Methods of Preparation for LMWHs and a Heparinoid

Therefore, a patient who bleeds immediately following an IV bolus of 5,000 U UFH will require the administration of 50 mg protamine. When UFH is given as an IV infusion, only heparin given during the preceding several hours needs to be included in this dose calculation, since the half-life of IV UFH is short (approximately 60 min). Therefore, a patient receiving a continuous IV infusion of 1,250 U per hour will require approximately 30 mg protamine. The neutralization of an SC dose of UFH may require a prolonged infusion of protamine. The aPTT can be used to assess the effectiveness of antiheparin therapy.

The risk of severe adverse reactions, such as hypotension and bradycardia, can be minimized by administering protamine slowly (ie, over > 1 to 3 min). Patients who have previously received protamine-containing insulin, have undergone a vasectomy, or have a known sensitivity to fish are at an increased risk to develop antiprotamine antibodies and to experience allergic reactions, including anaphylaxis. Patients who are at risk for protamine allergy can be pretreated with corticosteroids and antihistamines.

A number of other methods have been used to neutralize the effects of UFH. These include hexadimethrine, heparinase (neutralase), PF4, extracorporeal heparin-removal devices, and synthetic protamine variants. These therapies are not widely available.

LMWHs are derived from UFH by chemical or enzymatic depolymerization. The development of LMWHs for clinical use was stimulated by the following three main observations: (1) LMWHs have reduced anti-factor IIa activity relative to anti-factor Xa activity; (2) LMWHs have a more favorable benefit/risk ratio in animal studies; and (3) LMWHs have superior pharmacokinetic properties. Of these potential advantages, only the superior pharmacokinetic properties are of clear clinical importance.

LMWH fractions prepared from standard commercial-grade heparin have been shown to have a progressively lower effect on aPTT as they are reduced in molecular size, while still inhibiting activated factor X (ie, factor Xa). The aPTT activity of heparin reflects mainly its anti-factor IIa activity. The disassociation of anti-factor Xa activity from its effect on thrombin (IIa) activity (expressed as an aPTT measurement), which was described in 1976, challenged the prevailing biophysical model for the anticoagulant effect of heparin, which predicted that any heparin molecule, irrespective of chain length, would catalyze the inactivation of serine protease coagulation enzymes equally, provided that it contained the high-affinity binding site for AT.

Table 6 —Methods of Preparation for LMWHs and a Heparinoid

The explanation for the difference in anticoagulant profile between LMWHs and heparin was elucidated in subsequent studies.