Enoxaparin: assessment of effect

Enoxaparin, like any LMWH, is derived by depolymerization of unfractionated heparin and retains UFH’s ability to activate antithrombin and thereby provide anticoagulation. Largely secondary to its smaller molecular size, enoxaparin binds less to plasma proteins, macrophages, and endothelial cells, thereby promoting a more reliable dose-response relationship and longer plasma half-life compared to UFH.

Compared to UFH, enoxaparin has lower anti-IIa activity relative to anti-Xa activity and this translates into a reduced effect on the aPTT. The increase in the aPTT observed with UFH is largely due to its anti-IIa activity. Because of its more predicable pharmacokinetics, enoxaparin is given in fixed doses for thromboprophylaxis and total body weight (TBW)-adjusted doses for full anticoagulation, typically without laboratory monitoring. However, since LMWHs are renally-cleared, their half-life is prolonged in renal insufficiency. Additionally, dose-adjustment of enoxaparin can be troublesome in severely obese patients. Based on these observations, laboratory monitoring of LMWH has been advised in such situations, particularly when weight-based regimens are used.

Anti-Xa activity monitoring by a chromogenic assay is the most widely available and the test recommended by the College of American Pathologists for this purpose. Following a therapeutic weight-based dose of enoxaparin given subcutaneously, the anti-Xa activity peaks at 4 hours and this is the advised time to conduct monitoring assays. A conservative therapeutic range for peak effect with BID dosing of enoxaparin is 0.6-1.0 IU/mL for patients being treated for venous thromboembolism. In order to avoid an increased risk of bleeding, levels of >1 IU/mL should be avoided in patients with renal insufficiency or severe obesity.

Since intravascular volume and volume of distribution does not have a linear relationship with TBW, it has been thought that weight based regimens of LMWH for obese patients may lead to overdosing. Interestingly, anti-Xa activity is not significantly increased when LMWH is given to obese patients based on TBW. Additionally, an increased rate of bleeding is not seen with weight-based regimens. However, since few studies have included patients exceeding 150 kg and BMI > 50, it is reasonable to perform anti-Xa monitoring in such patients due to the above theoretical concerns.

The clearance of LMWH is directly proportional to the creatinine clearance (CrCl). The administration of multiple therapeutic doses of enoxaparin has been shown to result in significantly elevated anti-Xa levels in subjects with CrCl under 30 mL/min. Renal insufficiency has been shown to increase the risk of major bleeding complications following therapeutic anticoagulation with LMWH. In one large study, a CrCl < 30mL/min was associated with increased incidence of major hemorrhage in patients treated with enoxaparin. Based on this, UFH should be the first choice agent for therapeutic anticoagulation for patients with CrCl under 30 mL/min. If enoxaparin must be used, anti-Xa levels should be obtained to guide therapy.

Enoxaparin and other Low-Molecular-Weight-Heparins are mainly used for treatment and prophylaxis of DVT and venous thromboembolism. The effect of these agents on standard coagulation tests will vary (minimal for enoxaparin) as will the effect of protamine neutralization, which is incomplete for enoxaparin. Monitoring is usually not required or performed. However, if monitoring is considered necessary (e.g., renal failure, extreme obesity), the anti-Xa activity level is the appropriate test for assessing the level of anticoagulation.

Compared to Unfractionated-Heparin (UFH), enoxaparin has lower anti-IIa activity relative to anti-Xa activity and this translates into a reduced effect on the aPTT. The increase in the aPTT observed with UFH is largely due to its anti-IIa activity.

The Anti-Xa activity level is the most widely available test for monitoring the effect of LMWH (enoxaparin) and this is the test recommended by the College of American Pathologists for this purpose. Following a therapeutic weight-based dose of enoxaparin given subcutaneously, the anti-Xa activity (activity of LMWH) peaks at 4 hours and this is the advised time to conduct monitoring assays. Therapeutic range for treatment of DVT is approximately 0.5-1.0 U/mL and for DVT prophylaxis is 0.1-0.3. However, there may be some variability from laboratory to laboratory and between institutions.

The clearance of LMWH is directly proportional to the creatinine clearance (CrCl). A CrCl < 30mL/min has been shown to be associated with an increased incidence of major hemorrhage in patients treated with enoxaparin. Based on this, unfractionated-Heparin should be the agent of choice for therapeutic anticoagulation in patients with CrCl under 30 mL/min. If enoxaparin (or LMWH) must be used, then anti-Xa levels should be obtained to guide therapy.