hirudin and Anaphylaxis

Inflammatory plaques at injection sites are frequent side effects of heparin treatment and a clinical symptom of delayed-type hypersensitivity (DTH) to heparin. In most cases, changing the subcutaneous therapy from unfractionated to low-molecular-weight heparin or treatment with heparinoids does not provide improvement because of extensive cross-reactivity. Because of their completely different chemical structure, hirudins are a safe alternative for anticoagulation. Despite DTH to subcutaneously injected heparins, patients tolerate heparin intravenously. Therefore, in case of therapeutic necessity and DTH to heparins, the simple shift from subcutaneous to intravenous heparin administration is justified. Skin necrosis is a rare complication of anticoagulation. Heparin-induced skin necrosis is 1 of the symptoms of immune-mediated heparin-induced thrombocytopenia and should result in the immediate cessation of heparin therapy to prevent potentially fatal thrombotic events. This is in contrast to coumarin-induced skin necrosis, where therapy may be continued or restarted at a lower dose.

Topics: Anaphylaxis; Anticoagulants; Coumarins; Drug Eruptions; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Hypersensitivity, Delayed; Polysaccharides; Thrombin; Thrombocytopenia; Vitamin K

Allergic hypersensitivity to unfractioned or low-molecular-weight heparins is uncommon but is known, and in particular the most common form is localized dermatitis, although such cases have seldom turned into maculopapular exanthema. Since cross-reactions with other heparins are frequent, identification of therapeutic alternatives is essential.. This retrospective study included patients referred to the Department of Dermatology and Allergology at Tenon Hospital between 2000 and 2012 with suspicion of allergy to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and sensitized to at least one heparin (i.e. positive skin tests to at least one heparin). The heparins and hirudins used were tested in the forearm by means of intradermal skin tests. All patients were contacted in 2012 to establish whether they had used some form of heparin since the cutaneous allergy tests.. Nineteen patients had at least one positive skin test for heparin; 1 patient had presented anaphylactic shock, while 18 others had presented localized eczema (12) or generalized dermatitis (6). The heparin most often responsible for these adverse reactions was enoxaparin (13/19). An LMWH was responsible in most cases (18 vs. 1 with UFH). Of these 18 patients, 16 also presented positive skin tests for UFH, 9 for synthetic heparinoid and 1 for hirudin. 11/19 patients were tested for fondaparinux (a synthetic pentasaccharid) and all had negative skin tests. 5/7 patients with negative skin tests had taken fondaparinux without any visible reaction, whereas 2 who also tested negative experienced localized eruption at the injection site.. Our results underline the greater frequency of delayed hypersensitivity reactions compared with immediate reactions to heparins. Skin tests can help to identify substitution molecules. Fondaparinux might be an alternative but certain diagnosis relies on rechallenge.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Cross Reactions; Dose-Response Relationship, Immunologic; Drug Eruptions; Drug Hypersensitivity; Eczema; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparinoids; Hirudins; Humans; Male; Middle Aged; Polysaccharides; Retrospective Studies; Skin Tests; Young Adult

A patient with impaired left ventricular function was scheduled for coronary artery bypass grafting. The patient's history revealed a life-threatening allergy to fish proteins. Therefore, because of the threat of cross-reactivity to protamine, a standard anticoagulation protocol with heparin/protamine was disapproved. Instead, complete coronary artery revascularization was successfully performed off-pump using bivalirudin as the anticoagulant.

Topics: Anaphylaxis; Anticoagulants; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Drug Hypersensitivity; Heparin Antagonists; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Protamines; Recombinant Proteins

Topics: Anaphylaxis; Angina, Unstable; Antibody Formation; Anticoagulants; Cross Reactions; Drug Therapy, Combination; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

Lepirudin, a recombinant DNA derivative of hirudin, is used to prevent thromboembolic complications caused by heparin-induced thrombocytopenia type II. Anaphylactic and anaphylactoid reactions have been reported with its use in patients both with and without known previous exposure to lepirudin. We describe the case of a 57-year-old woman who received five uneventful courses of lepirudin therapy before having a severe anaphylactic reaction during administration of the intravenous bolus dose that began her sixth course. The patient experienced cardiorespiratory arrest but recovered from the reaction. The decision to administer lepirudin to a patient who has previously received it should be reached with due consideration of the risk:benefit ratio and strategies to manage risk resulting from readministration. Risk factors for an anaphylactic reaction to lepirudin may include use of an initial bolus dose, intravenous rather than subcutaneous administration, length of any single course of therapy beyond 3 days, and repeat administration of lepirudin within 100 days.

Topics: Anaphylaxis; Antibodies; Anticoagulants; Female; Heart Arrest; Hirudins; Humans; Injections, Intravenous; Middle Aged; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency; Respiratory Insufficiency; Risk Factors; Risk Management

To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy.. Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure.. No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg.. Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Female; Heparin; Hirudins; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Risk Factors; Thrombocytopenia

Topics: Anaphylaxis; Fibrinolytic Agents; Hirudins; Humans; Myocardial Ischemia; Recombinant Proteins; Time Factors

Approximately 40% of patients who receive lepirudin for 5-10 days develop antihirudin antibodies. These antibodies lead to decreased renal elimination of lepirudin, ultimately resulting in elevated activated partial thromboplastin times (aPTTs). A small percentage of patients with antihirudin antibodies develop hypersensitivity reactions to lepirudin with reexposure. Thus, patients who are reexposed to lepirudin must be monitored closely for hypersensitivity. A 45-year-old African-American woman received lepirudin for anticoagulation after being diagnosed with heparin-induced thrombocytopenia type II. She developed supratherapeutic aPTTs after 10 days of lepirudin therapy. Lepirudin was then withheld for 6 days, during which her aPTT remained supratherapeutic. After lepirudin infusion was restarted, the patient developed an anaphylactic reaction. She was treated appropriately with an antihistamine, a corticosteroid, and an anxiolytic agent. After the reaction resolved, the patient was rechallenged with lepirudin, and the anaphylactic reaction recurred.

Topics: Anaphylaxis; Anticoagulants; Female; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Thrombocytopenia

Topics: Anaphylaxis; Drug Interactions; Hirudins; Humans

Lepirudin (Refludan) is a hirudin derivative. It is a direct thrombin inhibitor obtained by recombinant technology from the medicinal leech and is approved for treatment of heparin-induced thrombocytopenia complicated by thrombosis. Because 3 cases of fatal anaphylaxis possibly associated with use of lepirudin have been reported, we initiated an investigation of putative lepirudin-associated anaphylaxis.. Aided by the manufacturer (Schering AG, Berlin, Germany), we used the lepirudin study databases to identify all patients in whom possible anaphylaxis/severe allergy was recorded from 1994 to September 2002. The 26 possible cases identified were reviewed independently by 2 investigators. After excluding patients with mild skin reactions, reactions likely caused by concomitant medications, poorly documented cases, and reactions that did not correspond temporally with lepirudin use, there remained 9 patients judged to have had severe anaphylaxis in close temporal association with lepirudin. All reactions occurred within minutes of intravenous lepirudin administration, with 4 fatal outcomes (3 acute cardiorespiratory arrests, 1 hypotension-induced myocardial infarction). In these 4 cases, a previous uneventful treatment course with lepirudin was identified (1 to 12 weeks earlier). We recorded high-titer IgG-anti-lepirudin antibodies in an additional patient with anaphylaxis. Because lepirudin has been used in approximately 35 000 patients, the risk of anaphylaxis is approximately 0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures).. Lepirudin can cause fatal anaphylaxis, particularly in patients who are treated within 3 months of a previous exposure. The overall risk/benefit assessment of lepirudin as a treatment for heparin-induced thrombocytopenia remains favorable.

Topics: Aged; Aged, 80 and over; Anaphylaxis; Anticoagulants; Cardiovascular Diseases; Databases, Factual; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Recombinant Proteins; Risk Assessment; Thrombocytopenia; Thromboembolism

We report a truck driver with severe soft tissue contusion of both legs who developed atypical heparin-induced thrombocytopenia (HIT) after a thrombosis prophylaxis with unfractionated heparin; despite a thrombosis the patient showed a systemic allergic reaction to heparin in combination with elevation of thrombocytes and positive heparin-dependent antibodies. Six days after the initial trauma deep vein thrombosis of the left lower leg was diagnosed and fasciotomy was performed, preventing an imminent compartment syndrome. Another 5 days later the patient developed exanthema of the trunk and upper extremities and urticaria on his face, as well as severe headache. His platelet count increased from 134,000/microliter to 258,000/microliter. After exclusion of other causes for these symptoms, a reaction to heparin-dependent antibodies (heparin-platelet-factor 4 complex) was demonstrated 2 days later. Thrombosis prophylaxis was changed to hirudin (Refludan) and elevation of thrombocytes to 445,000/microliter was noted. Shortly after rinsing of an intravenous line with less than 50 IE unfractionated heparin at day 36 after trauma the patient developed an anaphylactic shock, which could be managed with cortisone. We suggest that in HIT the thrombocytopenia may represent only one form of an allergic reaction to heparin. The cause of the thromboembolic event is an antigen-antibody reaction to heparin taking place on the surface of the thrombocyte. This is similar in all forms of systemic reaction to heparin application, even though the symptoms may vary. As thrombocytopenia may not be the main symptom of a heparin-induced antibody reaction--in our hospital only 5 of 10 patients with HIT--the disease should rather be named "heparin allergy". We suggest a new classification of different pattern of heparin allergy types I-IV. The new types I and II are similar to HIT types I and II. Type III is the reaction of antibodies without decrease of thrombocytes, and type IV the reaction of antibodies associated with systemic allergic symptoms.

Topics: Anaphylaxis; Antibodies; Compartment Syndromes; Drug Eruptions; Drug Hypersensitivity; Heparin; Hirudins; Humans; Leg Injuries; Male; Middle Aged; Platelet Count; Platelet Factor 4; Postoperative Complications; Soft Tissue Injuries; Thrombocytopenia; Thrombocytosis; Thrombophlebitis

Topics: Acute Disease; Adult; Anaphylaxis; Chymases; Drug Eruptions; Hirudins; Humans; Immunization; Immunoglobulin G; Injections, Intravenous; Injections, Subcutaneous; Intradermal Tests; Male; Recombinant Proteins; Serine Endopeptidases; Skin Tests; Tryptases; Urticaria

Topics: Anaphylaxis; Blood Coagulation; Hirudin Therapy; Hirudins; Humans; Hypersensitivity; Immune System Diseases