Structure elucidation and biological activity of the oversulfated chondroitin sulfate contaminant in Baxter heparin.
From late December 2007 to February 2008, the number of adverse responses to heparin infusions rose noticeably above baseline levels in North America, ultimately resulting in a widespread recall of all heparin vial products made by Baxter Healthcare. Using various analytical techniques and the de novo synthesis of a fully sulfated chondroitin sulfate (FSCS) derivative, the authors have confirmed the identity of the contaminant as an oversulfated chondroitin sulfate (OSCS) and have also defined the heterogeneity and concentration of this contaminant in various lots of heparin. Using both contaminated heparin products and the synthetically produced derivative, the authors have shown that the OSCS produces a dose-dependent hypotension in both pigs and rats and that the response in rats can be abrogated with bradyzide, a rodent-selective B(2) bradykinin receptor antagonist. The no observed effect level (NOEL) for this contaminant appears to be approximately 1 mg/kg, corresponding to a contamination level in finished lots of heparin of approximately 3%. Using human plasma, the OSCS derivative was shown to activate kallikrein. These data provide insight into the etiology of the adverse events, particularly refractory hypotension, observed in patients who were exposed to heparin contaminated with OSCS.
Baxter Healthcare, 25212 W. Illinois Rt. 120, WG2-1S, Round Lake, IL 60073, USA. jeff_mckee@baxter.com
Jeff
J
McKee
Shawn
S
Bairstow
Christina
C
Szabo
Joe
J
Ray
Todd
T
Wielgos
Peifeng
P
Hu
Ed
E
Chess
Mark
M
Nordhaus
Ton
T
Hai
Jennifer
J
Campbell
Shane
S
Donovan
Nelly
N
Viseux
Norbert
N
Riedel
Jon
J
Cammack
Richard
R
Johnson
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D002809:Chondroitin Sulfates / Q000008:administration & dosage / Q000032:analysis* / Q000633:toxicity; D004340:Drug Contamination; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D007022:Hypotension / Q000139:chemically induced; D007124:Immunoenzyme Techniques; D007610:Kallikreins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D000925:Anticoagulants; D006493:Heparin; D002809:Chondroitin Sulfates; D007610:Kallikreins