In January 2008, the US health system authorities began to receive isolated reports of hypersensibility reactions in hemodialysis patients. Symptoms included: hypotension, facial inflammation, tachycardia, hives, and nausea. Initially, enquiries were focused on filters and lines used in dialysis. However, the research carried out by the CDC (Center for Disease Control) proved that all known cases had in common the use of sodium heparin distributed by Baxter Healthcare.
Then, on February 2008, Baxter decided to withdraw all batches of its sodium heparin, as well as its HEPLOCK® (heparin lock flush) product. However, there were still reports of allergic reactions, including some fatal cases. Dialysis patients were not the only ones affected but also individuals undergoing cardiac surgery. After this, and after an accurate monitoring by the FDA (Food and Drug Administration) the fatal cases associated to the use of sodium heparin returned to the usual figures.
In Europe, batch recalls began in Germany in March 2008, after 80 patients suffered negative reactions such as respiratory failure, low blood pressure and heart shock. Late in that month, Germany’s recalls were followed by other European countries and Japan.
On March 2008, the FDA published analytic methods to detect contaminated heparin batches. They revealed a high degree of contamination in, at least, eleven countries: Australia, Canada, China, Denmark, France, Holland, Italy, Japan, New Zealand, and the United States.
The FDA’s investigation found out that Baxter and other suppliers had bought heparin for the American company SPL (Scientific Protein Laboratories). SPL in turn sourced the heparin from its Chinese factory located in Changzhou. Furthermore, it was determined that the contaminant was in the heparin material before it reached the US company. However, since the Chinese factory at Changzhou sourced its raw heparin from small suppliers, full traceability of the heparin supplies was not possible. FDA inspection at the Changzhou SPL facilities, revealed deficiencies in the procedures to remove impurities from heparin.
Figure. Timeline of the heparin crisis
By April 2008, an international group of laboratories together with the FDA and the pharmaceutical industry started working on the identification of the contaminant in heparin batches associated to adverse reactions. They concluded that the only contaminant present in the heparin batches was oversulphated condroitin sulphate (OSCS). OSCS is a semi-synthetic polymer obtained by chemical sulfonation of chondroitin sulfate, a glycosaminoglycan used for the osteoarthritis treatment.
Adverse reactions observed in patients treated with intravenously administered OSCS-spiked heparin have been explained through the interaction of the coagulation, kinin-kallikrein and complement systems.
When exposed to the negative charged surface of OSCS, factor FXII of the coagulation cascade is activated to factor XIIa. This resulted in the activation of the extrinsic coagulation pathway, activation of the kallikrein-kinin pathway (consequently forming the vasoactive bradikinin), and induction C3a and C5a production of anaphylatoxins.
Figure.. Current understanding of the biological activities associated to OSCS acute toxicity.
Consequences of the heparin crisis.
The heparin contamination crisis highlighted the need of a new characterization approach based on the molecular properties of heparin rather than on its anticoagulant activity. To this end, the use of orthogonal analytical methods have emerged as a convenient strategy for a comprehensive quality control of heparin.
In response to the contamination issue, extensive revisions of the unfractioned heparin monographs of both, the US and European Pharmacopeias, were performed.