Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity.
Patients undergoing anticoagulation with heparin or low molecular weight heparin (LMWH) require a superior antidote that possesses more selective biological actions and a better safety profile than protamine. We had previously developed 2 low molecular weight protamine (LMWP) fractions (TDSP4 and TDSP5) from thermolysin-digested protamine as potential nontoxic, heparin-neutralizing agents. In this, the second article in this series, studies focused on in vitro evaluation of heparin/LMWH-neutralizing efficacy and putative toxicity. These LMWP fractions, particularly TDSP5, were effective and fully capable of neutralizing a broad spectrum of heparin-induced anticoagulant activities (ie, aPTT, anti-Xa, and anti-IIa activities). Additionally, these LMWP fractions could neutralize the activities of commercial LMWH. As assessed by the anti-Xa assay, TDSP5 was as effective as, although less potent than, protamine in reversing the activity of Mono-Embolex (molecular weight 5000-7000) and 2 other different sizes (molecular weight of 3000 and 5000 d) of LMWH preparations. Furthermore, compared with protamine, TDSP5 exhibited a much-reduced toxicity and thus an improved safety profile, as reflected by its reduced ability to activate the complement system and cross-react with the antiprotamine antibodies, which are 2 primary indices of protamine toxicity.
Chang
L C
LC
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
Liang
J F
JF
Lee
H F
HF
Lee
L M
LM
Yang
V C
VC
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000925:Anticoagulants / Q000378:metabolism / Q000633:toxicity*; D000990:Antithrombin III / Q000378:metabolism; D001667:Binding, Competitive; D001777:Blood Coagulation / Q000187:drug effects; D003429:Cross Reactions; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000378:metabolism / Q000633:toxicity*; D006494:Heparin Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008970:Molecular Weight; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011479:Protamines / Q000737:chemistry* / Q000276:immunology; D011516:Prothrombin / Q000037:antagonists & inhibitors
D000906:Antibodies; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006494:Heparin Antagonists; D006495:Heparin, Low-Molecular-Weight; D010446:Peptide Fragments; D011479:Protamines; D000990:Antithrombin III; D011516:Prothrombin; C025337:Factor IIa; D006493:Heparin