On February 11, 2008, the US Food and Drug Administration (FDA) issued a MedWatch Alert[1] informing physicians and dialysis center staff about safety issues related to heparin sulfate. A total of 350 adverse reactions to heparin have been reported, and there have been 4 deaths.[1] The FDA Public Advisory follows on the heels of a voluntary recall of heparin by Baxter[2] and a recent publication in MMWR.[3] The FDA stated that Baxter had suspended manufacturing of multiple-dose vials of heparin sodium until a full investigation of the root cause of the problem had been completed.[1] The chronology of events leading to this advisory are shown in Table 1 .
Heparin is used ubiquitously as an anticoagulant in patients on hemodialysis. As well, Baxter manufactures more than 50% of all heparin used in the United States. Hence, the FDA advisory could have major impact. Already, the popular press has covered this recall extensively,[4,5,6,7] and many dialysis providers are bracing themselves for the possibility of a shortage of heparin for anticoagulation in dialysis patients. The purpose of this Expert Column is to briefly review the history and biochemistry of heparin, the use of heparin as an anticoagulant in dialysis, and the nature of the allergic reactions that have been reported thus far and to discuss alternative strategies to heparin.
Heparin: A Short Primer on Its History and Biochemistry
Heparin was discovered in 1916 by Jay McLean working in association with William Henry Howell at Johns Hopkins University.[8] Howell coined the term heparin. Heparin was first tested in clinical trials in the 1930s and was approved for use in 1937. Heparin is a highly sulfated glycosaminoglycan polymer with a molecular weight that in its commercial form ranges from 12 kDa to 15 kDa.[9] It consists of a variably sulfated repeating disaccharide unit. Heparin is derived from mucosal tissues of slaughtered animals such as porcine intestine or bovine lung. Pork heparin is widely used, whereas beef heparin is no longer commercially available. The reasons for this include the greater expense of beef heparin as well as concerns that beef heparin was associated with a higher incidence of thrombocytopenia.
Heparin is a naturally occurring anticoagulant produced by basophils and mast cells. Heparin binds to the enzyme inhibitor antithrombin III (AT-III) causing a conformational change that results in its active site being exposed. The activated AT-III then inactivates thrombin and other proteases involved in blood clotting, most notably Factor Xa.[10]
Heparin as an Anticoagulant in Dialysis Patients
Anticoagulation with agents like heparin is necessary to prevent clotting of the extracorporeal system. Blood exposed to the dialysis membrane, drip chamber, or tubing causes activation of the coagulation cascade. Studies demonstrate that bio-incompatible membranes, such as cuprophane, result in greater activation of the coagulation system than the more biocompatible membranes, such as polysulfone or polyacrylonitrile.[11] Routine anticoagulation with heparin is performed by using 2 strategies: a bolus or loading dose of heparin at the initiation of dialysis (50-100 IU/kg) and/or repeated bolusing or a continuous infusion (500-1500 IU/hour).[12] Heparin use in dialysis may be associated with heparin-induced thrombocytopenia (HIT), itching, allergic reactions, and hyperkalemia.
Heparin-associated allergic reactions have been reported in the literature to both unfractionated and low molecular weight heparins,[13,14,15,16] but these reactions are quite rare. The spectrum of hypersensitivity reactions to heparin includes heparin-induced immune thrombocytopenia, delayed-type skin reactions, allergic vasculitis, hypereosinophilia, and immediate hypersensitivity.[17,18] While it was initially thought that hypersensitivity reactions to heparin correlated with the molecular weight of the heparin (ie, higher molecular weight unfractionated heparins vs low molecular weight heparins), studies show cross-reactivity with low molecular weight heparin,[19] thus limiting the ability to substitute one heparin category with the other.
Allergic Reactions to Heparin
The CDC has created a working case definition for allergy reactions to heparin.[3,20] A confirmed case of acute allergic-type reaction is defined by an episode of anaphylactic or anaphylactoid reaction characterized by angioedema (particularly swelling of lips/mouth, tongue, throat, or eyelids) or urticaria. A probable case is defined as an episode that includes at least 2 of the following signs and symptoms: (1) generalized or localized sensations of warmth; (2) numbness or tingling of the extremities; (3) difficulty swallowing; (4) shortness of breath, audible wheezing, or chest tightness; (5) low blood pressure/tachycardia; or (6) nausea or vomiting.
The CDC has reported on 65 confirmed or probable cases among 53 hemodialysis patients during November 19, 2007-January 21, 2008, at 19 dialysis facilities in 12 states.[20] An additional 36 possible cases are being investigated. Most reactions resolved after interruption of the dialysis session or treatment with diphenhydramine or steroids at the facility. The majority of cases have occurred among adults. Previous clusters of acute allergic-type reactions among hemodialysis patients have been attributed to certain types of dialyzer membranes, ethylene oxide (used as a dialyzer sterilant), angiotensin-converting enzyme inhibitors, and the reuse of dialyzers. However, a common factor among the cases being investigated was receipt of heparin (1000 units/mL) from 30-mL or 10-mL vials manufactured by Baxter. In 61 (94%) of the 65 cases, the affected patient received Baxter heparin during hemodialysis. The FDA has stated that the heparin reactions involve "bolus" doses rather than continuous infusions.[21] The FDA using its MedWatch system has a total of 350 adverse events linked to heparin, whereas in 2007 only approximately 100 adverse events were reported. Of the 350 cases, 40% of the cases are estimated as serious. Most of these events have been reported at dialysis centers, although adverse reactions in patients undergoing heart surgery or patients undergoing apheresis have also been reported. The serious adverse reactions have included breathing difficulty, nausea, vomiting, excessive sweating, and hypotension. Four people have died after receiving heparin.
The Heparin Allergy Outbreak: More Questions Than Answers
Many questions about the heparin allergy outbreak remain unanswered. Does the heparin allergy originate from a single plant reflecting a quality problem? The implicated lots of heparin appear to originate from China.[21] Since this plant has not previously been inspected by the FDA, subtle modifications in the manufacturing process or quality issues could be playing a role.[22] While Baxter has suspended multiple-dose vials of heparin because reactions are associated with these multiple dosing vials, it is unclear if heparin from single-dose vials could also be implicated. It is also possible that storage of heparin in these multiple dosing vials could be of some significance. The FDA also recommends administering heparin at the lowest possible dose and as an infusion (not a bolus) whenever possible. The reasons why these factors could be important are obscure, especially if one invokes an immunological explanation. Given the uncertainty, the FDA has recommended avoiding the use of heparin from Baxter and suggested alternative suppliers such as APP Pharmaceutical in Schaumburg.
The FDA's recommendations[1] to physicians and dialysis professionals are shown in Table 2 .
In addition, both the CDC and the FDA recommend that providers should: (1) immediately discontinue use of and segregate the recalled lots of heparin; (2) report medication reactions to MedWatch, the online FDA reporting system for adverse medication events; and (3) report to their state or local health departments any acute allergic-type reactions that have occurred since November 2007 in patients receiving hemodialysis or intravenous medication infusion.
Alternatives to heparin in dialysis treatments should be considered. (A detailed review is beyond the scope of this article.) Prostacyclin has been used as an anticoagulant,[23] although its use is likely to be impractical since experience with prostacyclin is limited and associated with adverse effects such as hypotension, flushing, headache, and gastrointestinal symptoms. The use of low molecular weight heparin could also be considered, and literature supports its use.[24,25] However, cross-reactivity with unfractionated heparin is likely to be a limitation. As well, monitoring factor Xa levels in outpatient facilities is not feasible. Moreover, low molecular weight heparin requires dose adjustment, and details on dosing in patients on dialysis is quite limited. Other direct thrombin inhibitors such as hirudin have also been used in dialysis patients and could be considered.[26,27] Recombinant hirudin has the distinct advantage that it has no immunologic cross reactions with heparin. The use of recombinant hirudin in hemodialysis patients with different degrees of residual renal functions had previously limited its use. However, evidence supports its use as an alternative to heparin if dosage adjustment for residual renal function is made and monitoring using the ecarin clotting time is performed.[28] Other strategies include citrate regional anticoagulation,[29] although its use in the outpatient setting may be quite challenging. Perhaps the most practical approach is to avoid the use of a bolus dose of heparin. Instead, priming the membrane and tubing with heparin plus the use of low-dose heparin as a continuous infusion should be pursued. Heparin-free dialysis has also been tested and has been demonstrated to be effective,[30,31] although the use of intermittent saline flushes has been questioned.[32] More recently, data from studies using heparin-coated membranes suggests a novel alternative to heparin dosing during dialysis.[33,34]
Summary
In summary, heparin allergic reactions under normal circumstances are quite rare. This current cluster of cases represents an outbreak. It is likely that the increased rate of adverse reactions reflects some problems with the manufacturing or storage process. The FDA has recommended some important preventive strategies that seem practical. More information should be forthcoming as the FDA and the CDC investigate this outbreak.
Medscape Nephrology © 2008 Medscape
Cite this: Allergy to Heparin: The FDA Public Advisory - Medscape - Mar 03, 2008.
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