An update on heparin-induced thrombocytopenia: diagnosis and management

ABSTRACT

Introduction: Heparin-induced thrombocytopenia (HIT) is a drug-mediated, prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. A subset of anti-PF4/heparin antibodies are capable of intravascular platelet activation by cross-linking Fcgamma receptor IIA leading to platelet count decrease and/or thrombosis. HIT can be potentially associated with devastating complications such as life-threatening thrombosis making it one of the most serious adverse drug reactions. Diagnosis of HIT based on clinical information is often difficult.

Area covered: This review highlights the pathophysiology of HIT, emphasizing characteristic clinical features and the role of laboratory assays in the diagnosis of HIT. In addition, a summary of current therapeutic options for patients with HIT will be provided.

Expert opinion: A combination of clinical pretest scoring system and laboratory investigation is usually necessary to diagnose HIT. If HIT is strongly suspected, all sources of heparin must be stopped and an alternative non-heparin anticoagulant should be started to prevent new thromboembolic complications. However, heparin alternative anticoagulants bear a considerable bleeding risk, especially if given to patients with thrombocytopenia due to other reasons than HIT. A better understanding of clinical and laboratory features of HIT may help developing strategies to avoid complications induced by this serious adverse reaction against heparin.     

重症医学科病人中肝素诱导的血小板减少症

肝素诱导的血小板减少症(HIT)是一种与肝素相关的严重副反应。其中Ⅱ型HIT是一种免疫介导的常发生在使用普通肝素、但较少发生在使用低分子量肝素病人中的血栓形成并发症,可见于各临床专科,但易被临床医师忽视或漏诊,特别是重症医学科危重病人普遍存在血小板减少现象且通常可由HIT外的其它病症所致,诊断较为困难。应用4T评分表有助于这类病人的确诊与治疗用药的选择。确诊HIT需实验室检查发现存在HIT抗体,而血小板功能检测与抗原检测相结合可提高诊断试验的特异性和敏感度。HIT治疗较棘手,严重者会危及生命,故临床疑诊HIT即应尽早开始替代抗凝治疗,治疗药物可选择直接凝血酶抑制剂和Xa因子抑制剂。     

Argatroban use in heparin-induced thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is a serious, life-threatening complication which occurs in 1 – 3% of patients receiving heparin. Patients with untreated HIT have an up to 50% risk of developing life- and limb-threatening thromboembolic complications. Treatment is based upon clinical suspicion, stopping heparin therapy and initiation of anticoagulation with a rapidly acting alternative non-heparin anticoagulant, such as argatroban – a hepatically excreted direct thrombin inhibitor which is effective in the treatment of HIT. Objective: To summarize the pharmacological and clinical data, and discuss the impact of argatroban in the current treatment of HIT. Methods: A literature search was performed with the aid of Pubmed and Google. Search parameters of ‘argatroban’, ‘heparin-induced thrombocytopenia’ and ‘treatment’ were input into both search engines. Conclusion: Argatroban is a safe and effective treatment for HIT. In patients taking other hepatically cleared medications, lower initial doses may have to be used to avoid over-anticoagulation.     

Coronary arterial bypass surgery with beating heart in a patient with heparin-induced thrombocytopenia: Usage of thrombin inhibitor (Lepirudin; r-hirudin)

One of the most important adverse drug reactions that physicians encounter is the life-threatening prothrombotic syndrome known as heparin-induced thrombocytopenia (HIT). In patients with a history of heparin-induced thrombocytopenia and coronary arterial disease, alternative anticoagulatory regimens are needed during cardiac surgery for prevention of thrombosis. Treatment options for such patients now generally include the use of alternative anticoagulants such as lepirudin, bivalirudin, argatroban or danaparoid. In this article, we present a case where heparin-induced thrombocytopenia was properly performed coronary arterial bypass grafting by using lepirudin. (This sentence is confusing)     

Pharmacotherapy of heparin- induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-and-limb threatening condition that is associated with the development of antibodies that activate platelets and the coagulation system in the presence of unfractionated heparin or low molecular weight heparin. The binding of antibody to heparin-PF-4 complexes can activate platelets, leading to an acute, often catastrophic, thrombotic diathesis. The most common laboratory finding is the development of thrombocytopenia 5 or more days after beginning heparin treatment, which occur in up to 1 - 5% of patients exposed to heparin, depending on type of heparin and indication for anticoagulation. The onset of thrombocytopenia can be immediate or delayed for several weeks after the exposure to heparin. Approximately 50 - 60% of patients who develop HIT manifest acute venous or arterial thrombosis and a significant percentage of these patients die or develop vascular gangrene of a limb that requires amputation. Given the severe sequelae associated with HIT, recognition and immediate medical management is essential. Treatment of a patient with HIT is complex, as there are several different anticoagulants now available which have been shown to be useful. Optimal management depends on each patient's individual clinical manifestations, as well as the need for ongoing anticoagulation therapy. No single agent or treatment approach can be considered to be 'standard practice' as very few clinical trials have been completed, compare different treatment options. The use of warfarin alone in a patient with HIT, must be avoided in order to avoid the possibility of further activating coagulation, which may hasten the development of venous limb gangrene. There are several different tests available that detect HIT antibodies and each has different sensitivity and specificity for HIT. In this review we discuss the epidemiology and natural history of HIT, risk factors associated with the development of HIT and the clinical and laboratory tests that aid in the diagnosis and treatment. Special emphasis is given to addressing the management of HIT in special populations, particularly patients with renal or liver disease, acute coronary syndromes, pregnancy, paediatrics and patients who require cardiopulmonary bypass surgery.     

Management of heparin-induced thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic adverse effect of heparin treatment. The underlying cause is the formation of highly immunogenic complexes between negatively charged heparin and positively charged platelet factor 4 (PF4). Resulting antibodies against these PF4/heparin complexes can activate platelets via the platelet FcγIIa receptor, leading to thrombin generation and thus to the paradox of a prothrombotic state despite thrombocytopenia and application of heparin. Prompt diagnosis of HIT is important in order to change treatment to prevent severe thromboembolic complications. However, this is often difficult as thrombocytopenia is frequent in hospitalized patients and the commercially available laboratory tests for HIT antibodies have a high negative predictive value but only a poor positive predictive value. This leads to overdiagnosis and overtreatment of HIT, which also bear the risk for adverse outcomes.

Areas covered: This review aims at resuming recent data on HIT, thereby focusing on the role of new anticoagulants and providing a framework for diagnosis and treatment. Furthermore, it provides some insights into the pathogenesis of this peculiar adverse drug reaction and ventures a guess at its future relevance in clinical practice.

Expert opinion: New drugs which are strongly negatively charged should be assessed for their capacity to form complexes with PF4. If they do so, they bear the risk of inducing a HIT-like immune response. The immunology of HIT is still largely unresolved. Understanding HIT might provide insights into other immune and autoimmune response mechanisms.     

直接口服抗凝药诱导的血小板减少病例报告文献分析

目的: 分析直接口服抗凝药(direct oral anticoagulants, DOACs)诱导的血小板减少的发生情况及临床特点。方法: 检索PubMed、Embase、中国知网、万方期刊论文数据库, 收集DOACs诱导的血小板减少的病例报告类文献, 并对患者信息、DOACs使用情况、合并用药、血小板计数变化情况、处理及转归等进行描述性统计分析。结果: DOACs诱导的血小板减少在国内期刊并未见报道。共收集8篇国外文献报告(9例患者)。男性7例, 女性2例; 年龄43~80岁, ≥60岁者8例。4例患者使用利伐沙班、2例患者使用阿哌沙班和3例患者使用达比加群酯后发生血小板减少。9例患者发生DOACs诱导的血小板减少的时间为用药后第3天至4个月, 血小板计数最低降至1×10⁹/L。其中3例患者存在出血倾向。经停药、对症治疗后, 9例患者血小板计数均恢复正常。8例患者关联性评价为"很可能", 1例为"肯定"。结论: 使用DOACs后出现出血倾向的患者应注意监测血小板计数的变化, 以及时发现和处理DOACs诱导的血小板减少。     

Argatroban therapy in heparin-induced thrombocytopenia

Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI; in the USA). HIT is a relatively common extreme prothrombotic condition. When HIT is reasonably suspected, an alternative anticoagulant should be promptly initiated. In historical controlled studies, argatroban reduced new thrombosis, mortality from thrombosis and the composite of death, amputation or thrombosis, without increasing bleeding. With intravenous infusion, advantages include short half-life, easy monitoring and elimination primarily by hepatobiliary (rather than renal) means. In patients undergoing PCI, argatroban with or without glycoprotein IIb/IIIa inhibition leads to high rates of procedural success with low bleeding risk. Herein we review argatroban therapy for HIT and for PCI.     

Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia

Because patients with heparin-induced thrombocytopenia (HIT) have an extremely high frequency of developing thrombosis, treatment options other than heparin are essential. Prophylaxis against thrombosis should also be considered. The current American College of Chest Physicians guidelines for the treatment of acute heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) include the use of danaparoid, lepirudin or argatroban, alone or in combination with warfarin. For documented clinical thrombosis associated with HIT, patients should be treated with a direct thrombin inhibitor at therapeutic activated partial thromboplastin time for 7 to 10 days. Warfarin should not be used during the acute phase of HIT, unless a thrombin inhibitor is being used simultaneously. Conversion to warfarin can be done when the acute phase of HIT has passed. Due to the high likelihood of cross-reactivity, the use of low molecular weight heparins in patients with HIT is not recommended. For prophylactic treatment of HIT patients, despite a lack of other indications for anticoagulation, a direct thrombin inhibitor can be initiated with a low level of anticoagulation until the thrombocytopenia resolves. This regimen is continued until laboratory evidence is provided that the HIT antibody is no longer detectable. HIT patients, in addition to needing anticoagulation to treat thrombosis, can require anticoagulation for non HIT-related events, such as for the treatment of myocardial infarction, unstable angina and long-term anticoagulation for heart valves or atrial fibrillation. For these situations, and if immediate anticoagulation is needed, the use of a direct thrombin inhibitor with switch-over to warfarin is a useful option. However, optimal dosing regimens have not been established in all cases.     

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.     

Treatment of heparin-induced thrombocytopenia in cardiovascular patients

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome associated with heparin exposure, a falling platelet count and a high risk of thrombosis. Cardiovascular patients are at increased risk of HIT due to wide use of heparin in this population. Should HIT be suspected, heparin must be avoided in most situations, and anticoagulation with an alternative anticoagulant should be instituted. Preferred agents include the direct thrombin inhibitors argatroban and lepirudin, whilst bivalirudin or desirudin (other direct thrombin inhibitors) can be used in some situations. The indirect thrombin inhibitors, danaparoid and fondaparinux, can also be considered at times. These agents and their use in cardiac patients, including patients with acute coronary syndrome, percutaneous coronary interventions, acute ST elevation myocardial infarction or cardiac surgery, will be reviewed.     

Anticoagulants: therapeutics, risks, and toxicity--special emphasis on heparin-induced thrombocytopenia (HIT)

Anticoagulants are powerful and unavoidably dangerous drugs that must be carefully selected, monitored, and evaluated. Every patient undergoing treatment is at risk of excess bleeding, since the primary purpose of this class of drugs is to decrease clotting through a variety of biochemical and pharmacological mechanisms. Under the best of circumstances, significant numbers of patients (～10%) experience toxicity on traditional warfarin oral anticoagulants. Beyond the obvious type A pharmacological toxicity, heparin products carry a seemingly paradoxical/novel risk of increased coagulopathy with limb- and life-threatening thromboembolic injuries (heparin-induced thrombocytopenia [HIT]). As a result of the great toxicity risk, many patients suffer injuries, and litigation is threatened or initiated, frequently against pharmacists and their employers. This article reviews the therapeutic use of old and novel anticoagulants, lists the types of litigation related thereto, and discusses the HIT risk associated with heparin products treatment. Litigation can result from adverse drug reactions and toxicity from anticoagulants.     

Beyond heparin and warfarin: the new generation of anticoagulants

Heparin and warfarin are widely used for the prevention and treatment of venous and arterial thromboembolism. Although effective, both agents have important limitations; for example, both drugs must be monitored, which is inconvenient for patients and for physicians. Heparin requires parenteral administration and can cause heparin-induced thrombocytopenia, an immune-mediated process that can lead to life-threatening thrombosis. Warfarin also has its limitations. Due to its slow onset of action, warfarin must be overlapped with heparin (or another rapidly acting anticoagulant) when treating patients with established thrombosis or who are at high risk for thrombosis. Warfarin dosing is variable because its activity is influenced by dietary intake of vitamin K, genetic polymorphisms in enzymes that are involved in its metabolism and numerous drug–drug interactions that promote or reduce its activity. New anticoagulants have been developed to overcome these problems. Building on a better understanding of coagulation pathways, advances in structure-based drug design and information derived from natural anticoagulants isolated from hematophagous organisms, most of the new anticoagulants target specific coagulation enzymes. Focussing on drugs that have at least completed Phase II evaluation, this article briefly reviews the coagulation pathways and its natural regulators; outlines the limitations of existing anticoagulants and identifies the opportunities for new ones; highlights the properties of selected new anticoagulants; describes the clinical trial results with these agents; and provides a perspective on their potential strengths and weaknesses.     

Heparin induced thrombocytopenia: pathogenetic, clinical, diagnostic and therapeutic aspects

Heparin induced thrombocytopenia (HIT) in addition to bleeding complications are the most serious and dangerous side effects of heparin treatment. HIT remains the most common antibody-mediated, drug-induced thrombocytopenic disorder and a leading cause of morbidity and mortality. Two types of HIT are described: Type I is a transitory, slight and asymptomatic reduction of platelet count occurring during 1-2 days of therapy. HIT type II, which has an immunologic origin, is characterized by a thrombocytopenia that generally onset after the fifth day of therapy. Despite thrombocytopenia, haemorrhagic complications are very rare and HIT type II is characterized by thromboembolic complications consisting in venous and arterial thrombosis. The aim of this paper is to review new aspects of epidemiology, pathophysiology, clinical features, diagnosis and therapy of HIT type II. There is increasing evidence that platelet factor 4 (PF4) displaced from endothelial cells, heparan sulphate or directly from the platelets, binds to heparin molecule to form an immunogenic complex. The anti-heparin/PF4 IgG immune-complexes activates platelets through binding with the Fcgamma RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia and thrombosis. Cytokines are generated during this process and inflammation could play an additional role in the pathogenesis of thromboembolic manifestations. The onset of HIT type II is independent from dosage, schedule, and route of administration of heparin. A platelet count must be carried out prior to heparin therapy. Starting from the fourth day, platelet count must be carried out daily or every two days for at least 20 days of any heparin therapy regardless of the route of the drug administration. Patients undergoing orthopaedic or cardiac surgery are at higher risk for HIT type II. The diagnosis of HIT type II should be formulated on basis of clinical criteria and confirmed by in vitro demonstration of heparin-dependent antibodies detected by functional and antigen methods. However, the introduction of sensitive ELISA tests to measure anti-heparin/PF4 antibodies has showed the immuno-conversion in an higher number of patients treated with heparin such as the incidence of anti-heparin/PF4 exceeds the incidence of the disease. If HIT type II is likely, heparin must be immediately discontinued, even in absence of certain diagnosis of HIT type II, and an alternative anticoagulant therapy must be started followed by oral dicumaroids, preferably after resolution of thrombocytopenia. Further studies are required in order to elucidate the pathogenetic mechanism of thrombosis and its relation with inflammation; on the other hand large clinical trials are needed to confirm the best therapeutic strategies for HIT Type II.     

Early-onset heparin-induced thrombocytopenia after a 165-day heparin-free interval: case report and review of the literature

Early- or abrupt-onset immune-mediated heparin-induced thrombocytopenia (HIT) is defined as HIT that occurs less than 5 days after exposure to heparin in patients who have received heparin within the previous 100 days. We identified no reports in the literature of early-onset HIT in patients who had a heparin-free interval longer than 100 days. However, we report a case of early-onset immune-mediated HIT illustrated by a positive HIT result with serotonin release and enzyme-linked immunosorbent assays, and a decrease in platelet count to less than 100 x 10(3)/mm3 with no evidence of thrombosis, approximately 165 days after the patient's last exposure to heparin. We conclude that clinicians should choose alternative forms of anticoagulation in patients with even a remote history of HIT. If clinicians are compelled to reexpose patients to heparin, they should confirm a negative HIT assay result, monitor for clinical signs of HIT, and provide appropriate treatment if HIT is suspected.     

Management of heparin-induced thrombocytopenia

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic adverse effect of heparin treatment. The underlying cause is the formation of highly immunogenic complexes between negatively charged heparin and positively charged platelet factor 4 (PF4). Resulting antibodies against these PF4/heparin complexes can activate platelets via the platelet FcγIIa receptor, leading to thrombin generation and thus to the paradox of a prothrombotic state despite thrombocytopenia and application of heparin. Prompt diagnosis of HIT is important in order to change treatment to prevent severe thromboembolic complications. However, this is often difficult as thrombocytopenia is frequent in hospitalized patients and the commercially available laboratory tests for HIT antibodies have a high negative predictive value but only a poor positive predictive value. This leads to overdiagnosis and overtreatment of HIT, which also bear the risk for adverse outcomes. AREAS COVERED: This review aims at resuming recent data on HIT, thereby focusing on the role of new anticoagulants and providing a framework for diagnosis and treatment. Furthermore, it provides some insights into the pathogenesis of this peculiar adverse drug reaction and ventures a guess at its future relevance in clinical practice. EXPERT OPINION: New drugs which are strongly negatively charged should be assessed for their capacity to form complexes with PF4. If they do so, they bear the risk of inducing a HIT-like immune response. The immunology of HIT is still largely unresolved. Understanding HIT might provide insights into other immune and autoimmune response mechanisms.     

Fondaparinux as a treatment option for heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small-scale, in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.     

1例Ⅱ型血小板减少症的药学监护并文献复习

目的 探讨低分子肝素诱导的Ⅱ型血小板减少症（HIT）患者的药学服务要点,从而为临床药师参与此类患者的临床治疗提供参考。方法 临床药师对1例急性肺栓塞使用低分子肝素钠抗凝治疗导致Ⅱ型血小板减少症的患者进行用药分析及药学监护。检索近年来国内外的相关文献,并结合本病例进行相关性评价,帮助临床医生制订治疗方案。结果 急性肺栓塞患者治疗安全有效,血小板计数等指标恢复正常。结论 临床药师应用循证医学证据,充分发挥药学专业特长,积极参与临床Ⅱ型HIT患者的治疗监护,提高药物治疗的安全有效性。     

Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin?

The recognition and management of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) has been evolving over the past several years. Although HIT is a relatively uncommon adverse event in patients receiving heparin therapy, it bears a significant risk of thrombotic events. If patients are left untreated, 50% can develop thrombosis. Several direct thrombin inhibitors have been studied as alternative anticoagulants in patients with HIT. Lepirudin and argatroban are both approved by the United States Food and Drug Administration (FDA) for the management of HIT. Lepirudin requires dosage adjustments in patients with renal insufficiency and has potential for antibody formation. Argatroban requires dosage adjustments in patients with hepatic insufficiency. Argatroban increases the international normalized ratio when coadministered with warfarin, leading to dosage difficulties when transitioning to warfarin therapy. Bivalirudin is the most recent direct thrombin inhibitor to be introduced to the market, but it is not currently FDA approved for HIT. Controversy still exists over which direct thrombin inhibitor to use, especially in acutely ill patients and in those requiring invasive or surgical procedures. Bivalirudin has a relatively short half-life and a predictable response, which makes it attractive as an anticoagulant in patients requiring invasive or surgical procedures, those who are acutely ill, or patients with both renal and hepatic insufficiency. It offers promise as an additional direct thrombin inhibitor for use in patients with HIT, but additional studies need to be performed to further define its use.     

Heparin-induced thrombocytopenia: treatment options and special considerations

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect that typically manifests several days after the start of heparin therapy, although both rapid- and delayed-onset HIT have been described. Its most serious complication is thrombosis. Although not all patients develop thrombosis, it can be life threatening. The risk of developing HIT is related to many factors, including the type of heparin product administered, route of administration, duration of therapy, patient population, and previous exposure to heparin. The diagnosis of HIT is typically based on clinical presentation, exposure to heparin, and presence of thrombocytopenia with or without thrombosis. Antigen and activation laboratory assays are available to support the diagnosis of HIT. However, because of the limited sensitivity and specificity of these assays, bedside probability scales for HIT were developed. When HIT is suspected, prompt cessation of all heparin therapy is necessary, along with initiation of alternative anticoagulant therapy. Two direct thrombin inhibitors--argatroban and lepirudin--are approved for the management of HIT in the United States, and bivalirudin is approved for use in patients with HIT who are undergoing percutaneous coronary intervention. Other agents, although not approved to manage HIT, have also been used; however, their role in therapy requires further evaluation. A comprehensive HIT management strategy involves the evaluation of numerous factors. Many patients, including those undergoing coronary artery bypass surgery, those with acute coronary syndromes, those with hepatic or renal insufficiency, and children, require special attention. Clinicians must become familiar with the available information on this serious adverse effect and its treatment so that optimum patient management strategies may be formulated.