chondroitin-sulfates and Hypotension

The recent health care changes and approval of a generic low-molecular-weight heparin (LMWH) by the US Food and Drug Administration (FDA) merit a review of the facts regarding the new and generic anticoagulants. Fatal hypotension from anaphylactoid type reactions following heparin administration was responsible for more than 149 deaths all over the world. Researchers detected a heparin-like semisynthetic contaminant, over-sulfated chondroitin sulfate (OSCS), that appeared to be intentional. Low-molecular-weight heparins are produced using unfractionated heparin and OSCS has been found in various batches of LMWHs. Some newer anticoagulants are claiming to be free from the need to monitor for therapeutic effect and bleeding risk. Therefore, monitoring assays are not being developed and there is no antidote to reverse bleeding. In addition, there are concerns about reproducibility, product variation, and quality. In conclusion, although the generic LMWHs and newer anticoagulants may appear to be effective for qualified indications, their safety remains to be a concern.

Topics: Anaphylaxis; Animals; Anticoagulants; Chondroitin Sulfates; Drug Contamination; Drug-Related Side Effects and Adverse Reactions; Drugs, Generic; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hypotension; Monitoring, Physiologic; United States; United States Food and Drug Administration

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.

Topics: Anaphylaxis; Animals; Bradykinin; Chondroitin Sulfates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Contamination; Female; Heparin; Humans; Hypotension; Kallikrein-Kinin System; Male; Rats; Rats, Sprague-Dawley; Swine

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.

Topics: Animals; Anticoagulants; Chondroitin Sulfates; Drug Contamination; Heparin; Hypotension; Immunoenzyme Techniques; Kallikreins; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Sprague-Dawley; Swine

Topics: Anaphylaxis; Anticoagulants; Chondroitin Sulfates; Disease Outbreaks; Drug Contamination; Enzyme Activation; Heparin; Humans; Hypotension; Kallikreins; Platelet Activation; Prekallikrein; Prothrombin; Thrombin; Thrombocytopenia

Heparin is a commonly implemented anticoagulant used to treat critically ill patients. Recently, a number of commercial lots of heparin products were found to be contaminated with an oversulfated chondroitin sulfate (OSCS) derivative that could elicit a hypotensive response in pigs following a single high-dose infusion. Using both contaminated heparin products and the synthetically produced derivative, we showed that the OSCS produces dose-dependent hypotension in pigs. The no observed effect level (NOEL) for this contaminant appears to be approximately 1mg/kg, corresponding to a contamination level of approximately 3%. We also demonstrated that OSCS can be identified in heparin products using a simple, inexpensive, commercially available heparin enzyme immunoassay (EIA) kit that has a limit of detection of approximately 0.1%, well below the NOEL. This kit may provide a useful method to test heparin products for contamination with oversulfated GAG derivatives.

Topics: Animals; Chondroitin Sulfates; Drug Contamination; Heparin; Hypotension; Immunoenzyme Techniques; Magnetic Resonance Spectroscopy; Swine

Topics: Animals; China; Chondroitin Sulfates; Complement Activation; Complement C3a; Complement C5a; Drug Contamination; Heparin; Humans; Hypotension; Kallikreins; Kininogens

Topics: Anaphylaxis; Animals; Chondroitin Sulfates; Complement Activation; Dose-Response Relationship, Drug; Drug Contamination; Heparin; Humans; Hypotension; Injections, Intravenous; Injections, Subcutaneous; Kallikreins; Models, Animal; Rats; Swine

In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions.. Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case-control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants.. A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin.. Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.

Topics: Anticoagulants; Case-Control Studies; Chondroitin Sulfates; Disease Outbreaks; Drug Contamination; Edema; Heparin; Humans; Hypotension; Nausea; Renal Dialysis; Tachycardia; United States; Urticaria

Topics: Anaphylaxis; Animals; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Drug Contamination; Drug Recalls; Evidence-Based Medicine; Heparin; Humans; Hypotension; Risk Assessment

There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.. Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.. The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.. Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.

Topics: Anaphylaxis; Animals; China; Chondroitin Sulfates; Complement Activation; Complement C3a; Complement C5a; Drug Contamination; Drug Industry; Female; Germany; Heparin; Humans; Hypotension; Kallikreins; Middle Aged; Sus scrofa; United States; United States Food and Drug Administration