Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Philip C. Comp, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2003;23(6) 

In This Article

Heparin Family of Antithrombotic Agents

Appreciation of the powerful role of natural anticoagulant molecules in the neutralization of thrombin and factor Xa activities in vivo led to the successful development of methods for the isolation of heparin from porcine and bovine lung and intestinal mucosa and application of commercially obtained unfractionated heparin as a therapeutic modality for thrombotic disease.[24]

Unfractionated heparin preparations contain molecules of widely varying sizes (3000-30,000 daltons; mean 15,000 daltons), but anticoagulant activity is limited to the relatively small proportion of molecules (approximately 30%) whose structures include the pentasaccharide sequence.[15,16] This active fraction of heparin preparations is nonselective in its ability to enhance antithrombin III-mediated inhibition of both thrombin and factor Xa, demonstrating equipotent activities in antifactor IIa (thrombin)-specific and antifactor Xa-specific assays.[25] This equipotent activity reflects the fact that chains included in the active fraction contain the pentasaccharide sequence, as well as thrombin-binding sites within their structure.

As a therapeutic agent, unfractionated heparin has a number of limitations that directly stem from the basic structure of the heparin molecule, as well as the structural heterogeneity of heparin preparations. Heparin is heavily sulfated, causing it to bind nonspecifically to various plasma and cellular proteins.[26,27,28] This contributes to heparin's unfavorable pharmacokinetic properties, including a complex clearance mechanism and a relatively short, dose-dependent half-life.[29] It also leads to reduced bioavailability[25] and, consequently, an unpredictable anticoagulant response in different individuals, which requires frequent laboratory monitoring of activated partial thromboplastin time (aPTT) to ensure adequate anticoagulation without enhanced bleeding risk.[30] Heparin's high degree of nonspecific binding is directly responsible for a number of undesirable complications that represent major drawbacks to unfractionated heparin therapy[31]; these complications include changes in platelet function that contribute to bleeding complications, heparin resistance, osteoporotic changes, and, most important, heparin-induced thrombocytopenia[26,32,33,34] ( Table 1 ). To some extent, heparin dosing according to nomogram-based guidelines introduced over the past decade has improved heparin's efficacy and safety outcomes in venous thromboembolism treatment indications, presumably by ensuring timely achievement of therapeutic aPTT levels.[35]

The possibility that heparin's decreased bioavailability and undesirable medical complications were mediated by high-affinity binding of the larger, more heavily sulfated chains in heparin preparations contributed to the rationale for the development of LMWHs as a potential alternative to therapy with unfractionated heparin.[15,36]

Commercial LMWHs are generated from unfractionated heparin by either chemical or enzymatic depolymerization and then isolated by size chromatography; the mean size of chains in LMWH preparations is approximately 5000 daltons.[31] Short chains containing the pentasaccharide sequence predominate, but longer chains that contain the pentasaccharide sequence as well as thrombin-binding structures are included in all LMWH preparations to varying degrees. Thus, LMWH, which shares the same mechanism of antithrombin III-mediated inhibition as unfractionated heparin, targets factor Xa preferentially but also exerts some antifactor IIa activity, based on the degree to which longer chains are present in different commercial LMWH preparations.

As a therapeutic agent, LMWH is rapidly absorbed into plasma and has a longer half-life relative to that of unfractionated heparin.[25] The higher bioavailability of LMWH compared with that of unfractionated heparin leads to a more predictable dose response and, therefore, a reduced need for routine laboratory monitoring of hemostatic variables; this renders LMWH relatively easy to use in clinical practice ( Table 1 ). In fact, with the exception of full-dose LMWH administration during pregnancy, no LMWH monitoring is needed nor is it readily available since hospital laboratories do not routinely perform antifactor Xa assays. Monitoring the complete blood count every 3 days is reasonable, focusing on a potential decrease in platelet count or a decrease in hematocrit level.

Theoretically, higher bioavailability would be expected to translate, clinically, into improved benefit:risk ratios, and for the most part, the clinical experience comparing LMWH with unfractionated heparin for thromboprophylaxis in patients undergoing major orthopedic surgery supports this.[1] The higher bioavailability of LMWH is a function of the smaller size and lower sulfation level of heparin chains in LMWH preparations (which reduce the potential for nonspecific binding to plasma and cellular proteins) compared with those of unfractionated heparin. As a result, LMWH has a weaker effect on platelet function[32,37] and is associated with a lowered risk of osteopenic complications[28,38,39] and a very low frequency of clinical heparin-induced thrombocytopenia[40,41,42] ( Table 1 ).

Several LMWH preparations are available for thromboprophylaxis in major orthopedic surgery indications. The LMWHs used in the United States are dalteparin and enoxaparin, whereas, in addition to these, nadroparin and tinzaparin are approved for use in Canada. Dalteparin, enoxaparin, tinzaparin, nadroparin, reviparin, and certoparin are approved for use in different parts of Europe, depending on the preparation. (Note that as of the year 2000, ardeparin, which is registered in the United States, no longer is distributed.) These agents differ in their method of preparation and in their in vitro potency with respect to relative antifactor Xa:antifactor IIa activity ratio.[25,31,43] Biologic and biochemical characterization[44] and pharmacokinetic studies in animal models[45] and in human volunteers[46,47] have demonstrated considerable structural and functional variation among the various LMWHs, leading to the conclusion that different LMWHs are not, at least preclinically, bioequivalent.[48]

The heparinoids are glycosaminoglycans that are structurally distinct from heparin in terms of their predominant repeating disaccharide unit but are mechanistically related to the heparin family of antithrombotic agents in that their activity relies, in part, on a high-affinity antithrombin III-binding fraction that selectively enhances factor Xa inactivation.[49] The prototypic heparinoid is the antithrombotic agent danaparoid.

Danaparoid has a favorable pharmacokinetic profile with a predictable dose response, has minimal effects on platelet aggregation, and is associated with an extremely low risk of heparin-induced thrombocytopenia.[32,37,49] Danaparoid is approved in the United States for venous thromboembolism prophylaxis in hip replace-ment surgery, although its more frequent application is for the treatment of heparin-induced thrombocytopenia.[50]

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