Semin Thromb Hemost 2017; 43(03): 245-252
DOI: 10.1055/s-0036-1587690
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Laboratory Monitoring of Oral Vitamin K Anticoagulation

Karen A. Moffat
1   Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
2   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Clinton W. Lewis
2   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
27 September 2016 (online)

Abstract

Vitamin K antagonists (VKA) have been used for many years as effective anticoagulant therapy. The laboratory plays a crucial role in measuring the prothrombin time (PT) and calculating the international normalized ratio (INR). Each component of the calculation has the potential to increase error in the final result. This article discusses the laboratory aspects of monitoring VKA including sample requirements, PT, determination of the INR, point of care (POC) testing, external quality assurance/proficiency testing, and reversal strategies for VKA therapy. The implementation of the PT/INR reporting standard was a significant improvement in laboratory medicine. However, further room for improvement exists in the management of PT/INR testing, to clarify the role of POC testing and continue the harmonization process to ensure reliability and reproducibility of INR results.

 
  • References

  • 1 Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141 (6) 757-763
  • 2 Riva N, Ageno W. Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants. Semin Thromb Hemost 2015; 41 (2) 178-187
  • 3 Carter KL, Streiff MB, Ross PA , et al. Analysis of the projected utility of dabigatran, rivaroxaban, and apixaban and their future impact on existing Hematology and Cardiology Anticoagulation Clinics at The Johns Hopkins Hospital. J Thromb Thrombolysis 2012; 34 (4) 437-445
  • 4 Schulman S, Anderson DR, Bungard TJ , et al. Direct and indirect costs of management of long-term warfarin therapy in Canada. J Thromb Haemost 2010; 8 (10) 2192-2200
  • 5 Hylek EM. Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement. J Thromb Thrombolysis 2013; 35 (3) 333-335
  • 6 Tziomalos K, Giampatzis V, Bouziana SD , et al. Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation. J Thromb Thrombolysis 2016; 41 (2) 336-342
  • 7 Sjögren V, Grzymala-Lubanski B, Renlund H , et al. Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. Thromb Haemost 2015; 113 (6) 1370-1377
  • 8 Olson JD, Brandt JT, Chandler WL , et al. Laboratory reporting of the international normalized ratio: progress and problems. Arch Pathol Lab Med 2007; 131 (11) 1641-1647
  • 9 Loeliger EA, Poller L, Samama M , et al. Questions and answers on prothrombin time standardisation in oral anticoagulant control. Thromb Haemost 1985; 54 (2) 515-517
  • 10 Clinical and Laboratory Standards Institute (CSLI). Collection, Transport, and Processing of Blood Specimens for Testing Plasma Based Coagulation Assays and Molecular Hemostasis Assays - Approved Guideline. 5th ed. H21–A5, Vol. 28, No. 5. Wayne, PA: CLSI; 2008
  • 11 Clinical and Laboratory Standards Institute (CSLI). One Stage Prothrombin Time (PT) Test and Activated Partial Thromboplastin Time (APTT) Test - Approved Guideline. 2nd ed. H47–A2, Vol. 28, No. 20. Wayne, PA: CLSI; 2008
  • 12 Adcock DM, Kressin DC, Marlar RA. Effect of 3.2% vs 3.8% sodium citrate concentration on routine coagulation testing. Am J Clin Pathol 1997; 107 (1) 105-110
  • 13 Chuang J, Sadler MA, Witt DM. Impact of evacuated collection tube fill volume and mixing on routine coagulation testing using 2.5-ml (pediatric) tubes. Chest 2004; 126 (4) 1262-1266
  • 14 Dirckx JH. Armand J. Quick: pioneer and prophet of coagulation research. Ann Intern Med 1980; 92 (4) 553-558
  • 15 Woodhams BJ, Klein N, Harz D, Rose M, Ruiz JA. A study of the variability seen in the international normalized ratio obtained using different sensitivity thromboplastin reagents on different instrument types. Blood Coagul Fibrinolysis 1999; 10 (7) 423-427
  • 16 Tange JI, Grill D, Koch CD , et al. Local verification and assignment of mean normal prothrombin time and International Sensitivity Index values across various instruments: recent experience and outcome from North America. Semin Thromb Hemost 2014; 40 (1) 115-120
  • 17 Meneghelo ZM, Barroso CM, Liporace IL, Cora AP. Comparison of the international normalized ratio levels obtained by portable coagulometer and laboratory in a clinic specializing in oral anticoagulation. Int J Lab Hematol 2015; 37 (4) 536-543
  • 18 Lazo-Langner A, Villa-Márquez R, Hernández-Hernández D, Rojas-Maya S, Piedras J. Intrahospital correlation of the international normalized ratio. Clin Appl Thromb Hemost 2009; 15 (2) 220-224
  • 19 Smith SA, Comp PC, Morrissey JH. Phospholipid composition controls thromboplastin sensitivity to individual clotting factors. J Thromb Haemost 2006; 4 (4) 820-827
  • 20 Isert M, Miesbach W, Schüttfort G , et al. Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome. Ann Hematol 2015; 94 (8) 1291-1299
  • 21 Moore GW, Rangarajan S, Holland LJ, Henley A, Savidge GF. Low frequency of elevated prothrombin times in patients with lupus anticoagulants when using a recombinant thromboplastin reagent: implications for dosing and monitoring of oral anticoagulant therapy. Br J Biomed Sci 2005; 62 (1) 15-18 , quiz 47
  • 22 World Health Organization. Requirements for thromboplastins and plasma used to control oral anticoagulant therapy (Requirements for Biological Substances no. 30, revised 1982). In: WHO Expert Committee on Biological Standardization. Thirty-Third report. Annex 3, WHO Technical Report Series, no. 687. Geneva: World Health Organization; 1983
  • 23 van den Besselaar AM, Abdoel CF, Hubbard AR. Long-term stability of international standards for thromboplastin stored at -20°C, -70°C, and -150°C. Thromb Res 2015; 136 (1) 164-167
  • 24 van den Besselaar AM, Chantarangkul V, Tripodi A. Thromboplastin standards. Biologicals 2010; 38 (4) 430-436
  • 25 Thomson JM, Tomenson JA, Poller L. The calibration of the second primary international reference preparation for thromboplastin (thromboplastin, human, plain, coded BCT/253). Thromb Haemost 1984; 52 (3) 336-342
  • 26 Favaloro EJ, Adcock DM. Standardization of the INR: how good is your laboratory's INR and can it be improved?. Semin Thromb Hemost 2008; 34 (7) 593-603
  • 27 Cha CH, Park CJ, Kim DH , et al. Direct international normalized ratio determination using multicalibrators is more responsive than the conventional method for measuring prothrombin time. Int J Lab Hematol 2010; 32 (4) 392-397
  • 28 Brien WF, Crawford L, Raby A, Richardson H. In-house calibration of the international sensitivity index or calibration curve for determination of the international normalized ratio. Arch Pathol Lab Med 2004; 128 (3) 308-312
  • 29 van den Besselaar AM, Barrowcliffe TW, Houbouyan-Réveillard LL , et al; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the ISTH. Guidelines on preparation, certification, and use of certified plasmas for ISI calibration and INR determination. J Thromb Haemost 2004; 2 (11) 1946-1953
  • 30 Favaloro EJ, McVicker W, Lay M , et al. Harmonizing the international normalized ratio (INR) : standardization of methods and use of novel strategies to reduce interlaboratory variation and bias. Am J Clin Pathol 2016; 145 (2) 191-202
  • 31 Topic E, Nikolac N, Panteghini M , et al. How to assess the quality of your analytical method?. Clin Chem Lab Med 2015; 53 (11) 1707-1718
  • 32 van den Besselaar AM, Witteveen E, van der Meer FJ. Uncertainty of international sensitivity index and international normalized ratio. J Thromb Haemost 2013; 11 (8) 1615-1617
  • 33 Poller L, Keown M, Ibrahim S , et al; European Concerted Action on Anticoagulation. Comparison of local International Sensitivity Index calibration and ‘Direct INR’ methods in correction of locally reported International Normalized Ratios: an international study. J Thromb Haemost 2007; 5 (5) 1002-1009
  • 34 Poller L, Ibrahim S, Jespersen J, Pattison A. Coagulometer international sensitivity index (ISI) derivation, a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study. J Thromb Haemost 2012; 10 (7) 1379-1384
  • 35 Poller L, Ibrahim S, Keown M, Pattison A, Jespersen J. Simplified method for international normalized ratio (INR) derivation based on the prothrombin time/INR line: an international study. Clin Chem 2010; 56 (10) 1608-1617
  • 36 Favaloro EJ, McVicker W, Hamdam S, Hocker N. Improving the harmonisation of the International Normalized Ratio (INR): time to think outside the box?. Clin Chem Lab Med 2010; 48 (8) 1079-1090
  • 37 Poller L, Ibrahim S, Pattison A, Jespersen J ; European Action on Anticoagulation. INR derivation with the PT/INR Line simplified using a spreadsheet from the world wide web. J Clin Pathol 2011; 64 (10) 930-932
  • 38 Favaloro EJ, Hamdam S, McDonald J, McVicker W, Ule V. Time to think outside the box? Prothrombin time, international normalised ratio, international sensitivity index, mean normal prothrombin time and measurement of uncertainty: a novel approach to standardisation. Pathology 2008; 40 (3) 277-287
  • 39 Favaloro EJ, McVicker W, Zhang Y , et al. Improving the inter-laboratory harmonization of the international normalized ratio (INR): utilizing the concept of transference to estimate and/or validate international sensitivity index (ISI) and mean normal prothrombin time (MNPT) values and/or to eliminate measurement bias. Clin Lab Sci 2012; 25 (1) 13-25
  • 40 Health Quality Ontario. Point-of-care international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy: An evidence-based analysis. Ont Health Technol Assess Ser 2009; 9 (12) 1-114
  • 41 Kemna E, Jentink W, te Molder I, Straalman I. International Normalized Ratio (INR) testing: analytical and clinical performance of four point-of-care devices versus central laboratory instrumentation analysis. Clin Chem Lab Med 2016; 54 (3) e89-e92
  • 42 Kalçık M, Yesin M, Gürsoy MO , et al. Comparison of the INR values measured by CoaguChek XS coagulometer and conventional laboratory methods in patients on VKA therapy. Clin Appl Thromb Hemost 2015
  • 43 Ageno W, Gallus AS, Wittkowsky A , et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e44S-e88S
  • 44 Peña JA, Lewandrowski KB, Lewandrowski EL, Gregory K, Baron JM, Van Cott EM. Evaluation of the i-STAT point-of-care capillary whole blood prothrombin time and international normalized ratio: comparison to the Tcoag MDAII coagulation analyzer in the central laboratory. Clin Chim Acta 2012; 413 (11–12) 955-959
  • 45 Hur M, Kim H, Park CM , et al. Comparison of international normalized ratio measurement between CoaguChek XS Plus and STA-R coagulation analyzers. Biomed Res Int 2013; 2013: 213109
  • 46 Kitchen DP, Jennings I, Kitchen S, Woods TA, Walker ID. Bridging the gap between point-of-care testing and laboratory testing in hemostasis. Semin Thromb Hemost 2015; 41 (3) 272-278
  • 47 Bonar R, Mohammed S, Favaloro EJ. International normalized ratio monitoring of vitamin K antagonist therapy: comparative performance of point-of-care and laboratory-derived testing. Semin Thromb Hemost 2015; 41 (3) 279-286
  • 48 Bradbury MJ, Taylor G, Short P, Williams MD. A comparative study of anticoagulant control in patients on long-term warfarin using home and hospital monitoring of the international normalised ratio. Arch Dis Child 2008; 93 (4) 303-306
  • 49 Sharma P, Scotland G, Cruickshank M , et al. The clinical effectiveness and cost-effectiveness of point-of-care tests (CoaguChek system, INRatio2 PT/INR monitor and ProTime Microcoagulation system) for the self-monitoring of the coagulation status of people receiving long-term vitamin K antagonist therapy, compared with standard UK practice: systematic review and economic evaluation. Health Technol Assess 2015; 19 (48) 1-172
  • 50 Holbrook A, Schulman S, Witt DM , et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2 Suppl): e152S-e184S
  • 51 Molden E, Okkenhaug C, Ekker Solberg E. Increased frequency of CYP2C9 variant alleles and homozygous VKORC1*2B carriers in warfarin-treated patients with excessive INR response. Eur J Clin Pharmacol 2010; 66 (5) 525-530
  • 52 Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation 2012; 125 (23) 2944-2947
  • 53 Holbrook AM, Pereira JA, Labiris R , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
  • 54 Yates SG, Sarode R. New strategies for effective treatment of vitamin K antagonist-associated bleeding. J Thromb Haemost 2015; 13 (Suppl. 01) S180-S186
  • 55 Song MM, Warne CP, Crowther MA. Prothrombin complex concentrate (PCC, Octaplex) in patients requiring immediate reversal of vitamin K antagonist anticoagulation. Thromb Res 2012; 129 (4) 526-529
  • 56 Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost 2007; 98 (4) 790-797