Increased Antithrombotic and Bleeding Effects of Contaminated Heparins; Hematological Implications

Unfractionated heparin (UFH) is widely used for hemodialysis, plasmapheresis and surgical/procedural anticoagulation. Earlier this year several batches of unfractionated heparin (UFH) were recalled due to the presence of contaminants which mediated severe adverse events and deaths in over 100 patients. One of the main contaminants is reported to be a semi-synthetic oversulfated condroitin sulfate (OSCS) of mammalian origin. While the structure and molecular characteristics of the contaminant are reported, no data on the presence of the contaminant in UFH on the antithrombotic and bleeding effects is available. The purpose of this investigation is to investigate the effects of OSCS on the relative safety and efficacy of contaminated heparin (CH) in animal models. CH represented a specific batch of recalled heparin (Baxter; lot 117050). Contaminant free UFH (CFH) preparation (Abraxis; lot 405651) was used for comparison purposes. The USP potency of both CH and CFH exhibited similar USP potency and were compared in gravimetric dosing in intravenous studies. A rat model of jugular vein clamping induced thrombosis was used for the antithrombotic studies. A rat tail transaction model was used for the bleeding studies. Ex vivo studies were carried out to measure the anticoagulant, (aPTT) and anti-Xa effects. The CH was found to contain 30% OSCS were as the CFH did not contain any OSCS. Other studies were carried out in individual groups of 12 animals at 2.0mg/kg and 5.0mg/kg IV dosages. The bleeding studies were carried out 5 minutes after each agent were as the anticoagulation studies were measured with in a 45 to 60 minutes window. All results were compiled as mean and standard deviation and analyzed in appropriate statistical programs. In the bleeding studies a lower dosage of 2mg/kg produced no differences between the CH (37.0 +/− 1.48 min.) and the CFH (35.0 +/− 5.7 min.). However in the higher dosage of 5mg/kg the CUFH (67.8 +/− 1.8 min.) produced stronger bleeding effects than the CFH (57.1 +/− 1.9 min.) In the jugular vein clamping model the CH produced stronger antithrombotic effects (6.2 +/− 1.2 clamps) in comparison to the CFH (5.2 +/− 0.25 clamps) at 2mg/kg. At the %mg/kg groups the CH produced an even stronger antithrombotic effect (7.6 +/− 0.8 clamps) in comparison to CFH (6.2 +/− 0). The ex vivo analysis showed a stronger anticoagulant effect with the CH in the aPTT assay at the higher dose. Similarly the anti-Xa activity and anti-IIa activities were higher in the CH groups. At both the 2mg/kg IV and 5mg/kg IV dosage no physiologic distress was noted. These results demonstrate that while potency adjusted the CH produced stronger anticoagulation and bleeding effects in the comparison to the CFH. Therefore the presence of the OSCS contaminant augmented the anticoagulant and bleeding efefcts of CH and may have contributed to the increased clinical bleeding observed in patients treated with these agents.