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NewsletterJune 2002 Newsletter: Low-molecular-weight fragments and selectivity of Heparin
KW Tim Park, MD
Unfractionated heparin (UFH) is heterogeneous with respect to molecular size, mechanism of anticoagulant activity, and pharmacokinetic properties. Its molecular weight typically ranges from 3,000 to 30,000 Da, with a mean of about 15,000 Da, corresponding to about 45 monosaccharide chains. At the usual therapeutic concentrations, only about a third of an administered dose binds to antithrombin (AT) and this fraction is responsible for most of its anticoagulant activities. At supraclinical concentrations, both the high- and low-affinity heparin activate heparin cofactor II, augmenting the antithrombin effect. The heparin-AT complex inactivates a number of coagulation factors, including thrombin (IIa) and factors Xa, IXa, XIa, and XIIa, with IIa and Xa being the most responsive to inhibition. Whereas heparin must bind both AT and IIa for the latter's inhibition and thus heparin shorter than about 18 saccharides cannot effectively inhibit IIa, inhibition of Xa requires only a high-affinity pentasaccharide sequence of heparin binding to AT. By inactivating thrombin, heparin not only prevents fibrin formation, but also inhibits thrombin-induced activation of factor V and VIII. In addition, high-molecular-weight heparin binds platelets and increases bleeding time. Heparin also suppresses vascular smooth muscle proliferation and promotes bone loss by activating osteoclasts and inhibiting osteoblasts. Finally, by binding to platelets and platelet factor IV(PF4), heparin may lead to heparin-induced thrombocytopenia (HIT).
Low-molecular-weight heparins (LMWH) are derived from heparin by chemical or enzymatic deploymerization to yield fragments approximately one third in size. LMWHs that are currently approved for use either in the US or Europe include enoxaparin (Lovenox), nadroparin (Fraxiparin), delteparin (Fragmin), ardeparin (Normiflo), tinzaparin (Innohep), reviparin (Clivarine), and danaparoid sodium (Orgaran). Because of different ways of producing them, LMWHs are not mutually interchangeable in efficacy and each LMWH should be evaluated separately for efficacy and safety. The advantages of LMWHs over UFH are based on the former's reduced binding to proteins and cells. Because of the small size, LMWHs cannot easily bind to AT and thrombin simultaneously and their anti-thrombin activity is much less than their anti-Xa activity. PTT tends not to be affected by LMWHs. Because of reduced binding to plasma proteins, the dose-response relationship is more predictable for LMWHs than for unfractionated heparin and LMWHs may be administered on a per-weight basis without the need to monitor PTT or anti-Xa activity. Bioavailability of LMWHs is greater after subcutaneous administration than UFH. Because of reduced binding to platelets and PF4, the incidence of HIT is much reduced with LMWHs. There is also less activation of osteoclasts and less bone loss with LMWHs. LMWHs are primarily cleared by the kidneys and their half-life may be prolonged in patients with renal failure.
Because of the central role of thrombin in the pathogenesis of acute myocardial infarction (MI) and unstable angina by activation of platelets and induction of fibrin formation, various anti-thrombotic agents have been undergoing trials for efficacy and safety. Because of favorable phamacokinetics and ease of use without laboratory testing, LMWHs have been compared to UFH. To date, only trials comparing enoxaparin and UFH have shown superior results with the LMWH. All other LMWHs have not shown significantly different results from UFH. In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) trial, 3,171 patients with unstable angina or non-Q-wave MI were randomized to 1 mg/kg SC of enoxaparin q 12 h or UFH administered as an IV bolus followed by an infusion for 2 8 days. There was a 17% risk reduction in the primary end point of death, MI, or recurrent angina at 14 days with enoxaparin and 15% risk reduction at 30 days (P < 0.02 each). At 1 year, the difference in the end point remained significant. In TIMI-11B (Thrombolysis In Myocardial Infarction 11B) trial, 3,910 patients with unstable angina or non-Q-wave infarction were randomized to SC enoxaparin or IV heparin for 3+ days. Patients assigned to enxaparin then continued SC treatment at a lower dose for 43 days, while the other group received a placebo. There was a 18% relative risk reduction in the primary end point of death, MI, or urgent revascularization at 14 days (P = 0.029) and a 12% relative risk reduction at 43 days (P = 0.048). The difference in treatment duration (3 days of UFH vs 43 days of enoxaparin) bring to question the validity of comparing outcome at 14 and 43 days in this study. Finally, use of a fibrinolytic such as streptokinase and rTPA is often associated with a rise in thrombin levels, which may lead to failed reperfusion and reocclusion. LMWH has proven useful in this setting as well. In the ASSENT-3 (the ASsessment of the Safety and Efficacy of a New Thrombolytic regimen) trial, the combination of tenecteplase and enoxaparin was shown to be superior to the combination of tenecteplase and UFH and similar to the combination of tenecteplase and the glycoprotein IIb/IIIa inhibitor abciximab in reducing the composites of 30-day mortality, in-hospital infarction, or in-hospital refractory ischemia (11.4% vs 15.4%). To further refine anti-Xa selectivity, a pentasaccharide called Org31540/SR90107A has been synthesized. This pentasaccharide is analogous to the ATIII-binding sequence in heparin. The binding of Org31540/SR90107A to ATIII augments inactivation of factor Xa, but not of thrombin. The efficacy of Org31540/SR90107A depends on the central role of factor Xa in both the extrinsic and intrinsic system in generation of thrombin and fibrin. Org31540/SR90107A does not interact with platelets or PF4 and does not promote heparin-induced thrombocytopenia. Its anticoagulant effect is predictable on per-weight dosing and coagulation parameters do not need to be monitored. The efficacy of Org31540/SR90107A as an adjunct to fibrinolysis in acute MI was investigated in the PENTALYSE study. 333 patients with an acute ST-elevation MI were treated with aspirin and alteplase with either UFH or the pentasaccharide. Reocclusion of the infarct-related vessel on days 5 7 tended to be less with the pentasaccharide (0.9% vs 7.0%), though the P value did not reach significance (P = 0.065). There appeared to be fewer revascularizations performed in those treated with the pentasaccharide during a 30-day follow-up (39% vs. 51%, P=0.054). Another study comparing the pentasaccharide to enoxaparin in patients with acute non-ST-elevation MI (the PENTUA trial) is underway in Europe.
Despite the evolving applications of LMWHs and even the pentasaccharide in medical management of patients with unstable angina or acute MI, many questions remain regarding their application in cardiovascular surgical settings. For instance, would it be easier and associated with fewer complications to use LMWH instead of UFH for systemic heparinization in cardiac or vascular patients? LMWH would be administered on a per-weight basis and would not have to be accompanied by PTT or ACT monitoring. If so, what would be the appropriate dose for institution of cardiopulmonary bypass? Visentin et al. have reported using enoxaparin 3 5 mg/kg for cardiac surgery, with no ill effect on perioperative bleeding. How much can we reduce the incidence of clinically significant heparin-induced thrombocytopenia by using LMWH? Another question to be answered with increasing use of not only LMWHs, but also other antithrombotic agents such as glycoprotein IIb/IIIa inhibitors, fibrinolytics, and/or even hirudin in patients with an acute MI or unstable angina may be how to manage the coagulation in patients presenting for cardiac surgery shortly after administration of such agents. We await the results for future research.
References:
1. Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to antigoagulant therapy: heparin. A statement for healthcare professionals from the American Heart Association. Circulation 2001; 103:2994-3018
2. Turpie AGG, Antman EM. Low-molecular-weight heparins in the treatment of acute coronary syndromes. Arch Intern Med 2001; 161:1484-1490
3. Cohen M, Demers C, ?Gurfinkel EP, for the ESSENCE trial. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease: Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study group. N Engl J Med 1997; 337:447-452
4. Antman EM, McCabe CH, Gurfinkel EP, et al, for the TIMI-11B Investigators. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial. Circulation 1999; 100:1593-1601
5. The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358:605-613
6. Van de Werf F. New data in treatment of acute coronary syndromes. Am Heart J 2001; 142:S16-S21
7. Coussement PK, Bassand JP, Convens C, Vrolix M, et al. A synthetic factor Xa-inhibitor (ORG31540/SR90107A) as an adjuct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart J 2001; 22:1716-1724.
8. Visentin GP, Malik M, Cyganiak KA, Aster RH. Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin:platelet factor 4 complexes. J Lab Clin Med 1996; 128:376-383
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