From crisis to opportunity: A perspective on the heparin crisis

Thromb Haemost 2009; 102: 854–858 Heparin is a mixture of polysaccharide chains isolated from a biological source, porcine intestinal mucosa, and is used clinically primarily as a prophylactic agent to prevent thrombosis as well as an initial treatment of established venous thrombosis (1). Heparin has enjoyed widespread use as a medicinal agent; it and insulin are, on a unit basis, the most widely used medications in the clinic. Heparin is baseline therapy in a number of situations, such as kidney dialysis and medical intervention in the case of of acute coronary events. In terms of worldwide production, most of the crude, partially-purified, heparin is produced in China; in addition, China is a major locale for purification of crude heparin to form the active pharmaceutical ingredient. In late 2007 and early 2008, clusters of serious allergic-type events were reported in patients undergoing hemodialysis who were receiving heparin (Fig. 1). The first observation was made in a paediatric patient at Children’s Hospital in St. Louis (MO, USA) in mid-November, with additional cases reported in January of 2008. These initial cases were reported to the Missouri Department of Health and Senior Services which then promptly notified the Centers for Disease Control (CDC). On January 4th, the CDC alerted the US Food and Drug Administration (FDA) of the cluster of adverse events. The set of clinical findings coupled with the notion that heparin, a major pharmaceutical agent, was involved in the onset of adverse events triggered an investigation into the root cause in the hopes of quickly averting further harm to patients. The FDA, in conjunction with Baxter Laboratories (Deerfield, Illinois, USA), first withdrew from the market specific lots of heparin on January 17th, and later, on February 28th, all heparin manufactured by the company. Concomitant with the unfolding situation in the United States, suspect heparin lots were identified first in Germany and then in a number of other countries, including Canada, the Netherlands, France, Italy, Japan, China, Australia, and New Zealand. Efforts were made to identify the source of these allergictype reactions, and these initial investigations ruled out many obvious causes, such as the presence of adventitious viral agents or the presence of greater levels of protein impurities in suspect versus non-suspect lots of material (2). Shortly thereafter, on March 5th, the FDA released screening tests, employing nuclear magnetic resonance (NMR) and capillary electrophoresis (CE), which could be used to screen heparin lots and determine whether they were acceptable for use (3). Based on initial results from the screening tests and delineation of suspect lots from those that were clean, properties of the non-heparin material present within suspect lots could be surmised (Fig. 2). First, in the CE method, based on the migration properties of the unknown material with reference to heparin, as well as its UV-absorbing properties, the contaminant was likely to be a polysaccharide which had a higher charge density than heparin. Second, based on a distinctive proton NMR signature at 2.1–2.2 ppm, the polysaccharide contaminant was suspected to contain N-acetylgalactosamine. However, complicating the interpretation and identification of a contaminant was the fact that heparin can often be co-purified with other sulfated glycosaminoglycans, such as dermatan sulfate and chondroitin sulfate, which also contain N-acetylgalactosamine (see bottom panel of Fig. 2B). Thus, there was the additional question of whether the signatures associated with suspect heparin lots measured with these tests were simply “harmless” impurities within heparin or, conversely, an agent (or agents) which could lead to the development of allergic-type responses. An additional complicating factor was that, concurrent with the spike in serious adverse events, there was a widespread outbreak of blue-ear virus among Chinese pigs. Thus, were the signatures associated with suspect heparin the result of impurities arising from a change in manufacturing or the source material or were they the result of something else? To solve this set of questions, address the root cause of the spike in serious adverse events, and provide a scientific foundation upon which quality control tests could be developed, the FDA brought together a multidisciplinary team from the agency, academia, and industry. In a matter of weeks, beginning in early March, this team identified the signatures from the screening tests as belonging to oversulfated chondroitin sulfate (OSCS) (4), a complex polysaccharide mixture in its own right which had never before been observed in heparin. Multiple lines of evidence converged to provide definitive identification of OSCS including multidimensional NMR, enzymatic digestion and HPLC

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