chondroitin-sulfates and Anaphylaxis

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

In January 2008, fatal anaphylactoid reaction (AR) was found to be associated with oversulfated chondroitin sulphate (OSCS) contaminated heparin. Although attributed to bradykinin released during contact system activation by OSCS, no final evidence until now exists for a bradykinin release during incubation of contaminated heparin with human plasma. The first objective of our study was to measure and to characterize the kinetic profile of bradykinin release in human plasma incubated with OSCS and contaminated heparin. As these AR occurred mainly in the first minutes of the dialysis session, we examine the different factors likely to influence the kinin-forming capacity of OSCS: dilution of plasma, presence of an angiotensin converting enzyme inhibitor, capacity of the patient to metabolise kinins.

Topics: Aminopeptidases; Anaphylaxis; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Bradykinin; China; Chondroitin Sulfates; Dialysis; Drug Contamination; Heparin; Humans; Kinins; Sulfates

Heparin-induced anaphylactic and anaphylactoid reactions are of increasing clinical and scientific interest, particularly given the recent identification of a syndrome of heparin-induced anaphylaxis due to oversulfated chondroitin sulfate (OSCS), a contaminant in certain heparin preparations. However, heparin-induced anaphylactoid reactions also have been reported to be a consequence of immune-mediated heparin-induced thrombocytopenia (HIT).. To summarize the clinical features and pathophysiology of two distinct disorders, HIT-associated anaphylactoid reactions as well as anaphylaxis resulting from OSCS-contaminated heparin.. We review literature describing these two types of heparin-induced anaphylactic and anaphylactoid reactions, and seek potential pathophysiologic links between them.. Intravenous bolus heparin administered to patients with circulating 'HIT antibodies', usually as a result of recent heparin therapy, can produce anaphylactoid reactions, probably as a consequence of in vivo activation of platelets and, possibly, leukocytes. Affected patients often evince fever/chills, hypertension and/or acute respiratory compromise ('pseudo-pulmonary embolism'). In contrast, heparin-induced anaphylaxis is caused by activation of the contact system, with formation of vasoactive kinins (bradykinin, des-arg(9)-bradykinin). This latter syndrome has been linked in an epidemic form to administration of OSCS-contaminated heparin; these reactions feature prominent hypotension and laryngeal edema. Hemodialysis patients are at increased risk for both syndromes. There is evidence that OSCS-contaminated heparin itself increases the risk of HIT compared with non-contaminated heparin.. Two distinct syndromes of heparin-induced anaphylaxis and anaphylactoid reactions exist. These seem to share certain epidemiologic features, given that OSCS-contaminated heparin can produce anaphylaxis through contact system activation but also could increase risk of HIT and HIT-associated anaphylactoid reactions.

Topics: Anaphylaxis; Anticoagulants; Chondroitin Sulfates; Complement Activation; Drug Contamination; Heparin; Humans; Thrombocytopenia

Beginning in 2007, anaphylactoid reactions associated with unfractionated heparin (UFH) occurred and resulted in some fatalities. These reactions were reported to be linked to the complement and contact system activation induced by certain batches of UFH containing the adulterant oversulphated chondroitin sulphate (OSCS).. Drug-specific secretion of selected cytokines from peripheral blood mononuclear cells (PBMC) of patients with hypersensitivity reactions to contaminated heparin was compared with the respective in vitro cytokine pattern of individuals with or without hypersensitivity to heparin, different glycosaminoglycans or other drugs.. Study individuals (n = 13) were classified as follows: patients with hypersensitivity reactions to contaminated (OSCS) heparin (n = 3), noncontaminated heparin (n = 1) or other compounds (n = 3) and patients with ongoing heparin therapy without symptoms of intolerance (n = 2). Four healthy individuals served as controls. PBMC were incubated with six different glycosaminoglycan structures. Drug-specific intracellular interleukin (IL)-5, interferon (IFN)-γ and IL-10 production was investigated by flow cytometry, while secretion of IL-5, IL-2 and IFN-γ was analysed by enzyme-linked immunosorbent assay.. PBMC from individuals with hypersensitivity reactions to contaminated heparin secreted considerable amounts of IL-2 in vitro. There was a suggestion that ongoing heparin therapy and the Li-heparin in the vials may have an impact on the lymphocyte reactivity of PBMC.. The in vitro lymphocyte reactivity pattern of PBMC from individuals with hypersensitivity reactions to contaminated heparins was neither typical for an immune-mediated nor for a nonimmune-mediated reaction. Possible effects of heparins in the test system itself may require consideration.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Basophils; Chondroitin Sulfates; Cytokines; Drug Contamination; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Glycosaminoglycans; Heparin; Humans; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-5; Lymphocytes; Male; Middle Aged; Pilot Projects; Young Adult

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

Oversulfated chondroitin sulfate (OSCS) contaminated heparin has been associated with severe anaphylactoid reaction (AR), mainly in dialysed patients. Although attributed to bradykinin (BK) released during contact system activation by OSCS, no definitive evidence exists until now for a BK release during incubation of contaminated heparin with human plasma. In this study, we investigated the kinin forming capacity of OSCS and OSCS contaminated heparin when incubated in vitro with a pool of human plasma. At 100 microg/mL, OSCS liberates BK in a profile similar but not identical to dextran sulfate, a well known activator of the plasma contact system. The results have highlighted that the quantity of BK accumulated during contact system activation depends not only on the concentration of OSCS but also on the plasma dilution and the presence of an angiotensin converting enzyme inhibitor. We demonstrate a highly significant correlation between the concentration of OSCS present in the contaminated heparin and BK released concentration. In conclusion, for the first time, we show that OSCS contaminated heparin incubated with human plasma has the capacity to liberate BK at a concentration that could explain the role of this inflammatory peptide in the pathophysiology of AR associated with OSCS contaminated heparin.. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.

Topics: Anaphylaxis; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Bradykinin; Chondroitin Sulfates; Drug Contamination; Heparin; Humans; Plasma

Heparin-induced thrombocytopenia with thrombosis (HITT) is the most severe side effect of heparin administration. Patients with HITT may die or have permanent sequelae such as stroke or limb amputation. Contaminated heparin is associated with anaphylactic reactions and deaths by activating the contact system. It is also associated with high incidence of HIT via a yet unknown mechanism. This study showed that although oversulfated heparin byproduct induced thrombin activities in both normal and HIT patient plasmas through the contact system activation, authentic heparin induced thrombin activities only in HIT patient plasmas containing autoantibodies against protein/ heparin complex. These data suggest that the negatively charged immunoglobulin G (IgG)/platelet factor 4 (PF4)/heparin complex activate the contact system and produce thrombin in human plasma, and thrombin partially activates the platelets allowing subsequent platelet activation through IgG/Fc receptor II signaling. The newly discovered mechanism of heparin-induced thrombin activity could explain the increased incidence of HIT in patients exposed to contaminated heparin. Furthermore, the assays used in these studies would be valuable for HIT diagnosis, prevention, and treatment.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Animals; Anticoagulants; Autoantibodies; Autoimmune Diseases; CHO Cells; Chondroitin Sulfates; Cricetinae; Cricetulus; Disease Outbreaks; Drug Contamination; Enzyme Activation; Female; Heparin; Humans; Immunoglobulin G; Kallikreins; Male; Middle Aged; Platelet Activation; Platelet Factor 4; Prekallikrein; Prothrombin; Thrombin; Thrombocytopenia

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

Topics: Anaphylaxis; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Convalescence; Drug Contamination; Enzyme Activation; Heparin; Humans; Kallikreins; Kininogens; Platelet Activation; Prekallikrein; Prothrombin; Renal Dialysis; Thrombin; Thrombocytopenia

Thrombin generation is thought to be mediated predominantly by the tissue factor or ''extrinsic'' coagulation pathway. An alternate pathway to thrombin generation (the ''intrinsic'' pathway or contact system) has been observed when blood or plasma comes in contact with artificial surfaces. Here we present evidence for a new route to thrombin formation that begins with the activation of the contact system protein prekallikrein by oversulfated heparin (OS-HB). Kallikrein, instead of activated factor X, cleaves prothrombin to form thrombin. Thrombin then cleaves fibrinogen to form fibrin clots. Moreover, we show that OS-HB by-products induce kallikrein- and thrombin-like activities in normal human plasma and in human plasma devoid of coagulation factor X or downstream contact system components factor IX or factor XI. Oversulfated heparin by-product-induced thrombin generation may have had a role in the adverse reactions associated with the recent clinical use of contaminated heparin.

Topics: Anaphylaxis; Anticoagulants; Blood Coagulation; Chondroitin Sulfates; Coagulation Protein Disorders; Disease Outbreaks; Drug Contamination; Enzyme Activation; Fibrinogen; Heparin; Humans; Kallikreins; Phosphatidylethanolamines; Prekallikrein; Prothrombin; Silicon Dioxide; Thrombin

Topics: Adverse Drug Reaction Reporting Systems; Anaphylaxis; Anticoagulants; China; Chondroitin Sulfates; Drug Contamination; Drug Hypersensitivity; Heparin; Heparin, Low-Molecular-Weight; Humans; Infusions, Intravenous; Renal Dialysis; United States

Topics: Anaphylaxis; Chondroitin Sulfates; Complement Activation; Drug Contamination; Heparin; Humans; Thrombocytopenia

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

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

Results of several tests in guinea pigs performed in order to check the hypersensitivity hazard of chondroitin sulfate are reported. As per theoretical expectations, no immuno-enhancing effect leading to hypersensitivity was recorded.

Topics: Anaphylaxis; Animals; Body Weight; Chondroitin Sulfates; Dinitrochlorobenzene; Drug Hypersensitivity; Female; Guinea Pigs; Injections, Intradermal; Male; Skin