Oversulfated Chondroitin Sulfate and OSCS-Contaminated Heparin Cause Dose- and Route-Dependent Hemodynamic Effects in the Rat

Abstract

During 2007-2008, serious adverse events were reported following iv administration of certain batches of commercially available heparin in humans. Anaphylactoid reactions with acute hypotension were the hallmark of these cases. Subsequently, it was shown that a contaminant, oversulfated chondroitin sulfate (OSCS), was responsible for these adverse events. The present study was undertaken to further elucidate the risks related to OSCS-contaminated heparin preparations. Using an anesthetized rat hemodynamic model, marked diastolic blood pressure drops were induced with a single iv injection of a contaminated heparin (1000 IU/kg; 34% wt/wt OSCS). OSCS alone (0.8 and 20 mg/kg) or in combination (0.8-1.7 mg/kg) with uncontaminated heparin produced a similar hypotensive effect, whereas heparin spiked with 0.2 or 0.4 mg/kg OSCS produced no hemodynamic changes. In conscious rats, acute hypotensive effects were seen following single iv administration of OSCS-spiked heparin (1.7 or 3.0 mg/kg). Conversely, no hemodynamic effects were observed with same doses when administered sc. Pretreatment with a bradykinin-2 receptor antagonist (HOE140) fully abolished the hypotensive response after iv OSCS (1.7 mg/kg) administration, whereas pretreatment with the histamine (H1) receptor antagonist cetirizine did not. In vitro, OSCS (25 and 250 μg/ml) induced a robust, dose-related increase in kallikrein activity in rat and human plasma with a lower amplitude of response in dog and pig. The data suggest that the adverse events associated with OSCS-contaminated heparin are dependent upon the concentration of contaminant and its route of administration. Furthermore, the kallikrein-kinin system plays a pivotal role in the initiation of OSCS-related vascular effects.

Heparin Mimetics: Their Therapeutic Potential

“…It is likely that route of delivery, and the dose of the contaminated heparin delivered were factors contributing to the severity of the adverse events. These conclusions are supported by a rat study in which the hypotensive effects experienced by patients could be replicated in rats by intravenous delivery of OSCS-contaminated heparin, whereas subcutaneous administration was not effective, moreover, the hypotensive effect was dependent upon the concentration of the contaminating OSCS [ 147 ].…”

“…Rather kallikrein induced by FXIIa appeared to be the key initiating factor [ 145 ]. When screening for contact system activation and high kallikrein activities the choice of plasma is important as animal plasmas have been reported to differ according to species in their capacity to give rise to the high kallikrein activities seen with human plasma following stimulation with OSCS [ 145 , 147 ]. Curiously a veterinary drug, polysulfated glycosaminoglycan (PSGAG) marketed as Adequan ® , also an oversulfated chondroitin sulfate, is administered intramuscularly for animal (dog and horse) osteoarthritis.…”

Characterization of currently marketed heparin products: Adverse event relevant bioassays

“…Because of the symptoms and the known ability of dextran sulfate to activate the contact system [3], research quickly focused on OSCS mediated activation of the contact system as a prime biochemical mechanism to link contaminated heparin with the adverse events. In subsequent research, OSCS was found to activate the kallikrein-kinin (KK) pathway in human plasma and this pathway was proposed to cause the production of vasoactive mediators such as bradykinin (BK) and the anaphylatoxins C3a and C5a in a factor XIIa (FXIIa) dependent manner [4][5][6][7][8]. Consistent with this hypothesis, OSCS alone and OSCS contaminated heparin induced hypotension in swine or rat blood pressure models [4,5,7].…”

“…For the BK pathway, Adam et al showed a direct dose response relationship between OSCS and BK production in plasma [6]. Subsequently, McKee et al and Corbier et al showed in rat models that OSCS induced hypotension was fully abolished by pretreatment with a specific BK-receptor 2 antagonist [4,7] and that OSCS induced KK activity in rat plasma [4]. For C5a, Kishimoto et al showed significant C5a production with OSCS contaminated heparin via a FXIIa-dependent mechanism in human plasma [5].…”

“…In subsequent research, OSCS was found to activate the kallikrein-kinin (KK) pathway in human plasma and this pathway was proposed to cause the production of vasoactive mediators such as bradykinin (BK) and the anaphylatoxins C3a and C5a in a factor XIIa (FXIIa) dependent manner [4][5][6][7][8]. Consistent with this hypothesis, OSCS alone and OSCS contaminated heparin induced hypotension in swine or rat blood pressure models [4,5,7]. Thus a model was proposed where OSCS facilitates the autocatalytic activation of FXII to FXIIa which in turn activates the conversion of plasma pre-KK to KK [9].…”