 1.Adapted with permission from Petitou M et al. Nature. 1991;350(suppl):30-33; http://www.nature.com/ 2.Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 3.Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. 4.Nutescu EA, et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5.Weitz JI, Hirsh J. Chest. 2001;119(1 suppl):95S-107S. XIIa IIa Xa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIIIVIIIa Extrinsic system (tissue damage) X Xa VVa II FibrinogenFibrin (Thrombin) IIa Factor Xa inhibitors 4,5 Direct thrombin inhibitors 4,5 Vitamin K antagonists 4 Heparins 2,3

6. Choice of Anticoagulant What are my goals? Pharmacology Side effects

7. What is Heparin? Heterogenous branched glycosoaminoglycan MW 3,000 – 30,000 kd –average 15,000 kd 9 – 90 monosaccharides –average 45 –highly sulfated

8. How Does Heparin Work? Stearic change in AT-III Heparin/AT-III complex inactivate –Xa, IIa, IXa, XIa, XIIa Sugars 1 - 5 bind AT-III Other sugars –affect pharmacokinetics –affect binding properties to coagulation factors –cause problems 1/3 of UFH binds to AT-III

9. Low Molecular Weight Heparin Physiology –chemical or enzymatic digest of UFH –15 monosaccharides on average –MW 5 kD –binds AT-III primarily (not IIa or Xa ) –anti-Xa/IIa = 3 - 4 (UFH = 1) Metabolism –little cell, protein binding consistent renal clearance –T 1/2 varies with preparation

10. Theoretical Models for Differential Effects of Heparin and LMWH on Thrombin and Factor Xa LMWH: 15 Saccharide Units (mean) LMWH XaATIIaAT 55 10 Binds to AT but not to Thrombin Binds to AT Heparin: 45 Saccharide Units (mean) Xa AT IIa AT 55 13 Binds to AT and Thrombin

12. A 22 yo female presents with an iliofemoral DVT. Her aPTT is 37 sec (nl <32) and she is found to have a lupus anticoagulant. She weighs 55 kg and her creatinine is 0.5 mg/dl. She is started on weight - based UFH. Her aPTT at 4 hrs is 123 s. She could be anticoagulated by all of the following EXCEPT: 1. Decrease UFH with aPTT goal of 1.5-2.5 x her baseline 2. UFH monitoring heparin level 3. UFH correlating heparin level with the aPTT 4.LMWH without monitoring 5.Fondaparinux without monitoring

13. A 22 yo female presents with an iliofemoral DVT. Her aPTT is 37 sec (nl <32) and she is found to have a lupus anticoagulant. She weighs 55 kg and her creatinine is 0.5 mg/dl. She is started on weight - based UFH. Her aPTT at 4 hrs is 123 s. She could be anticoagulated by all of the following EXCEPT: 1. Decrease UFH with aPTT goal of 1.5-2.5 x her baseline 2. UFH monitoring heparin level 3. UFH correlating heparin level with the aPTT 4.LMWH without monitoring 5.Fondaparinux without monitoring

14. Heparin Therapy in APLS Lupus anticoagulant with prolonged baseline aPTT –use LMWH –use standard weight-based unfractionated heparin dosing 1. correlate aPTT with heparin level (3-4 points) use aPTT range that corresponds to therapeutic heparin level (0.3 – 0.7 iu/ml) 2. follow thrombin time if standardized in your lab

15. Normal Patient

16. A 34 year old African American male presents with a femoral DVT. He is given a 5000 u bolus of UFH and is started on a heparin drip at 1000 u/hr. The aPTT remains subtheraputic despite an increase to 1800 u/hr. A hematology consult is obtained on the 3rd hospital day for “inability to be anticoagulated”.

17. What is the most appropriate goal for UFH: 1.aPTT ratio 1.5 - 2.5 x baseline 2.aPTT that correlates with heparin level of 0.3 - 0.7 u/ml 3.Whatever the lab computer says the therapeutic range is

18. What is the most appropriate goal for UFH: 1.aPTT ratio 1.5 - 2.5 2.aPTT that correlates with heparin level of 0.3 - 0.7 u/ml 3.Whatever the lab computer says the therapeutic range is

19. Effect of Thromboplastin on aPTT Ranges (Anti-Xa 0.3 - 0.7 IU/ml)

20. Effect of Thromboplastin on aPTT Ranges (Anti-Xa 0.3 - 0.7 IU/ml)

21. Review of the patients records shows that he weighs 150 kg. His current aPTT is 38 sec (normal < 37.1) with an infusion rate of 1800 u/hr. The most appropriate rate for the UFH infusion is: 1. 2700 u/hr (18 u/kg/hr) 2. 2000 u/hr (18 u/kg/hr capped for patient size) 3. Continue at 1800 u/hr 4. Switch to LMWH because UFH doses above 2000 u/hr are too dangerous to use

22. Review of the patients records shows that he weighs 150 kg. His current aPTT is 38 sec (normal < 37.1) with an infusion rate of 1800 u/hr. The most appropriate rate for the UFH infusion is: 1. 2700 u/hr (18 u/kg/hr) 2. 2000 u/hr (18 u/kg/hr capped for patient size) 3. Continue at 1800 u/hr 4. Switch to LMWH because UFH doses above 2000 u/hr are too dangerous to use.

23. UFH Dosing Adopted from Raschke Arch Int Med 156:1645, 1996

24. Utilization management is pushing for discharge, but his INR is only 1.6. The most appropriate recommendation for the use of enoxaparin would be: 1. 150 mg (1 mg/kg) sc q 12 hr 2. 150 mg sc q 12 hr and check a heparin level immediately before the third dose 3. 150 mg sc q 12 hr and check a heparin level 3.5 - 4 hours after the third dose 4. 225 mg (1.5 mg/kg) sc q 24 hr 5. Enoxaparin contraindicated in a patient this large

25. Utilization management is pushing for discharge, but his INR is only 1.6. The most appropriate recommendation for the use of enoxaparin would be: 1. 150 mg (1 mg/kg) sc q 12 hr 2. 150 mg sc q 12 hr and check a heparin level immediately before the third dose 3. 150 mg sc q 12 hr and check a heparin level 3.5 - 4 hours after the third dose 4. 225 mg (1.5 mg/kg) sc q 24 hr 5. Enoxaparin contraindicated in a patient this large

26. Kinetics of LMWH Different for each LMH Doses not interchangable

27. Low Molecular Weight Heparin Dosing

28. LMWH in Obesity Relationship of intravascular volume and TBW is not linear –adipose tissue has a relative decrease in plasma volume compared to muscle –could lead to overdosing

29. Weight in LMWH Studies Actual weight dosed anti-Xa activity is not significantly increased in obesity

30. Recommendations For the Use of LMWH in Obesity Patient should receive LMWH dose based on actual body weight –if < 150 kg, monitoring not necessary on a routine basis –if > 150 kg, check heparin level 3.5 - 4 hrs after 3rd or 4 th dose dose reduce if > 1.0 IU/ml

31. A 24 yo dialysis dependant female is paraplegic. She receives enoxaparin 1 mg/kg q 12h for an acute DVT. One week later in rehab, she develops pain in her right shoulder. She is brought to the emergency room during the night with a 20 cm hematoma in her right supraclavicular fossa. What is her correct enoxaparin dose? A. 1 mg/kg q 12h B. 1 mg/kg qd C. Enoxaparin contraindicated with ESRD

32. A 24 yo dialysis dependant female is paraplegic. She enoxaparin 1 mg/kg q 12h for an acute DVT. One week later in rehab, she develops pain in her right shoulder. She is brought to the emergency room during the night with a 20 cm hematoma in her right supraclavicular fossa. What is her correct enoxaparin dose? A. 1 mg/kg q 12h B. 1 mg/kg qd C. Enoxaparin contraindicated with ESRD

33. LMWH Dosing in Renal Dysfunction LMWH accumulates as Ccr decreases –cutoff point varies between different LMWHs –Ccr 30 - 50 monitor heparin level if concern about dosing or bleeding –Ccr < 30 dose reduce monitor heparin level –Ccr < 10 do not use LMWH under any circumstances

34. Enoxaparin Dosing with Renal Dysfunction

35. Reversal of Unfractionated Heparin Protamine –1 mg inactivates 100 units of UFH –Give over 1-3 minutes to minimize risk of hypotension and bradycardia –Increased risk of allergic reaction vasectomy PZI insulin

36. Reversal of Unfractionated Heparin After heparin bolus –1 mg protamine per 100 units UFH 5000 unit bolus  50 mg protamine Constant infusion, –Heparin used during last 2 hours 1250 units/hr CI  25 mg protamine

37. Reversal of LMWH 60% reversible by protamine Within 8 hours of injection, –1 mg protamine per 100 anti-Xa units LMWH Enoxaparin: 100 anti-Xa units per mg –If bleeding persists, 0.5 mg protamine per 100 anti-Xa units LMWH

38. A 24 year old Hispanic female presents to her local hospital with left calf pain. Duplex shows a popliteal DVT. Therapy with UFH is initiated on Saturday. She is discharged on Sunday. Her only anticoagulation is 12 mg warfarin which she is told to start at 6 PM that night. She presents to Cooper Hospital on Monday evening with a leg that is painful and swollen to the groin. Duplex shows a DVT extending to the iliac vein.

39. Which of the following statements about anticoagulation after VTE is/are true? 1. Warfarin should only be given simultaneously with a heparin, DTI or other rapid acting anticoagulant 2. Warfarin should be started at a dose of 5 - 7.5 mg 3. Warfarin should be overlapped with heparin for a minimum of 5 days (no matter what the INR is) 4. Heparin should be stopped when the INR > 2.0 for 2 days or INR > 2.5 5. All of the above

40. Which of the following statements about anticoagulation after VTE is/are true? 1. Warfarin should only be given simultaneously with a heparin, DTI or other rapid acting anticoagulant 2. Warfarin should be started at a dose of 5 - 7.5 mg 3. Warfarin should be overlapped with heparin for a minimum of 5 days (no matter what the INR is) 4. Heparin should be stopped when the INR > 2.0 for 2 days or INR > 2.5 5. All of the above

41. A 60 year old female is taking a stable dose of coumadin as prophylaxis for atrial fibrillation (INR 2.6). She develops a UTI and is treated with bactrim. Two weeks later her INR is 6.9. She has no clinical bleeding. Her coumadin is held. The most appropriate adjunctive therapy would be: A. Transfuse 4-6 units FFP B. Transfuse 15 bags cryoprecipitate C. Vitamin K 0.5 mg sc x 1 D. Vitamin K 10 mg sc x 1 E. Vitamin K 10 mg sc x 3d F. Vitamin K 2.5 mg po x 1 G. No additional therapy is needed

42. A 60 year old female is taking a stable dose of coumadin as prophylaxis for atrial fibrillation (INR 2.6). She develops a UTI and is treated with bactrim. Two weeks later her INR is 6.9. She has no clinical bleeding. Her coumadin is held. The most appropriate adjunctive therapy would be: A. Transfuse 4-6 units FFP B. Transfuse 15 bags cryoprecipitate C. Vitamin K 0.5 mg sc x 1 D. Vitamin K 10 mg sc x 1 E. Vitamin K 10 mg sc x 3d F. Vitamin K 2.5 mg po x 1 G. No additional therapy is needed

43. Reversal of Warfarin INR < 5.0, no bleeding –lower dose or –omit dose, restart at lower dose Chest June, 2008

44. Reversal of Warfarin INR > 5.0 but < 9.0, no significant bleeding –omit 1 or 2 doses and restart at lower dose, or –omit dose, give vitamin k 1-2.5 mg po, or –for rapid reversal (i.e., surgery) 3 - 5 mg po (INR should decrease in 24 hr) can repeat vitamin k 1-2 mg po if goal not reached

45. Reversal of Warfarin INR > 9.0, no significant bleeding –hold warfarin –give vitamin K 2.5 - 5 mg po (INR should be significantly reduced in 24 - 48 hrs) –additional vitamin k po if needed –resume warfarin when INR therapeutic

46. Reversal of Warfarin Any INR > 3.0, serious bleeding –hold warfarin –vitamin k 10 mg slow iv infusion –repeat every 12 hours as needed –FFP, r-VIIa or prothrombin complex depending upon urgency of the situation

47. Reversal of Warfarin Any INR > 3.0, life threatening bleeding –hold warfarin –fresh frozen plasma, r-VIIa or prothrombin complex –vitamin k 10 mg slow iv infusion

48. Warfarin Pearls Coumadin if possible –If generic, keep track of brands Dose adjustment –Think in terms of a week –New warfarin dose = current dose x goal INR current INR –New dose = 35 mg x 2.5/5.0 –New dose = 17.5 mg/week = 2.5 mg/day

49. IVC Filter Indications Recent proximal DVT, and –Contraindication to anticoagulation current or recent active GI bleed intracranial bleed in last 5 days recent neurologic or ophthalmologic surgery cerebral metasteses at risk for bleeding –seminoma, melanoma, renal cell, choriocarcinoma planned major surgery in next 4 weeks severe, prolonged thrombocytopenia Recurrent pulmonary emboli while fully anticoagulated

50. New Anticoagulants Pentasaccharide –Fondaprinux (Arixtra) Oral IIa inhibitors –ximelagatran Oral Xa-inhibitors

51. Fondaparinux (Arixtra)

52. Theoretical Models for Differential Effects of Heparin and LMWH on Thrombin and Factor Xa Fondaparinux: 5 Saccharide Units Fondaparinux XaAT IIa AT 5 5 Binds to AT but not to Thrombin Binds to AT

53. New Anticoagulants Fondaparinux (Arixtra) –Synthetic pentasaccharide –Selective anti-Xa inhibitor no anti-IIa activity PT or PTT are insensitive –Renal excretion –T 1/2 17 – 20 hrs –Does not bind PF4 One reported case of HIT

54. FDA Approved –hip and knee surgery prophylaxis –treatment of DVT –treatment of PE when started in hospital –surgical DVT prophylaxis

55. Fondaparinux dosing for DVT or PE –< 50 kg  5 mg qd sc –50 – 100 kg  7.5 mg qd sc –>100 kg  10 mg qd sc Dose modification –Ccr 30 – 50, use with caution –Ccr < 30, contraindicated

56. Because of long half-life, anticoagulant effect may last for 2 – 4 days after stopping fondaparinux with normal renal function Anti-Xa activity can be measured –? <0.3 u/ml safe R-VIIa if severe bleeding