Unfractionated Heparin for the Treatment of Venous Thromboembolism: Best Practices and Areas of Uncertainty

 

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Abstract

Nearly 100 years after its discovery, unfractionated heparin (UFH) remains a widely used anticoagulant for the treatment of venous thromboembolism (VTE) and several other thrombotic and prothrombotic conditions. Decades of experience and investigation have contributed to our knowledge of this agent, but crucial questions regarding its optimal use in clinical practice remain unanswered. This review will critically examine the evidence for dosing and laboratory monitoring of UFH in the management of VTE, and highlight areas of uncertainty and future research.

• References

• 1 McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41: 250-257
  PubMedGoogle Scholar
• 2 Howell WH. The purification of heparin and its chemical and physiological reactions. Bull Johns Hopkins Hosp 1928; 42: 199-206
  PubMedGoogle Scholar
• 3 Mason EC. Blood coagulation. The production and prevention of experimental thrombosis and pulmonary embolism. Surg Gynecol Obstet 1924; 39: 421-428
  PubMedGoogle Scholar
• 4 Crafoord C. Preliminary report on postoperative treatment with heparin as a preventive of thrombosis. Acta Chir Scand 1937; 79: 407-426
  PubMedGoogle Scholar
• 5 Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011; 43 (7) 682-692
  CrossrefPubMedGoogle Scholar
• 6 Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res 1976; 9 (6) 575-583
  CrossrefPubMedGoogle Scholar
• 7 Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci U S A 1979; 76 (3) 1218-1222
  CrossrefPubMedGoogle Scholar
• 8 Ofosu FA, Sie P, Modi GJ , et al. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243 (2) 579-588
  PubMedGoogle Scholar
• 9 Casu B, Oreste P, Torri G , et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Chemical and 13C nuclear-magnetic-resonance studies. Biochem J 1981; 197 (3) 599-609
  PubMedGoogle Scholar
• 10 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984; 218 (3) 725-732
  PubMedGoogle Scholar
• 11 Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976; 53 (4) 691-695
  CrossrefPubMedGoogle Scholar
• 12 Schran HF, Bitz DW, DiSerio FJ, Hirsh J. The pharmacokinetics and bioavailability of subcutaneously administered dihydroergotamine, heparin and the dihydroergotamine-heparin combination. Thromb Res 1983; 31 (1) 51-67
  CrossrefPubMedGoogle Scholar
• 13 Dawes J, Papper DS. Catabolism of low-dose heparin in man. Thromb Res 1979; 14 (6) 845-860
  CrossrefPubMedGoogle Scholar
• 14 Bârzu T, Molho P, Tobelem G, Petitou M, Caen J. Binding and endocytosis of heparin by human endothelial cells in culture. Biochim Biophys Acta 1985; 845 (2) 196-203
  CrossrefPubMedGoogle Scholar
• 15 de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60 (6) 1251-1258
  PubMedGoogle Scholar
• 16 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 (18) 1109-1114
  CrossrefPubMedGoogle Scholar
• 17 Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med 1993; 119 (9) 874-881
  CrossrefPubMedGoogle Scholar
• 18 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 (11) 677-681
  CrossrefPubMedGoogle Scholar
• 19 Koopman MM, Prandoni P, Piovella F , et al; The Tasman Study Group. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334 (11) 682-687
  CrossrefPubMedGoogle Scholar
• 20 Breddin HK, Hach-Wunderle V, Nakov R, Kakkar VV ; CORTES Investigators. Clivarin: Assessment of Regression of Thrombosis, Efficacy, and Safety. Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001; 344 (9) 626-631
  CrossrefPubMedGoogle Scholar
• 21 Garcia DA, Baglin TP, Weitz JI, Samama MM. American College of Chest Physicians. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e24S-e43S
  CrossrefPubMedGoogle Scholar
• 22 Kearon C, Ginsberg JS, Julian JA , et al; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA 2006; 296 (8) 935-942
  CrossrefPubMedGoogle Scholar
• 23 Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. 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 (22) 2562-2568
  CrossrefPubMedGoogle Scholar
• 24 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 Engl J Med 1989; 320 (6) 352-357
  CrossrefPubMedGoogle Scholar
• 25 Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287 (7) 324-327
  CrossrefPubMedGoogle Scholar
• 26 Prandoni P, Carnovali M, Marchiori A. Galilei investigators. Arch Intern Med 2004; 164: 1077-1083
  CrossrefPubMedGoogle Scholar
• 27 Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 2010; 137 (6) 1382-1390
  CrossrefPubMedGoogle Scholar
• 28 Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look. Thromb Haemost 2006; 96 (5) 547-552
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Anand S, Ginsberg JS, Kearon C, Gent M, Hirsh J. 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 (15) 1677-1681
  CrossrefPubMedGoogle Scholar
• 30 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 (17) 2029-2032
  CrossrefPubMedGoogle Scholar
• 31 Hull RD, Raskob GE, Rosenbloom D , et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992; 152 (8) 1589-1595
  CrossrefPubMedGoogle Scholar
• 32 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 (9) 782-798
  PubMedGoogle Scholar
• 33 Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism and deep venous thrombosis. Arch Intern Med 1988; 148 (6) 1321-1325
  CrossrefPubMedGoogle Scholar
• 34 Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151 (2) 333-337
  CrossrefPubMedGoogle Scholar
• 35 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 (4) 637-647
  PubMedGoogle Scholar
• 36 Margolis J. The kaolin clotting time; a rapid one-stage method for diagnosis of coagulation defects. J Clin Pathol 1958; 11 (5) 406-409
  CrossrefPubMedGoogle Scholar
• 37 Lippi G, Favaloro EJ. Activated partial thromboplastin time: new tricks for an old dogma. Semin Thromb Hemost 2008; 34 (7) 604-611
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 Favaloro EJ, Bonar R, Sioufi J , et al; Royal College Pathologists of Australasia Quality Assurance Program in Haematology. An international survey of current practice in the laboratory assessment of anticoagulant therapy with heparin. Pathology 2005; 37 (3) 234-238
  CrossrefPubMedGoogle Scholar
• 39 Scully MF, Decousus HA, Ellis V, Parker C, Girard P, Kakkar VV. Measurement of heparin in plasma: influence of inter-subject and circadian variability in heparin sensitivity according to method. Thromb Res 1987; 46 (3) 447-455
  CrossrefPubMedGoogle Scholar
• 40 Barton JC, Poon MC. Coagulation testing of Hickman catheter blood in patients with acute leukemia. Arch Intern Med 1986; 146 (11) 2165-2169
  CrossrefPubMedGoogle Scholar
• 41 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
  CrossrefPubMedGoogle Scholar
• 42 Cuker A, Raby A, Moffat KA, Flynn G, Crowther MA. Interlaboratory variation in heparin monitoring: Lessons from the Quality Management Program of Ontario coagulation surveys. Thromb Haemost 2010; 104 (4) 837-844
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Stepniakowski K, Egan BM. Additive effects of obesity and hypertension to limit venous volume. Am J Physiol 1995; 268 (2 Pt 2) R562-R568
  PubMedGoogle Scholar
• 44 Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost 1992; 67 (6) 639-643
  PubMedGoogle Scholar
• 45 Rapaport SI, Vermylen J, Hoylaerts M , et al. The multiple faces of the partial thromboplastin time APTT. J Thromb Haemost 2004; 2 (12) 2250-2259
  CrossrefPubMedGoogle Scholar
• 46 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 (1) 49-56
  CrossrefPubMedGoogle Scholar
• 47 Delorme MA, Inwood MJ, O'Keefe B. Sensitivity of the thrombin clotting time and activated partial thromboplastin time to low level of antithrombin III during heparin therapy. Clin Lab Haematol 1990; 12 (4) 433-436
  PubMedGoogle Scholar
• 48 Lippi G, Salvagno GL, Ippolito L, Franchini M, Favaloro EJ. Shortened activated partial thromboplastin time: causes and management. Blood Coagul Fibrinolysis 2010; 21 (5) 459-463
  CrossrefPubMedGoogle Scholar
• 49 Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood 1977; 49 (2) 171-184
  CrossrefPubMedGoogle Scholar
• 50 Hull RD, Raskob GE, Pineo GF , et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326 (15) 975-982
  CrossrefPubMedGoogle Scholar
• 51 Prandoni P, Lensing AW, Büller HR , et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339 (8791) 441-445
  CrossrefPubMedGoogle Scholar
• 52 Lindmarker P, Holmström M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72 (2) 186-190
  PubMedGoogle Scholar
• 53 Simonneau G, Sors H, Charbonnier B , et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med 1997; 337 (10) 663-669
  CrossrefPubMedGoogle Scholar
• 54 Hull RD, Raskob GE, Brant RF , et al; American-Canadian Thrombosis Study Group. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. Arch Intern Med 2000; 160 (2) 229-236
  CrossrefPubMedGoogle Scholar
• 55 Merli G, Spiro TE, Olsson CG , et al; Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134 (3) 191-202
  CrossrefPubMedGoogle Scholar
• 56 A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med 1996; 335 (11) 775-782
  CrossrefPubMedGoogle Scholar
• 57 Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 1996; 94 (5) 911-921
  CrossrefPubMedGoogle Scholar
• 58 Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet 1999; 353 (9151) 429-438
  CrossrefPubMedGoogle Scholar
• 59 Baglin T, Barrowcliffe TW, Cohen A, Greaves M ; British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133 (1) 19-34
  CrossrefPubMedGoogle Scholar
• 60 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 (5) 668-673
  PubMedGoogle Scholar
• 61 Cuker A, Ptashkin B, Konkle BA , et al. Interlaboratory agreement in the monitoring of unfractionated heparin using the anti-factor Xa-correlated activated partial thromboplastin time. J Thromb Haemost 2009; 7 (1) 80-86
  CrossrefPubMedGoogle Scholar
• 62 Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother 2011; 45 (7-8) 861-868
  CrossrefPubMedGoogle Scholar
• 63 Ansell J. Will the new target-specific oral anticoagulants improve the treatment of venous thromboembolism?. Thromb Haemost 2012; 107 (6)
  PubMedGoogle Scholar
• 64 Ware JH, Hamel MB. Pragmatic trials—guides to better patient care?. N Engl J Med 2011; 364 (18) 1685-1687
  CrossrefPubMedGoogle Scholar