Heparin Formulations

I received this question from Vicki Cardone, hematology supervisor at our own Children’s Hospital of Alabama, Birmingham, AL.

“Is the anti-Xa used to monitor both unfractionated heparin (UFH) and low molecular weight heparin (LMWH)? Are they the same thing?”

Hi, Vicki; good to hear from you. You can use the chromogenic anti-Xa heparin assay to monitor UFH, LMWH, and the synthetic pentasaccharide Fondaparinux (Arixtra). Although many of us maintain a separate standard curve for UFH and LMWH, researcher Dave McGlasson showed that one curve can be used for both. He calls this the “hybrid” curve. You must use a separate curve for Fondaparinux, however.

Mr. McGlasson modified Stago’s heparin standard set, but Aniara has a hybrid standard curve set that requires no modification. Aniara also provides a Fondaparinux curve.

UFH is a highly sulfated glycosaminoglycan polysaccharide that was isolated in 1918 and first used as an anticoagulant in 1937. It is extracted from porcine intestines (mostly) or bovine lungs, has a molecular weight of 12,000 to 15,000 Da and is at least 18 saccharides long. A specific pentasaccharide sequence within the larger molecule binds plasma antithrombin and causes a conformational change. The activated antithrombin neutralizes thrombin and factor Xa to provide anticoagulation. UFH is traditionally measured using the partial thromboplastin time (PTT) but can be more accurately measured using the chromogenic anti-Xa heparin assay. Because it has a one-hour half-life, UFH is administered intravenously. It requires daily monitoring because its dose-response varies by the individual.

LMWH is derived chemically (Enoxaparin, trade mark Lovenox) or enzymatically (Tinzaparin, trade mark Innohep) from UFH. The mean molecular weight is 5000 Da. LMWH was first approved in the US in 1992 and has replaced UFH in many applications because it can be administered by subcutaneous injection, has a predictable dose-response curve and requires laboratory monitoring only in renal disease, cancer, children or pregnancy. LMWH also binds and activates antithrombin, which when activated neutralizes Xa but not thrombin (unlike UFH). LMWH cannot be assayed using the PTT as the curve is too flat, but is easily monitored using the anti-Xa assay. The therapeutic range is 0.5 to 1.0 IU/mL when injected twice a day and 1.0 to 2.0 IU/mL when injected once a day.

Fondaparinux is a synthetic pentasaccharide that activates antithrombin. The activated antithrombin neutralizes factor Xa, and may be monitored using the anti-Xa assay but not the PTT. Fondaparinux has a longer half-life than LMWH and has comparable efficacy and safety data.

There are several direct anti-Xa oral anticoagulants under development, and one, Rivaroxaban, that has completed phase III trials. These will most likely replace the current heparin formulations within the next five years, marking the end of an era, because of their convenience, efficacy, and safety.

I hope this helps. I’m currently developing a new lecture module for Fritsma Factor called “Anticoagulant Monitoring” but meanwhile, you can get more details in chapter 46 of Rodak BF, Hematology Clinical Principles and Applications, 3rd edition.