Subscribe to RSS
DOI: 10.1160/TH06-05-0290
Monitoring unfractionated heparin with the aPTT: Time for a fresh look
Publication History
Received
26 May 2006
Accepted after revision
31 July 2006
Publication Date:
01 December 2017 (online)
Summary
Laboratory monitoring is widely recommended to measure the anticoagulant effect of unfractionated heparin and to adjust the dose to maintain levels in the target therapeutic range.The most widely used laboratory assay for monitoring unfractionated heparin therapy is the activated partial thromboplastin time (aPTT). A fixed therapeutic range for the aPTT of 1.5 to 2.5 times the control value has become widely accepted,but the evidence supporting this range is weak and the clinical validity of using the aPTT for predicting thrombotic or bleeding events is questionable. The aPTT test is also affected by numerous preanalytic and analytic variables that are unrelated to the anticoagulant effect of unfractionated heparin, further eroding its potential value for monitoring unfractionated heparin treatment. Unfractionated heparin dose appears to be more important than the aPTT in predicting clinical efficacy. Despite serious limitations,the reliance on the aPTT is likely to continue because of its ready availability and familiarity of clinicians with the test. The focus of clinicians who manage unfractionated heparin therapy should be to ensure that an adequate starting dose of unfractionated heparin is used and that the aPTT method is standardized. Future research efforts should be directed towards developing methods to improve standardization of the aPTT assay for monitoring unfractionated heparin. Direct measures of the concentration of unfractionated heparin in the blood are attractive because these assays are not affected by many of the biologic variables that interfere with the aPTT and may be suitable for automation. However, currently available unfractionated heparin assays are much more expensive than the aPTT, are not widely available, and their validity has not been adequately assessed in clinical outcome studies.
-
References
- 1 Hirsh J, Raschke R. Heparin and low-molecularweight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S-203S.
- 2 Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci USA 1979; 76: 1218-22.
- 3 Lindahl U, Backstrom G, Hook M. et al. Structure of the antithrombin-binding site in heparin. Proc Natl Acad Sci USA 1979; 76: 3198-202.
- 4 Young E, Podor TJ, Venner T. et al. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arterioscler Thromb Vasc Biol 1997; 17: 1568-74.
- 5 Young E, Venner T, Ribau J. et al. The binding of unfractionated heparin and low molecular weight heparin to thrombin-activated human endothelial cells. Thromb Res 1999; 96: 373-81.
- 6 Olson JD, Arkin CF, Brandt JT. et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122: 782-98.
- 7 Francis JL, Groce III JB. Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy 2004; 24: 108S-19S.
- 8 Kassai B, Shah NR, Leizorovicza A. et al. The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests. J Clin Epidemiol 2005; 58: 1042-51.
- 9 Basu D, Gallus A, Hirsh J. et al. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287: 324-7.
- 10 Chiu HM, Hirsh J, Yung WL. et al. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood 1977; 49: 171-84.
- 11 Turpie AG, Robinson JG, Doyle DJ. et al. Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N EnglJ Med 1989; 320: 352-7.
- 12 Hull RD, Raskob GE, Hirsh J. et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109-14.
- 13 Camilleri JF, Bonnet JL, Bouvier JL. et al. Intravenous thrombolysis in myocardial infarction Influence of the quality of the anticoagulation on the early recurrence rate of angina or infarction. Arch Mal Coeur Vaiss 1988; 81: 1037-41.
- 14 Kaplan K, Davison R, Parker M. et al. Role of heparin after intravenous thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1987; 59: 241-4.
- 15 Hull RD, Raskob GE, Brant RF. et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997; 157: 2562-8.
- 16 Raschke RA, Reilly BM, Guidry JR. et al. The weight-based heparin dosing nomogram compared with a „standard care” nomogram.A randomized controlled trial. Ann Intern Med 1993; 119: 874-81.
- 17 Holm HA, Abildgaard U, Kalvenes S. Heparin assays and bleeding complications in treatment of deep venous thrombosis with particular reference to retroperitoneal bleeding. Thromb Haemost 1985; 53: 278-81.
- 18 Nieuwenhuis HK, Albada J, Banga JD. et al. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood 1991; 78: 2337-43.
- 19 Koopman MM, Prandoni P, Piovella F. et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home The Tasman Study Group. N EnglJ Med 1996; 334: 682-7.
- 20 Levine M, Gent M, Hirsh J. et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-81.
- 21 Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators. N Engl J Med 1997; 337: 657-62.
- 22 Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med 2003; 138: 720-3.
- 23 Anand S, Ginsberg JS, Kearon C. et al. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin. Arch Intern Med 1996; 156: 1677-81.
- 24 Anand SS, Bates S, Ginsberg JS. et al. Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times. Arch Intern Med 1999; 159: 2029-32.
- 25 Kearon C, Ginsberg JS, Julian J. et al. Fixed-dose, weight-adjusted, unfractionated heparin (UFH) given subcutaneously (sc) without laboratory monitoring for acute treatment of venous thromboembolism (VTE): Randomized comparison with low-molecular-weightheparin (LMWH). Blood. 2004 104. (Abstract).
- 26 van den Besselaar AM, Sturk A, Reijnierse GL. Monitoring of unfractionated heparin with the activated partial thromboplastin time: determination of therapeutic ranges. Thromb Res 2002; 107: 235-40.
- 27 Rapaport SI, Vermylen J, Hoylaerts M. et al. The multiple faces of the partial thromboplastin time APTT. J Thromb Haemost 2004; 02: 2250-9.
- 28 Granger CB, Hirsh J, Califf RM. et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 1996; 93: 870-8.
- 29 Anand SS, Yusuf S, Pogue J. et al. Relationship of activated partial thromboplastin time to coronary events and bleeding in patients with acute coronary syndromes who receive heparin. Circulation 2003; 107: 2884-8.
- 30 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests; a presumptive test for hemophilia and a simple one-stage antihemophilic factor assy procedure. J Lab Clin Med 1953; 41: 637-47.
- 31 White GC. The partial thromboplastin time: defining an era in coagulation. J Thromb Haemost 2003; 01: 2267-70.
- 32 Margolis J. The kaolin clotting time; a rapid onestage method for diagnosis of coagulation defects. J Clin Pathol 1958; 11: 406-9.
- 33 Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Pathol 1961; 36: 212-9.
- 34 Brandt JT, Triplett DA. Laboratory monitoring of heparin Effect of reagents and instruments on the activated partial thromboplastin time. Am J Clin Pathol 1981; 76: 530-7.
- 35 Bain B, Forster T, Sleigh B. Heparin and the activated partial thromboplastin time--a difference between the in-vitro and in-vivo effects and implications for the therapeutic range. Am J Clin Pathol 1980; 74: 668-73.
- 36 Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer. AmJ Clin Pathol 1988; 89: 19-23.
- 37 Zanke B, Shojania AM. Comparison of two APTT methods of monitoring heparin therapy APTT ratio and heparin response of pooled normal plasma. Am J Clin Pathol 1990; 93: 684-9.
- 38 Brill-Edwards P, Ginsberg JS, Johnston M. et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993; 119: 104-9.
- 39 Kitchen S, Jennings I, Woods TA. et al. Wide variability in the sensitivity of APTT reagents for monitoring of heparin dosage. J Clin Pathol 1996; 49: 10-4.
- 40 Kitchen S, Preston FE. The therapeutic range for heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays. Thromb Haemost 1996; 75: 734-9.
- 41 Baker BA, Adelman MD, Smith PA. et al. Inability of the activated partial thromboplastin time to predict heparin levels Time to reassess guidelines for heparin assays. Arch Intern Med 1997; 157: 2475-9.
- 42 Rosborough TK. Comparing different lots of activated partial thromboplastin time reagent: analysis of two methods. Am J Clin Pathol 1998; 110: 173-7.
- 43 Bates SM, Weitz JI, Johnston M. et al. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001; 161: 385-91.
- 44 Volles DF, Ancell CJ, Michael KA. et al. Establishing an institution-specific therapeutic range for heparin. Am J Health Syst Pharm 1998; 55: 2002-6.
- 45 Rosborough TK. Comparison of anti-factor Xa heparin activity and activated partial thromboplastin time in 2,773 plasma samples from unfractionated heparintreated patients. Am J Clin Pathol 1997; 108: 662-8.
- 46 Manzato F, Mengoni A, Grilenzoni A. et al. Evaluation of the activated partial thromboplastin time (APTT) sensitivity to heparin using five commercial reagents: implications for therapeutic monitoring. Clin Chem Lab Med 1998; 36: 975-80.
- 47 Koerber JM, Smythe MA, Begle RL. et al. Correlation of activated clotting time and activated partial thromboplastin time to plasma heparin concentration. Pharmacotherapy 1999; 19: 922-31.
- 48 Raschke RA, Guidry JR, Foley MR. Apparent heparin resistance from elevated factor VIII during pregnancy. Obstet Gynecol 2000; 96: 804-6.
- 49 Reed SV, Haddon ME, Denson KW. An attempt to standardize theAPTT for heparin monitoring, using the P.T ISI/INR system of calibration Results of a 13 centre study. Thromb Res 1994; 74: 515-22.
- 50 Vand V, Poller L. TheAPTT monitoring of heparin-the ISTH/ICSH collaborative study. Thromb Haemost 1995; 73: 73-81.
- 51 Spinler SA, Wittkowsky AK, Nutescu EA. et al. Anticoagulation monitoring part 2: Unfractionated heparin and low-molecular-weight heparin. Ann Pharmacother 2005; 39: 1275-85.
- 52 Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. J Am Med Assoc 2006; 295: 1050-7.
- 53 Hron G, Eichinger S, Weltermann A. et al. Prediction of recurrent venous thromboembolism by the activated partial thromboplastin time. J Thromb Haemost 2006; 04: 752-6.
- 54 Tripodi A, Chantarangkul V, Martinelli I. et al. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood 2004; 104: 3631-4.
- 55 Levine MN, Hirsh J, Gent M. et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154: 49-56.
- 56 Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005; 105: 453-63.