Portal de Periódicos da CAPES

Editorial I

2002; Elsevier BV; Volume: 88; Issue: 4 Linguagem: Inglês

10.1093/bja/88.4.467

1471-6771

Julia A. M. Anderson, Evgueni L. Saenko,

Intramuscular injections and effects

Heparin was discovered at the beginning of the twentieth century by McLean (1916).1McLean J. The thromboplastic action of cephalin.Am J Physiol. 1916; 41: 250-257Crossref Google Scholar Twenty years later (1936) its chemical structure was accredited to the Swedish chemist Jorpes.2Jorpes JE. On heparin, its chemical nature and properties.Acta Med Scand. 1936; 88: 427-433Crossref Scopus (5) Google Scholar Sixty-five years on it is the most widely used anticoagulant, but are all its actions fully understood? How does it achieve pain relief when administered intravenously for the treatment of overt deep venous thrombosis? Why do some recipients develop heparin-associated thrombocytopenia, and what is the relevance of the occurrence of heparin resistance? Heparin is a negatively charged, sulphated glycosaminoglycan, composed of alternating uronic and glucuronic acid residues. Commercial preparations are isolated from porcine intestinal mucosa or bovine lung, and are heterogeneous mixtures of polysaccharide chains ranging in molecular weight from 3000 to 30 000, with a mean molecular weight of 15 000.3Hirsh J. Heparin.New Engl J Med. 1991; 324: 1565-1574Crossref PubMed Scopus (1010) Google Scholar Heparin principally exerts its anticoagulant effect by activating antithrombin (AT); the heparin-antithrombin (H-AT) complex then inactivates thrombin, activated factor X (fXa) and other activated clotting factors.4Rosenberg RD Bauer KA. The heparin-antithrombin system: a natural anticoagulant mechanism.in: Colman RW Hirsh J Marder VJ Salzman EW Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd Edn. J. B. Lippincott Co., Philadelphia, PA1994: 1373-1392Google Scholar A unique combination of disaccharide units makes up the critical pentasaccharide sequence containing the high affinity binding site for antithrombin. This sequence occurs in only about one third of heparin chains and is randomly distributed. In purified systems, heparin and low molecular weight heparin (LMWH) have been shown to have AT-independent effects on blood coagulation by the direct inhibition of the intrinsic tenase (X-ase) complex, a phospholipid membrane complex of activated factor VIII in association with activated factor IX which generates fXa.5Barrow RT Parker ET Krishnaswamy S Lollar P. Inhibition by heparin of the human blood coagulation intrinsic pathway factor X activator.J Biol Chem. 1994; 269: 26796-26800PubMed Google Scholar In plasma milieu, the AT-dependent effect predominates. The clinical effectiveness of heparin is dependent on achieving an in vitro defined anticoagulant effect, although there is considerable in vivo variation in response to a fixed dose of heparin between individuals. This is partly reflective of the pharmacokinetic limitations of heparin, caused by the binding of heparin to plasma proteins,6Young E Prins M Levine MN Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance.Thromb Haemost. 1992; 67: 639-643Crossref PubMed Scopus (223) Google Scholar in addition to the problems encountered in measuring its desired anticoagulant effect. These add to create a phenomenon known as 'heparin resistance', which should be taken into consideration to prevent the over-administration of heparin, with potential haemorrhagic consequences, particularly postoperatively and in the setting of cardiac bypass surgery. In the treatment of venous thromboembolism the phenomenon is of unclear clinical significance. In the context of venous thromboembolism, heparin resistance is defined as the need for more than 35 000 U 24 h−1 to prolong the activated partial thromboplastin time (APTT) into the therapeutic range. In contrast, during cardiac bypass procedures, the definition of heparin resistance is based on the activated clotting time (ACT), with at least one ACT less than 400 s after heparinization and/or the need for exogenous antithrombin administration. What causes heparin resistance, and which patient groups are susceptible? This question can be answered by understanding some of the limitations of unfractionated heparin. Although highly effective in the prevention and treatment of venous thromboembolism, acute coronary syndromes, and in patients undergoing surgery utilizing cardiac bypass, heparin has well described limitations categorized as 'biophysical' and 'pharmacokinetic'.6Young E Prins M Levine MN Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance.Thromb Haemost. 1992; 67: 639-643Crossref PubMed Scopus (223) Google Scholar, 7Hirsh J Warkentin TE Shaughnessy SG et al.Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring efficacy, and safety.Chest. 2001; 119: 64S-94SAbstract Full Text Full Text PDF PubMed Scopus (1243) Google Scholar, 8Hogg PJ Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy.Proc Natl Acad Sci USA. 1989; 86: 3619-3623Crossref PubMed Scopus (318) Google Scholar The biophysical limitations reflect the inability of the H-AT complex to inactivate fXa bound to platelets within prothrombinase, the phospholipid-membrane bound factor Va (fVa)-fXa complex, in addition to the resistance of fibrin-bound thrombin to inactivation by heparin.8Hogg PJ Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy.Proc Natl Acad Sci USA. 1989; 86: 3619-3623Crossref PubMed Scopus (318) Google Scholar Pharmacokinetic limitations are caused by the binding of heparin to plasma proteins including platelet factor 4 (PF4), fibrinogen, factor VIII and histidine-rich glycoprotein.6Young E Prins M Levine MN Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance.Thromb Haemost. 1992; 67: 639-643Crossref PubMed Scopus (223) Google Scholar 9Levine SP Sorenson RR Harris MA Knieriem LK. The effect of platelet factor 4 (PF4) on assays of plasma heparin.Br J Haematol. 1984; 57: 585-596Crossref PubMed Scopus (35) Google Scholar 10Cirisano FD Lee S Greenspoon JS. Apparent heparin resistance from elevated factor VIII in a patient with postoperative deep venous thrombosis. A case report.J Reprod Med. 1996; 41: 191-194PubMed Google Scholar As many heparin-binding proteins are acute-phase reactants, the phenomenon of heparin resistance is often encountered in acutely ill patients, in patients with malignancy, and during peri- or post-partum periods.11Whitfield LR Lele AS Levy G. Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin.Clin Pharmacol Ther. 1983; 34: 23-28Crossref PubMed Scopus (34) Google Scholar In addition to altered mechanisms of heparin clearance, heparin resistance has also been associated with drug-induced causes including aprotinin12Fisher AR Bailey CR. Heparin resistance after aprotinin.Lancet. 1992; 340: 1230-1231Abstract PubMed Scopus (11) Google Scholar and nitroglycerin,13Raschke R Guidry J Laufer N Peirce JC. Nitroglycerin-induced heparin resistance.Am Heart J. 1991; 121: 1849Abstract Full Text PDF PubMed Scopus (3) Google Scholar although the latter is controversial. Its association with low antithrombin levels is also a point of heated discussion in the literature; heparin therapy produces a decrease in circulating antithrombin that is independent of the initial dose, is detectable after 1 day, and peaks after 2–4 days. Cessation of therapy leads to a normalization of levels,14Marciniak E Gockerman JP. Heparin-induced decrease in circulating antithrombin III.Lancet. 1977; 2: 581-584Abstract PubMed Scopus (261) Google Scholar 15Kitchen S. Problems in laboratory monitoring of heparin dosage.Br J Haematol. 2000; 111: 397-406Crossref PubMed Scopus (53) Google Scholar but it is not clear if this reduction in AT contributes to the heparin resistance seen in patients undergoing treatment for venous thromboembolism, or in patients undergoing cardiac bypass surgery. The complexities involved in accurately assessing the anticoagulant effect of heparin in the laboratory do not simplify matters. The APTT is the most commonly used laboratory test for monitoring heparin in the UK.15Kitchen S. Problems in laboratory monitoring of heparin dosage.Br J Haematol. 2000; 111: 397-406Crossref PubMed Scopus (53) Google Scholar As a global test of the intrinsic and common pathways, the APTT is influenced by blood collection techniques including: sampling tube composition; type of anticoagulant used; and timing of sample collection in relation to therapy,15 to avoid PF4-mediated neutralization of heparin.9Levine SP Sorenson RR Harris MA Knieriem LK. The effect of platelet factor 4 (PF4) on assays of plasma heparin.Br J Haematol. 1984; 57: 585-596Crossref PubMed Scopus (35) Google Scholar APTT reagents have different levels of heparin responsiveness producing a further problem.15Kitchen S. Problems in laboratory monitoring of heparin dosage.Br J Haematol. 2000; 111: 397-406Crossref PubMed Scopus (53) Google Scholar There are a number of situations in which the APTT lies within the target range for heparin therapy whilst the heparin level is suboptimal, such as the presence of acquired and congenital clotting factor deficiencies, the presence of lupus anticoagulant, and the effect of warfarin. In contrast, the previously described conditions causing heparin resistance lead to situations where excessive doses of heparin are required to prolong the APTT into a therapeutic range. In a randomized controlled trial by Levine, 131 patients with heparin resistance were studied, and the effect of monitoring the APTT was compared to anti-Xa heparin activity. No significant difference was noted in terms of clinical outcome, but the group monitored by anti-Xa levels required significantly less heparin.16Levine MN Hirsh J Gent M. A randomised 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: 49-56Crossref PubMed Google Scholar The development of heparin resistance is therefore a clear indication for the use of the heparin assay to measure the anticoagulant effect of this drug. Modern heparin assays are based on chromogenic anti-fXa assays which measure the heparin-antithrombin inhibitory effect towards fXa. Like all biological assays, there are limitations; and results may differ depending on the technique employed and on the presence or absence of exogenous antithrombin in the sample. Although originally time-consuming, a new bedside anti-fXa monitoring test has recently been developed which permits a quicker and more accurate assessment of the true anticoagulant effect of heparin, and which may prove invaluable in the context of cardiac bypass surgery.17Frank RD Lanzmich R Floege J. Factor Xa-activated clotting time (Xa-ACT) for bedside monitoring of LMWH-anticoagulation.Thromb Haemost. 2001; (Supplement Abstract): P683Google Scholar At present, the ACT is the most commonly used laboratory test to control heparin effect on extracorporeal membranes. However, ACT results are highly dependent on the instrumentation employed, and may also vary with the presence of haemodilution and hypothermia.18Ferguson JJ. Conventional antithrombotic approaches.Am Heart J. 1996; 130: 651-657Abstract Full Text PDF Scopus (19) Google Scholar Cardiac surgery produces a unique activation of coagulation due to the presence of the cardiopulmonary bypass (CPB) circuit.19Hunt BJ Parratt RN. Haemostasis and cardiac bypass.Cont Med Educ Bull. 1999; 2: 13-16Google Scholar Whilst not yet fully elucidated, the mechanisms of activation of coagulation during CPB may involve activation of fX by the tissue factor-mediated pathway within the pericardial cavity, in addition to direct generation of fXa on the surface of monocytes by Cathepsin G, a substance released from activated monocytes.20Parratt R Hunt BJ. Direct activation of factor X by monocytes occurs during cardiopulmonary bypass.Br J Haematol. 1998; 101: 40-46Crossref PubMed Scopus (36) Google Scholar The inhibition of fXa in these situations involves the AT-dependent mechanism of action of heparin. The imbalance caused by the increased activation of fX via the extrinsic pathway relative to the generation of fXa by the intrinsic pathway may, in part, account for the reduced effect of heparin in some patients during CPB. Currently it is believed that haemostasis is maintained by the generation of fXa by the X-ase complex. The activity of this membrane complex is directly inhibited by heparin5Barrow RT Parker ET Krishnaswamy S Lollar P. Inhibition by heparin of the human blood coagulation intrinsic pathway factor X activator.J Biol Chem. 1994; 269: 26796-26800PubMed Google Scholar and may contribute to the anticoagulant effect of heparin in situations where intrinsic activation of fX plays a major role. In its turn, this suggests that the relative contribution of the intrinsic and extrinsic pathways towards fXa generation may be linked to the dosage of heparin required to achieve a desired anticoagulant effect. In general, heparin is administered at a dose of 3 mg kg−1 body weight to prevent extracorporeal clot formation, with repeated doses to maintain the ACT greater than 400 s. This heparin regime was, however, established empirically and aims to maintain levels at 3 IU ml−1,19Hunt BJ Parratt RN. Haemostasis and cardiac bypass.Cont Med Educ Bull. 1999; 2: 13-16Google Scholar so is this level of heparinization necessary? Are there any potential solutions to the problems created by heparin resistance during CPB in the foreseeable future? Considering alternative therapies, argatroban, a selective, reversible thrombin inhibitor, has been successfully used as an anticoagulant in canine models of CPB in combination with heparinized CPB circuits.21Sakai M Ohteki H Narita Y Naitoh K Natsuaki M Itoh T. Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model.Cardiovasc Surg. 1999; 7: 187-194Crossref PubMed Scopus (0) Google Scholar Another direct thrombin inhibitor, hirudin, originally derived from the salivary glands of the medicinal leech, Hirudo medicinalis, and now available in recombinant form, has been successfully used to prevent clotting within the CPB circuit in patients with heparin-induced thrombocytopenia. There are drawbacks; the antithrombotic effects still require monitoring by a whole blood assay based on the prothrombin-activating snake venom, ecarin, known as the ecarin clotting time,22Potzsch B Madlener K Seelig C Riess CF Greinacher A Muller-Berghaus G. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass—assessment of the whole blood ecarin clotting time.Thromb Haemost. 1997; 77: 920-925PubMed Google Scholar and reversibility of the drugs depends on haemodialysis. The role of these direct thrombin inhibitors, in addition to other new anti-fXa inhibitors such as inhibitors of the tissue factor pathway and Pentasaccharide (Org31540/SR90107A), and heparin-coated CPB circuits, have yet to be evaluated in terms of safety and efficacy by appropriately powered, prospective studies.23Despotis GJ Joist JH. Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update.J Cardiothorac Vasc Anesth. 1999; 13 (36-7): 18-29PubMed Google Scholar Perhaps the most promising of these drugs may be pentasaccharide, the first of a new class of highly selective fXa inhibitors. Given as a once daily subcutaneous dose, it has a pharmacokinetic profile such that the monitoring is not required. Phase II and III trials have demonstrated high efficacy compared to low molecular weight heparins in the prevention of venous thromboembolism, and preliminary results in cardiology trials have also shown great promise.24Turpie AGG. The role in cardiology of the first synthetic factor Xa inhibitor: lessons from the results of the clinical programme in venous thromboembolism.Thromb Haemost. 2001; (Supplement Abstact): SY112Google Scholar At present, heparin remains the optimal means of anticoagulation in CPB circuits, but improvements are needed in terms of practical bedside monitoring of its anticoagulant effect which, in turn, may permit a reassessment of the optimal level of ACT to achieve prior to starting the bypass circuit. There is still much to learn about heparin resistance. In the context of venous thromboembolism, is heparin resistance of any clinical relevance? What is the outcome in patients treated with empirical doses of heparin when the APTT cannot be prolonged into the therapeutic range? In the context of cardiac bypass surgery, where activation of coagulation and fibrinolysis involve as yet poorly understood mechanisms, and where postoperative bleeding complications lead to increased blood product usage and other postoperative complications, what is the optimal means of monitoring the anticoagulant and antithrombotic effect? With the recent development of delivery systems that make it possible to give heparin orally,25Weitz JI Hirsh J. New anticoagulant drugs.Chest. 2001; 119: 95S-107sAbstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar and the development of new synthetic indirect and direct fXa inhibitors, these questions become increasingly pressing.