hirudin and Drug-Hypersensitivity

Heparins are widely used as anticoagulants. Immunologically-mediated side effects raise the question as to whether other substances with heparin-like pharmacological effects can be safely applied. Hypersensitivity reactions to heparin consist of heparin-induced immune thrombocytopenia, allergic vasculitis, hypereosinophilia, immediate hypersensitivity as well as delayed-type skin reactions. Hypersensitivity to unfractionated and low-molecular-weight heparins and semisynthetic heparinoids is increasingly common, and the pathogenesis, however, is still not fully understood. Clinically, this phenomenon is of relevance because of its increasing incidence and the resulting therapeutic difficulties that arise because several cross-reactions between unfractionated and low-molecular-weight heparins as well as between various heparins and heparinoids have been observed. In some patients with cross-reactivity between various heparins and semisynthetic heparinoids, recombinant hirudins, may be safe and effective. Combined allergy to recombinant hirudins and heparins, however, has been reported. Therefore, there is an urgent need for therapeutic alternatives.

Topics: Anticoagulants; Drug Hypersensitivity; Heparin, Low-Molecular-Weight; Heparinoids; Hirudins; Humans

Delayed hypersensitivity to heparins and heparinoïd is a problem for prophylaxis of thrombo embolic diseases. The hirudins did not seem to have any cross-reactivity with the two others groups of anticoagulants. We present two clinical cases of delayed type reactions to heparins and heparinoïd and we reviewed the literature about adverse reactions to low molecular weight heparins and the alternative possibilities.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dalteparin; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Enoxaparin; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Hypersensitivity, Delayed; Nadroparin; Recombinant Proteins; Skin Tests

The pathogenesis of allergic reactions to heparin is poorly understood. Clinically, this phenomenon is very relevant because of its increasing incidence and the resulting therapeutic difficulties. Since Plancherel's first description in 1952, nearly 70 cases have been reported in the literature, among which female patients dominate. Heparin causes all kind of allergic reactions from type I to type IV. The most dangerous hypersensitivity reaction is heparin-induced thrombocytopenia (HIT), which is a type II antibody-mediated reaction. Heparin is a mucopolysaccharide with strong protein binding potency, which seems to play an important pathogenetic role, as the heparin molecule adheres to unknown dermal or subcutaneous proteins. The heparin group contains a variety of structures with varying molecular weights. The allergen has yet to be identified. Several cross-reactions between high- and low-molecular weight heparins have been demonstrated as well as between heparin and heparinoids so that there may be more than one epitope of the heparin molecule with allergic potency. Allergic reactions after the use of alternate drugs such as heparinoids and hirudin also causes severe therapeutic difficulties.

Topics: Drug Hypersensitivity; Heparin; Heparinoids; Hirudins; Humans; Recombinant Proteins

REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding.. We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions.. 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002).. The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin.. Regado Biosciences Inc.

Topics: Aged; Anticoagulants; Aptamers, Nucleotide; Coagulants; Drug Hypersensitivity; Early Termination of Clinical Trials; Europe; Factor IXa; Female; Hemorrhage; Hirudins; Humans; Male; Middle Aged; North America; Oligonucleotides; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins

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

Hypersensitivity to heparin and heparin-like compounds is a rare condition that represents therapeutic challenges for patients requiring a cardiopulmonary bypass (CPB). We here report the case of a woman with a combined allergy to heparins (fractionated and unfractionated), danaparoid and fondaparinux. She underwent a mitral valve replacement under CBP using lepirudin for systemic anticoagulation. The use of lepirudin instead of unfractionated heparin (UFH) in this setting has many important implications. Lepirudin therapeutic index is narrow and so, overdosing can lead to catastrophic bleeding, whereas underdosing can result in clotting in the CPB tubing. Monitoring of lepirudin activity is essential. The usual activated clotting time monitoring is not a reliable method to monitor anticoagulation with lepirudin in the operating theater. Our experience suggests that the diluted thrombin time provides a valuable alternative during CPB.

Topics: Adult; Anticoagulants; Blood Coagulation; Cardiopulmonary Bypass; Drug Hypersensitivity; Drug Monitoring; Female; Heparin; Hirudins; Humans; Mitral Valve; Mitral Valve Insufficiency; Recombinant Proteins; Thrombin Time; Thrombosis

A 68-year-old male was admitted for implantation of an implantable cardioverter defibrillator (ICD). He had a prosthetic mechanical valve for which he was receiving anticoagulation with warfarin, but had developed an allergy to heparin. Therefore, we decided to use bivalirudin for anticoagulation, which permitted him to undergo the procedure without complications.

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Defibrillators, Implantable; Drug Hypersensitivity; Fibrinolytic Agents; Heart Valve Prosthesis; Heparin; Hirudins; Humans; Male; Mitral Valve; Peptide Fragments; Prosthesis Implantation; Recombinant Proteins; Thrombosis; Warfarin

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: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Drug Hypersensitivity; Fibrinolytic Agents; Hemorrhage; Hirudins; Humans; Risk Assessment; Syndrome; Thrombosis

Immune reactions to heparin and in particular heparin-induced thrombocytopenia are not rare and potentially fatal complications of heparin treatment. These conditions are frequently underdiagnosed in cardiac surgery. Moreover, few data are available in the literature about the use of alternative anticoagulants to heparin in this setting. We describe the successful use of bivalirudin in 2 patients with hypersensitivity to heparin who underwent cardiac surgery.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cardiac Surgical Procedures; Drug Hypersensitivity; Female; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

The standard agent used for systemic anticoagulation during cardiopulmonary bypass is heparin. Alternative methods of anticoagulation are required for patients with heparin hypersensitivity. We present the case of a patient with heparin hypersensitivity who was anticoagulated with bivalirudin during cardiopulmonary bypass for coronary artery bypass grafting. This presented unusual challenges surrounding the monitoring of anticoagulation and the method of myocardial protection.

Topics: Adult; Anticoagulants; Cardiopulmonary Bypass; Combined Modality Therapy; Coronary Artery Bypass; Coronary Stenosis; Drug Hypersensitivity; Heparin; Hirudins; Humans; Male; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Ventricular Dysfunction, Left; Ventricular Fibrillation

Heparin-induced IgE-mediated hypersensitivity and anaphylactoid reactions, although rare, can pose a serious clinical problem for patients requiring cardiopulmonary bypass (CPB). Bivalirudin is a bivalent reversible direct thrombin inhibitor, with a half-life of 25 min, eliminated mostly by proteolytic cleavage. There are some reports on the use of bivalirudin for cardiac surgery, particularly for heparin-induced thrombocytopenia (HIT), but none on cases of heparin allergy. We report a case of heparin allergy successfully managed for CPB with bivalirudin anticoagulation.

Topics: Cardiopulmonary Bypass; Drug Hypersensitivity; Heparin; Hirudins; Humans; Immunoglobulin E; Male; Middle Aged; Peptide Fragments; Recombinant Proteins

Argatroban is a synthetic thrombin inhibitor that acts independently of any cofactor. It inhibits free as well as fibrin- and clot-bound thrombin. The clinical history of two patients is presented, both with previous allergic reactions toward heparin and hirudin. In both patients, antibodies against hirudin were documented. Argatroban was successfully used in both patients without any side effects. We conclude argatroban to be the drug of choice in patients with intolerance to heparin and hirudin. Moreover, genetic variations affecting the hepatic catabolism of argatroban might exist, because very different dosages of argatroban were needed in the two patients.

Topics: Adolescent; Adult; Aged; Arginine; Contraindications; Drug Hypersensitivity; Female; Heparin; Hirudins; Humans; Middle Aged; Pipecolic Acids; Sulfonamides

Heparin is routinely used for anticoagulation during cardiopulmonary bypass; it is fast acting, is easily monitored, and has an antidote. Heparin-induced thrombocytopenia (HIT) can be a life-threatening condition requiring an alternative anticoagulant (hirudin) if cardiac surgical intervention is considered. At full anticoagulant doses, the effects of hirudin are difficult to monitor; therefore, we present a case in which off-pump coronary artery bypass grafting was performed in an HIT patient in whom the lower doses of hirudin could safely be monitored with easily available tests.

Topics: Coronary Artery Bypass, Off-Pump; Drug Hypersensitivity; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Intraoperative Care; Middle Aged; Monitoring, Intraoperative; Thrombocytopenia

Apart from bleeding complications, heparin-induced thrombocytopenia (HIT) type II is the most severe side effect of heparin therapy. It is widely agreed that its most important clinical symptom is thrombocytopenia, with or without thromboembolism.Assuming, unlike other authors, that thrombosis is the leading clinical symptom of HIT type II, we investigated the frequency of an immunological reaction indicative of HIT type II in patients suffering from thrombosis. From January 1999 to December 2000, 77% ( n=6713) of our in-patients received heparin for more than 5 days as thrombosis prophylaxis. When thrombosis was suspected on the grounds of clinical appearances, the patient concerned underwent phlebography, and two different serological tests for anti-heparin antibodies were also carried out. In such cases, patients were immediately switched to hirudin instead of heparin. In 29 out of 101 patients, the clinical suspicion of thrombosis was confirmed. Three patients developed pulmonary embolism. In 4 patients both serological tests revealed the presence of anti-heparin antibodies. Three of the remaining 72 patients with negative phlebography results were found to have antibodies on serological testing. In none of the 7 patients with a confirmed diagnosis of HIT type II was the classical sign of thrombocytopenia was present. Even with thorough clinical and phlebographic examinations, the incidence of HIT type II is only 0.13% in our institution. One of the 7 patients with thrombosis was not thrombocytopenic but did show the typical immunological reaction. Since the incidence of HIT type II is low and thrombocytopenia is not a reliable indicator for HIT II, the need for frequent thrombocyte counts (twice weekly) should be reconsidered.However,patients developing thrombosis while receiving heparin need to be treated for clinically suspected HIT type II until the final diagnosis is made.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Antibodies; Anticoagulants; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phlebography; Platelet Count; Platelet Factor 4; Pulmonary Embolism; Thrombocytopenia; Thrombophlebitis; Thrombosis

Thromboembolic disease during pregnancy has traditionally been treated with heparin. If heparin cannot be used, then treatment options remain limited. Despite the recent availability of new anticoagulation agents, data relating to their use during pregnancy is lacking. Hirudin, a relatively new anti-thrombotic agent, through animal models has been shown to have a very low transplacental transfer, thus making it a candidate drug to be used during pregnancy in case of heparin allergy. This report describes a case of heparin allergy in a pregnant patient with recurrent DVT that was successfully managed with hirudin and coumadin.

Topics: Adult; Contraindications; Drug Hypersensitivity; Female; Heparin; Hirudins; Humans; Pregnancy; Pregnancy Complications, Hematologic; Venous Thrombosis; Warfarin

Hirudin is one of the new synthetic antithrombin agents, which is most commonly used in patients with type II heparin-induced thrombocytopenia and in patients with hypersensitivity reactions to unfractionated heparin as well as low-molecular-weight heparins. Hirudin is comparable to heparin as an antithrombotic agent and also has been studied as a primary treatment in patients who experienced acute myocardial infarctions. We describe a patient with a history of type II heparin-induced thrombocytopenia who was placed on intravenous hirudin therapy. After extravasation of the intravenous hirudin site, the patient developed a delayed hypersensitivity reaction that histologically showed an epithelioid granulomatous infiltrate. Although rare reports of hypersensitivity reactions to hirudin have been published, these reactions have not been well characterized and the histopathologic changes have not been described.

Topics: Biopsy; Calcinosis; Collagen; Dermatitis, Contact; Drug Hypersensitivity; Epithelioid Cells; Fibrinolytic Agents; Granuloma; Heparin; Hirudins; Humans; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Skin; Thrombocytopenia

Topics: Anticoagulants; Cross Reactions; Dalteparin; Drug Hypersensitivity; Female; Hirudins; Humans; Hypersensitivity, Delayed; Middle Aged; Nadroparin; Recombinant Proteins; Skin Tests

Topics: Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Drug Hypersensitivity; Female; Heparin, Low-Molecular-Weight; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Hypersensitivity, Delayed; Recombinant Proteins; Skin Tests

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

The immunogenic potential of natural and recombinant hirudin was investigated using baboons. Animals received 4 intravenous hirudin injections of 1,000 antithrombin units/kg at certain times (day 1, 3, 8 and 42) and were checked for an immune response. None of the tests performed (in vitro histamine-release, ELISA for detection of humoral hirudin-specific IgG and IgM antibodies by indirect ELISA, direct skin test) revealed any kind of sensitization to hirudin. Urinary excretion of hirudin was not diminished by successive injections, if diuresis was within normal ranges. In summary, these results confirm previous observations indicating the weak antigenic potential of hirudin. Therefore, immune reactions to hirudin in man during therapeutic measures requiring several exposures to the inhibitor should not to be expected under normal circumstances.

Topics: Animals; Antibody Formation; Drug Hypersensitivity; Hirudins; Histamine Release; In Vitro Techniques; Injections, Intravenous; Male; Papio; Recombinant Proteins; Skin Tests