The t1/2 of heparin in plasma depends on the dose administered. When doses of 100, 400, or 800 units/kg of heparin are injected intravenously, the half-lives of the anticoagulant activities are approximately 1, 2.5, and 5 hours, respectively (see Appendix II for pharmacokinetic data). Heparin appears to be cleared and degraded primarily by the reticuloendothelial system; a small amount of undegraded heparin also appears in the urine. LMWHs and fondaparinux have longer biological half-lives than heparin, 4-6 hours and ∼17 hours, respectively. Because these smaller heparin fragments are cleared almost exclusively by the kidneys, the drugs can accumulate in patients with renal impairment, which can lead to bleeding. Both LMWH and fondaparinux are contraindicated in patients with a creatinine clearance <30 mL/min. In addition, fondaparinux is contraindicated in patients with body weight <50 kg undergoing hip fracture, hip replacement, knee replacement surgery, or abdominal surgery.
Administration and Monitoring. Full-dose heparin therapy usually is administered by continuous intravenous infusion. Treatment of venous thromboembolism is initiated with a fixed-dose bolus injection of 5000 units or with a weight-adjusted bolus, followed by 800-1600 units/hour delivered by an infusion pump. Therapy routinely is monitored by measuring the aPTT. The therapeutic range for heparin is considered to be that which is equivalent to a plasma heparin level of 0.3-0.7 units/mL, as determined with an anti-factor Xa assay (Hirsh et al., 2001). The aPTT value that corresponds to this range varies depending on the reagent and instrument used to perform the assay. An aPTT two to three times the normal mean aPTT value generally is assumed to be therapeutic; however, values in this range obtained with some aPTT assays may overestimate the amount of circulating heparin and therefore be subtherapeutic. The risk of recurrence of thromboembolism is greater in patients who do not achieve a therapeutic level of anticoagulation within the first 24 hours. Initially, the aPTT should be measured and the infusion rate adjusted every 6 hours; dose adjustments may be aided by use of nomograms; weight-based nomograms appear to outperform those that used fixed doses (Hirsh et al., 2001). Once a steady dosage schedule has been established in a stable patient, daily laboratory monitoring usually is sufficient.
Very high doses of heparin are required to prevent coagulation during cardiopulmonary bypass. The aPTT is infinitely prolonged over the dosage range used. A less sensitive coagulation test, such as the activated clotting time, is employed to monitor therapy in this situation. Because the activated clotting time can be performed in a point-of-care fashion, patients undergoing coronary angioplasty also typically have their heparin therapy monitored this way.
For therapeutic purposes, heparin also can be administered subcutaneously on a twice-daily basis. A total daily dose of ∼35,000 units administered as divided doses every 8-12 hours usually is sufficient to achieve an aPTT of twice the control value (measured midway between doses). Monitoring generally is unnecessary once a steady dosage schedule is established. For low-dose heparin therapy (to prevent DVT and thromboembolism in hospitalized medical or surgical patients), a subcutaneous dose of 5000 units is given two to three times daily. Laboratory monitoring of heparin administered in this way usually is unnecessary because low-dose regimens have negligible effects on the aPTT.
LMWH preparations include Enoxaparin (lovenox), dalteparin (fragmin), tinzaparin (innohep, others), ardeparin (normiflo), nadroparin (fraxiparine, others), and reviparin (clivarine) (the latter three are not available in the U.S. currently). These agents differ considerably in composition, and one cannot assume that two preparations that have similar anti-factor Xa activity will have equivalent anti-thrombotic effects. The more predictable pharmacokinetic properties of LMWH, however, permit administration in a fixed or weight-adjusted dosage regimen once or twice daily by subcutaneous injection.
Because LMWHs produce a relatively predictable anticoagulant response, monitoring is not done routinely. Patients with renal impairment may require monitoring with an anti-factor Xa assay because this condition may prolong the t1/2 and slow the elimination of LMWHs. Obese patients and children given LMWHs also may require monitoring. Specific dosage recommendations for various LMWH preparations may be obtained from the manufacturer's literature.
Fondaparinux (arixtra) is administered by subcutaneous injection, reaches peak plasma levels in 2 hours, and is excreted in the urine (t1/2 ∼17 h). It should not be used in patients with renal failure. Because it does not interact significantly with blood cells or plasma proteins other than antithrombin, fondaparinux can be given once a day at a fixed dose without coagulation monitoring. Fondaparinux appears to be much less likely than heparin or LMWH to trigger the syndrome of heparin-induced thrombocytopenia (see later in the chapter). Fondaparinux is approved for thromboprophylaxis in patients undergoing hip or knee surgery or surgery for hip fracture (Buller et al., 2003) and in general medical or surgical patients. It also can be used for initial therapy in patients with pulmonary embolism or DVT.
Idraparinux, a hypermethylated version of fondaparinux, underwent phase III clinical testing. This drug has a t1/2 of80 hours and is given subcutaneously on a once-weekly basis. To overcome the lack of an antidote, a biotin moiety was added to idraparinux to generate idrabiotaparinux, which can be neutralized with intravenous avidin. Ongoing phase III clinical trials are comparing idrabiotaparinux with warfarin for treatment of pulmonary embolism or for stroke prevention in patients with atrial fibrillation. Idraparinux, idrabiotaparinus, and avidin are not available for routine clinical use.
Heparin Resistance. The dose of heparin required to produce a therapeutic aPTT varies due to differences in the concentrations of heparin-binding proteins in plasma, such as histidine-rich glycoprotein, vitronectin, and large multimers of von Willebrand factor and platelet factor 4; these proteins competitively inhibit binding of heparin to antithrombin. Some patients do not achieve a therapeutic aPTT unless very high doses of heparin (>50,000 units/day) are administered. Such patients may have "therapeutic" concentrations of heparin in plasma at the usual dose when measured using an anti-factor Xa assay. This "pseudo" heparin resistance occurs because these patients have short aPTT values prior to treatment, as a result of increased concentrations of factor VIII. Other patients may require large doses of heparin because of accelerated clearance of the drug, as may occur with massive pulmonary embolism. Patients with inherited antithrombin deficiency ordinarily have 40-60% of the usual plasma concentration of this inhibitor and respond normally to intravenous heparin. However, acquired antithrombin deficiency, where concentrations may be <25% of normal, may occur in patients with hepatic cirrhosis, nephrotic syndrome, or disseminated intravascular coagulation; large doses of heparin may not prolong the aPTT in these individuals.
Because LMWHs and fondaparinux exhibit reduced binding to plasma proteins other than antithrombin, heparin resistance rarely occurs with these agents. For this reason, routine coagulation monitoring is unnecessary. Occasional patients, particularly those with underlying cancer, develop recurrent thrombosis despite therapeutic doses of a LMWH. Anti-factor Xa assays often are subtherapeutic in these patients, and higher doses of LMWH are needed to achieve a therapeutic response.