Study of Octaplex dosing accuracy: An in vitro analysis

Summary

Prothrombin complex concentrates (PCC) are recommended for urgent warfarin reversal. However, disagreement exists regarding the proper dosing strategy (i.e. fixed vs. weight-based). We measured the in vitro effect of PCC dosing on international normalised ratio (INR) and factor activity. Plasma from warfarin-anticoagulated patients with stable INRs was collected. PCC doses of 1,000, 2,000 and 3,000 IU were added to the samples, and INR and factor activity were analysed before and after PCC. Twenty-three of thirty subjects enrolled had complete data for analysis. INRs were below 1.5 in all samples post-1,000 IU, and decreased further with subsequent doses (p<0.001). Factors II, VII, and X increased with consecutive doses (p<0.01). Linear correlation was seen between INR and factors II, VII and X. Factor IX did not increase consistently nor show correlation with INR reversal. Weight-based dosing was then estimated; INRs were all <1.2 (0.9–1.2) and activity >0.50 IU for factors II, VII and X (0.96–1.52, 0.51–1.45 and 0.81–1.38, respectively). Factor IX did not uniformly correct above 0.50 IU (0.31–1.31). We confirm in vitro that 1,000 IU of Octaplex^® is able to correct INR to <1.5 but factors were not uniformly >0.50 IU until 2,000 IU, and not >1.00 IU until 3,000 IU. This suggests that INR correction alone may not accurately reflect factor activity, and lends support for weight-based dosing.

Keywords

Thrombosis - vitamin K-dependent factors - factor concentrates

• References

• 1 Vigue B.. Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Crit Care 2009; 13: 209.
• 2 Wittkowsky AK, Devine EB.. Frequency and causes of overanticoagulation and underanticoagulation in patients treated with warfarin. Pharmacotherapy 2004; 24: 1311-1316.
• 3 Dentali F, Crowther MA.. Management of excessive anticoagulant effect due to vitamin K antagonists. Hematology Am Soc Hematol Educ Program 2008; 266-270.
• 4 Samsa GP, Matchar DB, Goldstein LB. et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.. Arch Intern Med 2000; 160: 967-973.
• 5 Hylek EM, Chang YC, Skates SJ. et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation.. Arch Intern Med 2000; 160: 1612-1617.
• 6 Oden A, Fahlen M.. Oral anticoagulation and risk of death: a medical record linkage study. Br Med J 2002; 325: 1073-1075.
• 7 Levi M, Eerenberg E, Kamphuisen PW.. Periprocedural reversal and bridging of anticoagulant treatment. Neth J Med 2011; 69: 268-273.
• 8 Libby EN, Garcia DA.. A survey of oral vitamin K use by anticoagulation clinics. Arch Intern Med 2002; 162: 1893-1896.
• 9 Watson HG, Baglin T, Laidlaw SL. et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin.. Br J Haematol 2001; 115: 145-149.
• 10 Garcia D, Crowther MA, Ageno W.. Practical management of coagulopathy associated with warfarin. Br Med J 2010; 340: c1813.
• 11 Lin Y, Callum J.. Emergency reversal of warfarin anticoagulation. CMAJ 2010; 182: 2004.
• 12 Schulman S.. Clinical practice. Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003; 349: 675-683.
• 13 Recommendations for use of Octaplex^® in Canada NAC Octaplex® Subcommittee National Advisory Committee and Blood and Blood Products. 2008; 1-6.
• 14 NAC PCC Working Group. Recommendations for Use of Prothrombin Complex Concentrates in Canada. National Advisory Committee and Blood and Blood Products 2011; 1-6.
• 15 van Aart L, Eijkhout HW, Kamphuis JS. et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial.. Thromb Res 2006; 118: 313-320.
• 16 Koc U, Bostanci EB, Karaman K. et al. Basic Hemostatic Parameters in Patients with Long-Term Oral Anticoagulation Undergoing Cholecystectomy.. J Laparoendosc Adv Surg Tech A 2011; 21: 417-425.
• 17 Srivastava A.. Dose and response in haemophilia--optimization of factor replacement therapy.. Br J Haematol 2004; 127: 12-25.
• 18 Pearson TC, Guthrie DL, Simpson J. et al. Interpretation of measured red cell mass and plasma volume in adults: Expert Panel on Radionuclides of the International Council for Standardization in Haematology. Br J Haematol 1995; 89: 748-756.
• 19 Hoots W.. Emergency management in hemophilia. 2nd ed.. Oxford, UK.: Wiley-Blackwell; 2010
• 20 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 160S-98S.
• 21 Riess HB, Meier-Hellmann A, Motsch J. et al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation.. Thromb Res 2007; 121: 9-16.
• 22 Dentali F, Marchesi C, Pierfranceschi MG. et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A metaanalysis. Thromb Haemost 2011; 106: 429-438.
• 23 Burbury KL, Milner A, Snooks B. et al. Short-term warfarin reversal for elective surgery--using low-dose intravenous vitamin K: safe, reliable and convenient.. Br J Haematol 2011; 154: 626-634.