Contaminants in Heparins: Are All Facts Known?

Abstract

D espite several publications on the issues related to the chemical nature of the heparin contaminants and their mechanism of action in mediating the adverse reactions, many questions related to this problem have remained unresolved. Several groups of investigators have continued to work to provide additional information. However, certain stipulations and restricted availability of the contaminated heparins and blood plasma samples from patients who suffered from adverse effects have delayed this work. Although the heparin contaminant was identified to be oversulfated chondroitin sulfate (OSCS) with similar molecular weight profile to heparin, its biologic actions were not fully explored. Moreover, the main mechanism of action was stated to be the activation of the contact system leading to the formation of the mediators causing hemodynamic aberrations. It should be noted that the OSCS may have different origins and can be obtained from bovine, porcine, ovine, and other sources. In addition to differences in their molecular profile, the biologic actions may also be different. Because heparin is a polypharmacologic agent, it is no surprise that oversulfated glycosaminoglycans such as OSCS may also exert multiple effects on blood and plasmatic processes. In this issue of CATH, The Washington University Medical School group led by Dr L. Zhang reports on some additional observations gleaned from a careful analysis of the contaminants in heparin. They have found evidence of a new pathway of thrombin formation that begins with the activation of the contact system component kallikrein and leads directly to the cleavage of prothrombin. These authors showed that kallikrein can directly activate prothrombin into thrombin, which may lead to some of the processes such as the upregulation of nitric oxide and activation of platelets among other complicated processes. Additionally, these investigators have also provided evidence that besides OSCS, contaminated heparins also contain chemically modified heparin byproducts as an additional group of contaminants in recalled heparins. The suggestion that OSCS and oversulfated heparin byproducts can directly generate thrombin that may result in the activation of platelets resulting in thrombocytopenia responses also makes sense. That is why, an initial occurrence of HIT response was observed during the time of the contaminant crisis. The same group has recently reported on the identification of chemically sulfated/desulfated glycosaminoglycans in recalled heparin and development of a simple assay for the measurement of contaminants in heparins. Contaminated heparin was linked to over 100 reported deaths and several hundreds of adverse reactions. While the published reports indicated that carryover dermatan sulfate and OSCS originating from animal cartilage were the main contaminants, the 3 communications in this issue, along with other publications, clearly indicate that the OSCS is not the sole contaminant in heparin and other contaminants such as chemically modified heparin byproducts, and carryover heparin From the Loyola University Medical Center, Maywood, IL, USA (JW, DAH); University of Michigan Medical School, Ann Arbor, MI (ER); and University of Calgary, Alberta, Canada (RDH).