bivalirudin and Thrombocytopenia

Extracorporeal membrane oxygenation (ECMO) offers therapeutic options in refractory respiratory and/or cardiac failure. Systemic anticoagulation with heparin is routinely administered. However, in patients with heparin-induced thrombocytopenia or heparin resistance, the direct thrombin inhibitor bivalirudin is a valid option and has been increasingly used for ECMO anticoagulation. We aimed at evaluating its safety and its optimal dosing for ECMO.. Systematic web-based literature search of PubMed and EMBASE performed via National Health Service Library Evidence and manually, updated until January 30, 2016.. The search revealed 8 publications relevant to the topic (5 case reports). In total, 58 patients (24 pediatrics) were reported (18 received heparin as control groups). Bivalirudin was used with or without loading dose, followed by infusion at different ranges (lowest 0.1-0.2 mg/kg/h without loading dose; highest 0.5 mg/kg/h after loading dose). The strategies for monitoring anticoagulation and optimal targets were dissimilar (activated partial thromboplastin time 45-60 seconds to 42-88 seconds; activated clotting time 180-200 seconds to 200-220 seconds; thromboelastography in 1 study).. Bivalirudin loading dose was not always used; infusion range and anticoagulation targets were different. In this systematic review, we discuss the reasons for this variability. Larger studies are needed to establish the optimal approach with the use of bivalirudin for ECMO.

Topics: Adult; Anticoagulants; Antithrombins; Child; Extracorporeal Membrane Oxygenation; Heart Failure; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Respiratory Insufficiency; Thrombocytopenia; Thrombolytic Therapy

Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low-molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia's risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality.

Topics: Anticoagulants; Antithrombins; Arginine; Cardiopulmonary Bypass; Fondaparinux; Heparin; Hirudins; Humans; Incidence; Peptide Fragments; Percutaneous Coronary Intervention; Pipecolic Acids; Plasmapheresis; Platelet Function Tests; Platelet Transfusion; Polysaccharides; Recombinant Proteins; Risk Factors; Sulfonamides; Thrombocytopenia

Numerous GPIs are available for PCI. Although they were tested in randomized controlled trials, a comparison between the different GPI strategies is lacking. Thus, we performed a Bayesian network meta-analysis to compare different glycoprotein IIb/IIIa inhibitor (GPI) strategies with heparin and bivalirudin for percutaneous coronary intervention (PCI).. MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov were searched by two independent reviewers for randomized controlled trials comparing high-dose bolus tirofiban, abciximab, eptifibatide, heparin with provisional glycoprotein IIb/IIIa inhibitors, and bivalirudin with provisional GPI that reported clinical outcomes. Mixed treatment comparison model generation was performed to directly and indirectly compare between different anticoagulation strategies for all-cause mortality, myocardial infarction, major adverse cardiovascular events, major bleeding, minor bleeding, need for transfusion, and thrombocytopenia.. A total of 41 randomized controlled trials with 38,645 patients were included in the analysis, among which 2654 were randomized to high-dose bolus tirofiban, 6752 to abciximab, 1669 to eptifibatide, 16,500 to heparin, and 11,070 to bivalirudin. Mean age was 64±11years, 75% were male, 91% were treated with stenting, 71% with clopidogrel, and 74% for acute coronary syndrome. High-dose bolus tirofiban was associated with a significant reduction in all-cause mortality compared with heparin (OR 0.57 [credible intervals 0.37, 0.9]) and eptifibatide (OR 0.44 [credible intervals 0.19, 1.0]). GPI regimens had less myocardial infarction and major adverse cardiovascular events but greater bleeding compared with heparin and bivalirudin. There was no difference among the GPI therapies for other outcomes, including myocardial infarction, major adverse cardiovascular events, and major bleeding.. Our network meta-analysis of 38,645 patients demonstrated that GPI regimens were associated with a reduction in recurrent myocardial infarction or major adverse cardiovascular events for PCI, while bivalirudin was associated with the lowest risk of bleeding.

Topics: Aged; Anticoagulants; Bayes Theorem; Blood Transfusion; Coronary Thrombosis; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Risk Assessment; Risk Factors; Thrombocytopenia; Time Factors; Treatment Outcome

Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen.. This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 - 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD.. Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Coronary Artery Disease; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Practice Guidelines as Topic; Recombinant Proteins; Thrombocytopenia

This patient presented for emergency cardiac surgery following two episodes of thrombocytopaenia, one before and one associated with exposure to unfractionated heparin in a seven-week period of intensive care management. Although the diagnosis of heparin induced thrombocytopaenia (HIT) was uncertain on clinical grounds when assessed by current criteria, the positive antibody status directed management in accordance with the internationally recognised guidelines published by the American College of Chest Physicians (ACCP) Evidence-based Clinical Practice Guidelines. An alternative anticoagulant to unfractionated heparin was indicated for cardiopulmonary bypass. Bivalirudin was selected because of recent literature supporting its safe use.

Topics: Aged; Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Male; Peptide Fragments; Platelet Function Tests; Recombinant Proteins; Thrombocytopenia

Limitations and contraindications of heparins and oral vitamin K antagonists have led to the development of new anticoagulant drugs over the last few years. Argatroban is an intravenous direct thrombin inhibitor currently indicated for the prophylaxis and treatment of thrombosis associated with heparin-induced thrombocytopenia (HIT) and for patients at risk of HIT undergoing percutaneous coronary intervention (PCI). The role of argatroban for the treatment of acute coronary syndrome (ACS) is under evaluation.. This article reviews the potential use of argatroban for the treatment of ACS and presents the pharmacokinetic data currently available. The authors also present the pharmacodynamic literature of agratroban in addition to highlighting the safety and tolerability of the drug.. Theoretically, argatroban's pharmacokinetics makes it an attractive alternative to heparin. Pharmacological advantages of argatroban over heparin include a more-predictable anticoagulant response and the absence of a risk of HIT. Furthermore, argatroban has a fast and predictable dose-dependent anticoagulant effect with low inter-individual variability. It is non-immugenic, not susceptible to degradation by proteases and it is cleared via the liver. These characteristics confer argotroban a different profile from other anticoagulants. Agatroban is an effective alternative for patients when heparin, lepirudin and bivalirudin cannot be used. Its utility in ACS and PCI in non-HIT patients has been evaluated but further studies are warranted to define its role in this context.

Topics: Acute Coronary Syndrome; Animals; Antithrombins; Arginine; Disease Models, Animal; Drug Evaluation; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Pipecolic Acids; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Bivalirudin use for anticoagulating patients undergoing cardiac surgery, particularly those with or at risk for heparin-induced thrombocytopenia, has expanded over the past several years. The purpose of this review is to provide a summary of the following: the differences between indirect and direct thrombin inhibition, unfractionated heparin's limitations (i.e., heparin-induced thrombocytopenia), bivalirudin's pharmacology, recent cardiac surgery trials comparing bivalirudin and unfractionated heparin as anticoagulants, the growing role of bivalirudin-mediated anticoagulation for various surgical procedures, and the potential of bivalirudin-mediated vascular graft patency.. A systematic search of the English literature was performed using PubMed from the United States National Library of Medicine. Pertinent articles from 1992-2010 were obtained from this search, and their reference lists were used to retrieve additional relevant articles.. In small studies in the cardiac surgery arena, bivalirudin has demonstrated a similar safety and efficacy profile compared with unfractionated heparin. Bivalirudin's role as an anticoagulant in various cardiac surgical procedures (i.e., heart transplant) and vascular surgical procedures is growing and reviewed. Additionally, the molecular basis for the potential for bivalirudin-mediated improvement in vascular graft patency after coronary artery bypass graft procedures is discussed.. Although bivalirudin is not approved for cardiac surgery in the United States, it can be used in this setting in Canada as an anticoagulant in patients with heparin-induced thrombocytopenia provided the cardiac anesthesiologist is knowledgeable about potential complications from its use and knows how to manage or mitigate their incidence appropriately. During cardiopulmonary bypass, bivalirudin anticoagulation protocols must be thoroughly followed to attain optimal clinical outcomes. Additionally, further studies with bivalirudin are needed to determine the best monitoring modality and dosing regimen.

Topics: Antithrombins; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Vascular Patency

Heparin-induced thrombocytopenia (HIT) is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the American College of Chest Physicians, patients with HIT require parenteral anticoagulation with a direct thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. The transition to oral anticoagulation must be undertaken cautiously and only after the platelet count has recovered. Patients with a remote history of HIT can have cardiac surgery safely with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and the goal-activated coagulation time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in percutaneous coronary intervention.

Topics: Animals; Cardiac Surgical Procedures; Hematology; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

An estimated 1-3% of patients who receive therapeutic anticoagulation with unfractionated heparin (UFH) develop antibodies to heparin with concomitant development of thrombocytopenia, defined as HIT or Heparin-Induced Thrombocytopenia. HIT complicates the management of patients presenting for cardiac surgery, particularly those who need cardiopulmonary bypass (CPB) which requires a large dose of UFH. A portion of these patients will have significant thrombotic complications referred to as HITT (Heparin-induced thrombocytopenia with thrombosis). In patients with established or suspected HIT, all heparin must be withheld and an alternative form of anticoagulation utilized for CPB. Various approaches and pharmacological alternatives have been described but no regimen has replaced the routine use of UFH anticoagulation with protamine reversal after CPB. We review the use of bivalirudin as a reliable and safe alternative anticoagulation strategy during cardiopulmonary bypass with specific emphasis on patients with HIT and outlining some recent patents.

Topics: Anticoagulants; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Patents as Topic; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an important, increasingly recognized antibody-mediated complication of heparin therapy occurring in approximately 0.5-5% of patients receiving heparin for at least 5 days. HIT is a prothrombotic disorder that typically presents with a 50% platelet count drop, thrombotic event manifesting usually 5-14 days after starting heparin, or both. HIT antibodies usually decrease to negative titers/levels within 3 months. When there is clinical suspicion of HIT, heparin should be discontinued and alternative anticoagulation should be considered, as well as laboratory evaluation for HIT.. HIT immunoassay results should be used for clinical decision-making about initial anticoagulation management. Recent data reevaluate the importance of absolute titers of HIT antibodies as a risk factor for clinical occurrence. Although laboratory assays are routinely used, current data suggest that increasing optical densities are more likely associated with a positive 14C-serotonin release assay and HIT. HIT is also associated with a greater risk for adverse events, so even though alternative anticoagulation is used, clinicians should be aware of this hypercoagulable syndrome.. For patients with HIT, alternative anticoagulation is available, but for cardiovascular surgery, if the operation cannot be delayed until HIT antibodies have become negative, alternative anticoagulation strategies are recommended, although patients with HIT are at a greater risk for adverse outcomes.

Topics: Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Activation; Platelet Count; Platelet Factor 4; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) remains under-recognized despite its potentially devastating outcomes. It begins when heparin exposure stimulates the formation of heparin-platelet factor 4 antibodies, which in turn triggers the release of procoagulant platelet particles. Thrombosis and thrombocytopenia that follow comprise the 2 hallmark traits of HIT, with the former largely responsible for significant vascular complications. The prevalence of HIT varies among several subgroups, with greater incidence in surgical as compared with medical populations. HIT must be acknowledged for its intense predilection for thrombosis and suspected whenever thrombosis occurs after heparin exposure. Early recognition that incorporates the clinical and serologic clues is paramount to timely institution of treatment, as its delay may result in catastrophic outcomes. The treatment of HIT mandates an immediate cessation of all heparin exposure and the institution of an antithrombotic therapy, most commonly using a direct thrombin inhibitor. Current "diagnostic" tests, which primarily include functional and antigenic assays, have more of a confirmatory than diagnostic role in the management of HIT. Special attention must be paid to cardiac patients who are often exposed to heparin multiple times during their course of treatment. Direct thrombin inhibitors are appropriate, evidence-based alternatives to heparin in patients with a history of HIT, who need to undergo percutaneous coronary intervention. As heparin remains one of the most frequently used medications today with potential for HIT with every heparin exposure, a close vigilance of platelet counts must be practiced whenever heparin is initiated.

Topics: Anticoagulants; Antithrombins; Cardiac Surgical Procedures; Heart Diseases; Heparin; Hirudins; Humans; Immunoassay; Monitoring, Physiologic; Peptide Fragments; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a significant cause of morbidity and mortality in hospitalized patients, due to life and limb-threatening thrombosis. Prompt recognition, laboratory testing, and alternate anticoagulation are essential. At present, HIT remains an underdiagnosed and undertreated condition. This review will discuss the relative merits of the approved treatment options, as well as address additional anticoagulants that show promise for the future.. Argatroban and lepirudin are well studied and approved drugs for treatment of HIT. Both of these drugs are equal in efficacy, and differences in pharmacokinetic profiles allow the choice of drug to be tailored to the clinical scenario. Bivalirudin and fondaparinux have been used to treat HIT in small case series. New oral anticoagulants, such as factor IIa and factor Xa inhibitors, may provide a novel treatment approach in HIT.. First-line therapies for HIT are argatroban or lepirudin. Patient-specific factors determine which drug should be used, and taking advantage of their differences allows effective anticoagulation with minimal risk of bleeding. Bivalirudin and fondaparinux require further study before they can be recommended. Once proven well tolerated and effective for treating thrombosis, these new oral anticoagulants should next be studied for treating HIT.

Topics: Anticoagulants; Fibrinolytic Agents; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Polysaccharides; Recombinant Proteins; Thrombocytopenia

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax(®), The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Antithrombins; Endovascular Procedures; Hemostasis, Surgical; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Topics: Anticoagulants; Arginine; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Monitoring, Physiologic; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Count; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Safety Management; Severity of Illness Index; Sulfonamides; Survival Rate; Thrombocytopenia; Thrombosis; Time Factors

To evaluate the use of bivalirudin in patients with heparin-induced thrombocytopenia (HIT) undergoing cardiovascular surgery.. Relevant information was identified through a search of MEDLINE (1966-April 2008), International Pharmaceutical Abstracts (1960-April 2008), and Cochrane Databases (publications archived until April 2008) using the terms bivalirudin, heparin-induced thrombocytopenia, and cardiovascular surgery.. Prospective and retrospective studies, case reports, and case series in adults were eligible for inclusion if bivalirudin had been used in a patient with known HIT undergoing any cardiovascular surgical procedure other than percutaneous coronary intervention.. Two small, open-label, multicenter clinical trials were identified that evaluated treatment with bivalirudin in patients with HIT undergoing coronary artery bypass graft surgery. One looked at on-pump cardiopulmonary bypass (CPB), while the other looked at off-pump CPB. Procedural success was achieved at day 7 in 94% (n = 46) of patients in the on-pump CPB study and in 92% (n = 47) of patients in the off-pump CPB study. Dosing strategies varied between the 2 trials, with the on-pump study using a 1-mg/kg bivalirudin bolus followed by a 2.5-mg/kg/h infusion; the off-pump study used a 0.75-mg/kg bolus followed by a 1.75-mg/kg/h infusion. In addition, 10 case reports met the criteria to be included in the review and are summarized. In these cases, procedural success was reported using various bivalirudin doses in valve repair and replacement, right ventricular assist device implantation, and heart transplantation.. Growing data demonstrate procedural success with bivalirudin in patients with HIT undergoing cardiovascular surgery. However, bivalirudin dosing and goal-activated clotting times varied between the studies and case reports. Bivalirudin represents a viable alternative to heparin in patients with HIT undergoing cardiovascular surgery; however, further trials are warranted to identify optimal dosing and monitoring parameters.

Topics: Cardiovascular Surgical Procedures; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Previously, indirect thrombin inhibitors such as unfractionated heparin or low-molecular-weight heparin were used as a standard anticoagulation during percutaneous coronary intervention to prevent procedural thrombotic complications but at a risk of hemorrhagic complications. More recently, bivalirudin, a member of the direct thrombin inhibitor class, has been shown to have 1) predictable pharmacokinetics, 2) ability to inhibit free- and clot-bound thrombin, 3) no properties of platelet activation, 4) avoidance of heparin-induced thrombocytopenia, and 5) a significant reduction of bleeding without a reduction in thrombotic or ischemic endpoints compared to heparin and glycoprotein IIbIIIa inhibitors when used in patients presenting with acute coronary syndrome who are planned for an invasive treatment strategy.

Topics: Acute Coronary Syndrome; Anemia; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Blood Coagulation; Comorbidity; Coronary Thrombosis; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin exposure that can progress to severe thrombosis, amputation, or death. HIT is an immune response in which antibodies cause platelet activation, platelet aggregation, the generation of procoagulant platelet microparticles, and activation of leukocytes and endothelial cells. Early diagnosis based on a comprehensive interpretation of clinical and laboratory information is important to improve clinical outcomes. However, limitations of the laboratory assays and atypical clinical presentations can make the diagnosis difficult. Clinical management of patients with HIT is with a non-heparin anticoagulant such as a direct thrombin inhibitor or danaparoid followed by a vitamin K antagonist for long-term treatment. The new anti-factor Xa drugs (fondaparinux, rivaroxaban, apixaban) and other non-heparin antithrombotic agents can potentially be used for the treatment of HIT if clinically validated. Important drug-specific limitations and dosing and monitoring guidelines must be respected for patient safety. Issues still exist regarding the optimal clinical management of HIT.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Enzyme-Linked Immunosorbent Assay; Factor Xa Inhibitors; Heparin; Heparitin Sulfate; Hirudins; Peptide Fragments; Pipecolic Acids; Platelet Factor 4; Platelet Function Tests; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Bivalirudin is a direct thrombin inhibitor (DTI) frequently used for anticoagulation in the setting of invasive cardiology, particularly percutaneous coronary intervention (PCI). Bivalirudin has a unique pharmacologic profile: unlike other marketed DTIs, it undergoes predominant non-organ elimination (proteolysis), and has the shortest half-life (approximately 25 min). Its affinity for thrombin is intermediate between that of lepirudin (highest) and argatroban (lowest)--this helps explain why it interferes with functional clotting assays to an extent intermediate between that achieved by these two other DTIs. This effect is best known for the PT (INR)--higher affinity for thrombin corresponds to lower molar DTI requirements to prolong the APTT; in turn, lower concentrations required for APTT prolongation (and, presumably, in-vivo effect) result in reduced PT (INR) prolongation. Bivalirudin is primarily used for its first FDA-approved indication, namely anticoagulation during percutaneous transluminal coronary angioplasty ("balloon angioplasty"), the most frequent type of PCI. Bivalirudin is also indicated for PCI with provisional use of glycoprotein IIb/IIIa antagonist therapy, and for patients with, or at risk of, heparin-induced thrombocytopenia (HIT), or HIT with thrombosis syndrome (HITTS), undergoing PCI. The bivalirudin development program has used a "quadruple" endpoint comprising a "triple" efficacy endpoint plus major bleeding - this approach anticipated the subsequent emphasis on strategies to improve clinical outcomes through bleeding reduction. Besides summarizing the key trials evaluating bivalirudin use for acute coronary syndrome (especially employing PCI), we review also the studies of bivalirudin as anticoagulant for "on-" and "off-pump" cardiac surgery, including both HIT and non-HIT situations.

Topics: Acute Coronary Syndrome; Amino Acid Sequence; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Blood Coagulation; Cardiac Surgical Procedures; Fibrinolytic Agents; Hemorrhage; Hemostasis, Surgical; Heparin; Hirudins; Humans; Molecular Sequence Data; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Thrombocytopenia; Thrombosis

Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Arginine; Drug Interactions; Economics, Pharmaceutical; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Topics: Ancrod; Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombocytopenia

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.

Topics: Anticoagulants; Antithrombins; Arginine; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors such as heparin. Bivalirudin, a bivalent direct thrombin inhibitor, is most commonly used in clinical practice and has a proven role in contemporary interventional medicine with elective percutaneous coronary intervention (PCI) as well as in patients with non-ST-elevation acute coronary syndrome (NSTEACS). Results from well-controlled clinical trials have shown that bivalirudin is associated with an approximate 50% reduction in major bleeding while having similar effects on incidence of death and myocardial infarction (MI) compared with herapin or enoxaparin and glycoprotein IIb/IIIa inhibitors. Bivalirudin has been successfully used in off- and on-pump cardiac surgery. Argatroban is the most evaluated among the univalent direct thrombin inhibitors inhibiting only the catalytic site of thrombin. It has been associated with similar rates of major bleeding compared with heparin in patients with acute MI receiving either streptokinase or alteplase with no effects on clinical endpoints. In a meta-analysis of 11 randomised trials where direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatan or inogatran) were compared with unfractionated heparin in >35,000 patients with ST-elevation MI (STEMI) or NSTEACS there was no mortality difference between treatment groups but the incidence of MI at 30 days was significantly reduced in patients treated with direct thrombin inhibitors compared with heparin (4.7% vs 5.3%; p < 0.004). The role of direct thrombin inhibitors in both primary angioplasty for STEMI and angioplasty after fibrinolytic therapy needs to be established. Overall, the efficacy and improved safety profile make bivalirudin an attractive first-line anticoagulant for elective PCI and in patients with NSTEACS undergoing an invasive strategy.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Fibrinolysis; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombin; Thrombocytopenia

Accomplishing a successful percutaneous coronary intervention in a patient with a suspected or diagnosed heparin-induced thrombocytopenia (HIT) requires the selection of an appropriate alternative anticoagulant and a thorough assessment of bleeding and thrombotic risks. In this review, we suggest an evidence-based management algorithm that takes into account the clinical phase of HIT (acute, recent, and remote HIT) and the associated risk when patients present with acute coronary syndrome. The algorithm also integrates preventive measures directed at decreasing the bleeding risk associated with the antithrombotic and invasive therapies used for HIT and percutaneous coronary intervention.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Fondaparinux; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombocytopenia; Vitamin K

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 dicuma

Topics: Animals; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Hemorrhage is the most common and best-recognized complication of heparin treatment. However, a potentially more dangerous complication is the development of heparin-induced thrombocytopenia (HIT). All patients exposed to heparin, irrespective of the dose and route of administration, are at risk of developing HIT. It is due to the formation of antibodies against the heparin-platelet factor 4 complex, which cause secondary activation of platelets, coagulation and, finally, increased thrombin production. The main symptom is the sudden onset of thrombocytopenia involving a drop in the platelet count to less than 50% of the basal level, with or without the appearance of thrombotic complications some 5 to 14 days after the start of heparin therapy. Heparin-induced thrombocytopenia can be detected early in patients receiving heparin by monitoring the platelet count. Demonstration of heparin-dependent platelet activation using an antigen or functional assay confirms the clinical diagnosis. Once the diagnosis of HIT has been confirmed serologically or there is a high level of suspicion of HIT, heparin must be suspended and treatment with an alternative anticoagulant should be considered. This review contains a discussion of the diagnosis and treatment of this syndrome.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia

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.

Topics: Anticoagulants; Clinical Trials as Topic; Heparin; Hirudins; Humans; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombocytopenia

Topics: Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sensitivity and Specificity; Sulfonamides; Thrombocytopenia; Thrombosis

Although heparin/protamine has been the standard anticoagulation regimen in cardiac surgery for decades, it induces negative reactions within the vasculature. Heparin-induced thrombocytopenia (HIT) is a highly prothrombotic immune reaction to heparin that may result in death, limb ischemia leading to amputation, graft occlusion, and other severe thrombotic events. Patients undergoing cardiac surgery are at high risk for HIT antibody seroconversion and at risk for clinical HIT. For patients with acute or subacute HIT and needing urgent cardiac surgery, accepted protocols for alternative, non-heparin anticoagulation are needed. The direct thrombin inhibitor bivalirudin offers promise in this area and is currently being evaluated in multicenter trials as an alternative for heparin/protamine in patients with HIT undergoing cardiac surgery.

Topics: Anticoagulants; Autoantibodies; Autoimmune Diseases; Cardiac Surgical Procedures; Heparin; Hirudins; Humans; Multicenter Studies as Topic; Peptide Fragments; Recombinant Proteins; Thoracic Surgery; Thrombocytopenia

Unfractionated heparin, derived from porcine intestine, is the prototype of a rapidly acting anticoagulant. It has been used for over 60 years to arrest or prevent thrombus growth. Low-molecular-weight heparins, available in the last 20 years, are manufactured from unfractionated heparin and have superior dose-response relationships because of fewer nonspecific reactions with plasma proteins and cells. Fondaparinux is a recently approved five-saccharide synthetic molecule that carries the evolution of heparin further. It is a pure Xa inhibitor, with minimal nonspecific interactions. It does not appear to elicit the antibody that leads to heparin-induced thrombocytopenia (HIT). All of these agents are given either intravenously or subcutaneously. They act indirectly by activating the natural plasma inhibitor, antithrombin III. Direct thrombin inhibitors bind directly to thrombin's active site without interaction with the cofactor, antithrombin III. Lepirudin (Refludan; Berlex, Wayne, NJ) and argatroban (Argatroban; GlaxoSmithKline, Research Triangle Park, NC) are given intravenously and are usually used in HIT and thrombosis associated with HIT. Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a parenteral direct thrombin used in place of heparin in percutaneous coronary interventions. Ximelagatran (Exanta; AstraZeneca, Wilmington, DE) is an oral direct thrombin inhibitor under development for both acute and chronic anticoagulation.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Embolism; Enzyme Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Venous Thrombosis

The use of unfractionated heparin, the traditional antithrombotic agent during percutaneous coronary interventions (PCI), is associated with the risk of heparin-induced thrombocytopenia, a rare but often fatal clinical condition. This article focuses on several issues related to heparin-induced immune-mediated thrombocytopenia (HIT, type II) and alternative modes of periprocedural anticoagulation in patients with suspected or known HIT. The hypercoagulable state characterizing HIT, along with mechanical plaque disruption resulting from PCI place patients with HIT at particular risk of thrombosis during PCI. Given that a diagnosis of HIT precludes any further use of heparin, other treatment modalities are essential. Direct thrombin inhibitors are the drugs of choice in this challenging situation. These agents offer several advantages as anticoagulants for patients with HIT: (1) the ability to inhibit both thrombin that is bound to fibrin (clot-bound thrombin) and fluid-phase free thrombin; (2) rapid achievement of steady state; and (3) no cross-reactivity with HIT antibodies. Recent data on the use of bivalirudin, lepirudin, and argatroban in the setting of PCI in patients with HIT are encouraging. Optimal dosing regimens for argatroban, lepirudin, and bivalirudin should be further established in PCI patients.

Topics: Anticoagulants; Arginine; Blood Platelets; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Skin; Sulfonamides; Thrombin; Thrombocytopenia; Time Factors

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombins; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Unfractionated heparin given during cardiopulmonary bypass is remarkably immunogenic, as 25% to 50% of postcardiac surgery patients develop heparin-dependent antibodies during the next 5 to 10 days. Sometimes, these antibodies strongly activate platelets and coagulation, thereby causing the prothrombotic disorder, heparin-induced thrombocytopenia. The risk of heparin-induced thrombocytopenia is 1% to 3% if unfractionated heparin is continued beyond the first postoperative week. When cardiac surgery is urgently needed for a patient with acute or subacute heparin-induced thrombocytopenia, options include an alternative anticoagulant (bivalirudin, lepirudin, or danaparoid) or combining unfractionated heparin with a platelet antagonist (epoprostenol or tirofiban). As heparin-induced thrombocytopenia antibodies are transient, unfractionated heparin alone is appropriate in a patient with previous heparin-induced thrombocytopenia whose antibodies have disappeared.

Topics: Anticoagulants; Cardiac Surgical Procedures; Diagnosis, Differential; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thrombosis

The treatment of patients with acute coronary syndromes has changed dramatically over the last several years. Most patients now undergo some form of percutaneous coronary intervention (PCI), which includes either stent placement or percutaneous transluminal coronary angioplasty (PTCA). Along with new medical interventions for acute coronary syndromes comes the need for new antithrombotic therapies. Combination therapy with antiplatelet agents (aspirin, adenosine diphosphate inhibitors), glycoprotein (GP) IIb-IIIa receptor inhibitors, and anticoagulants (unfractionated heparin or low-molecular-weight heparins) is administered, depending on the type of intervention and severity of the coronary lesion. Bivalirudin is a direct thrombin inhibitor that recently was approved as an alternative to heparin in patients undergoing PTCA. Compared with unfractionated heparin, bivalirudin reduces the rate of death, myocardial infarction, or revascularization, with a concurrent reduction in bleeding. This agent offers promise as a replacement for unfractionated heparin in PCI and is being studied in comparison with unfractionated heparin plus GP IIb-IIIa receptor inhibitors in patients undergoing intracoronary stent placement.

Topics: Angioplasty, Balloon, Coronary; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Randomized Controlled Trials as Topic; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombosis; Treatment Outcome

Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.. This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes.. Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles.. Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups.. Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis

Much progress has been made in understanding and treating acute coronary syndromes. For patients undergoing percutaneous transluminal coronary angioplasty, anticoagulant therapy during the procedure must strike a balance between providing sufficient anticoagulation to prevent thrombus formation and ischemic complications while averting hemorrhagic complications. Bivalirudin, a thrombin-specific anticoagulant, is the only anticoagulant that reduces both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is easy to use, provides predictable anticoagulation, inactivates both free and clot-bound thrombin, and blocks thrombin-mediated platelet activation and aggregation. Drug-drug interaction studies have found no clinically relevant interactions between bivalirudin and ticlopidine, abciximab, tirofiban, or eptifibatide. Bivalirudin is well tolerated by patients who previously received low-molecular-weight heparin (LMWH), when LMWH is discontinued 8-14 hours before bivalirudin is started. Similarly, switching from heparin to bivalirudin at the time of PCI reduces both ischemic and bleeding events.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Coronary Thrombosis; Drug Interactions; Fibrinolytic Agents; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombocytopenia; Ticlopidine

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Thrombosis; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Safety; Thrombocytopenia; Treatment Outcome

Revascularization procedures and particularly percutaneous transluminal coronary angioplasty are being performed more and more often in patients with unstable coronary artery disease, despite the fact that these procedures are known to carry a higher risk in such patients than in those with stable disease. This article reviews studies that have investigated the potential of modern antithrombotic therapy -- low-molecular-weight heparin, anti-Xa agents, direct antithrombin inhibitors and glycoprotein IIb/IIIa inhibitors -- to reduce the post-procedural event rate in such patients. The results are promising.

Topics: Abciximab; Angina, Unstable; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Aspirin; Clinical Trials as Topic; Combined Modality Therapy; Diabetes Complications; Drug Therapy, Combination; Eptifibatide; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Immunoglobulin Fab Fragments; Myocardial Revascularization; Oligosaccharides; Peptide Fragments; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Tirofiban; Treatment Outcome; Tyrosine

Heparin-induced thrombocytopenia (HIT) requires alternative anticoagulation strategies. We investigated outcomes in patients with HIT antibodies undergoing low-dose bivalirudin anticoagulation during left ventricular assist device implantation on an extracorporeal life support system (ECLS) and compared the results with non-HIT patients treated with heparin and receiving left ventricular assist device implantation with ECLS support.. The institutional ventricular assist device database was searched for the period from March 2012 to March 2016. The primary end-point was the need for early (<7 days) surgical re-exploration due to persistent haemorrhage or cardiac tamponade postoperatively. The secondary clinical end-points were delayed chest closure, stroke, intracranial bleeding, re-thoracotomy >7 days and mortality up to 1 year. Unadjusted comparison was used for the entire groups. Because of non-random group assignment, propensity score matching was also performed to compare treatment effects.. Twenty-one patients were treated with bivalirudin and 36 patients with heparin. INTERMACS levels were lower, inotropic score was higher and the prevalence of mechanical ventilation and preoperative ECLS implants was also significantly higher in the heparin group than in the bivalirudin group (P-values <0.05). The primary end-point was reached by 19% in the bivalirudin group and 16.7% in the heparin group (bivalirudin group: odds ratio 1.18, 95% confidence interval 0.29-4.76; P = 0.820). The propensity score-matched groups also showed no difference in this regard (P = 0.455). All secondary clinical end-points were comparable between groups, both in the unadjusted analysis and in the propensity score-matched groups.. In patients with HIT antibodies, low-dose bivalirudin anticoagulation on ECLS support appears to be a feasible option for left ventricular assist device implantation.

Topics: Antibodies; Anticoagulants; Antithrombins; Blood Coagulation; Extracorporeal Membrane Oxygenation; Female; Fibrinolytic Agents; Heart Failure; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Thrombolytic Therapy

The aim of this study was to evaluate a direct thrombin inhibitor (DTI) titration protocol in patients with suspected HIT. This observational study compared patients treated with argatroban or bivalirudin according to the University of Colorado Hospital DTI titration protocol versus a control group treated prior to protocol implementation. Protocol patients had DTI initial doses based on organ function and fixed dosage adjustments of 10, 25, or 50%. Initial doses and titrations in the control group were made per physician discretion. A total of 130 patients were enrolled: 47 in the protocol group and 83 in the control group (median age 54 years, 63% male, 78% critically ill, and 54% received argatroban). Goal aPTT was achieved with initial DTI dose in 64% of protocol patients and 46% of control patients (P = 0.07). Median (IQR) time to goal aPTT was reduced in the protocol group compared to the control group [5 hr (2-10 hr) vs. 13 hr (6-29 hr); P < 0.0001]. Median time to dose stabilization was 10 hr (6-27 hr) and 22 hr (13-40 hr) in the protocol and control groups, respectively; P < 0.0001. Median number of titrations to goal was 0 (0-1) versus 1 (0-4), respectively; P = 0.02. Median percentage of aPTT values in goal was 67% (41-100%) versus 53% (33-76%), respectively; P = 0.027. The DTI titration protocol shortened time to achieve goal aPTT, reduced time to dose stabilization, decreased the number of titrations required to achieve aPTT goal, and improved the percentage of aPTT values in goal range.

Topics: Adult; Aged; Antithrombins; Arginine; Empirical Research; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Nomograms; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Bivalirudin is direct thrombin inhibitor used in patients with heparin-induced thrombocytopenia. A pharmacokinetic and--dynamic model that predicts the partial thromboplastin time (PTT) based on the past infusion rates of bivalirudin following dose adjustment would be useful to guide optimal therapy. In this retrospective study we randomized 132 patients to a derivation and a validation cohort, and tested two models. The first model is a single-state linear model; the other incorporates a non-linear element to account for renal elimination of bivalirudin. Both models predicted PTT changes equally well with root-mean squared errors of 15 to 16 seconds (Pearson correlation coefficients for both were 0.67). Intra- and inter-individual variability of response to bivalirudin was significant. Although a high percentage of patients had moderate to severe renal dysfunction at one point during the bivalirudin infusion, the non-linear model that incorporates variable renal clearance of drug did not perform better than the linear model. This finding persisted even in the subgroup analysis of patients with moderate and low estimated glomerular filtration rates.

Topics: Antithrombins; Cardiac Surgical Procedures; Computer Simulation; Dose-Response Relationship, Drug; Drug Therapy, Computer-Assisted; Glomerular Filtration Rate; Hirudins; Humans; Models, Cardiovascular; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Bivalirudin demonstrated similar efficacy but resulted in a lower rate of bleeding compared to unfractionated heparin (UFH) plus platelet glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention. It has not been clearly evaluated whether this can also be applied to patients with diabetes mellitus. A total of 335 consecutive patients with diabetes mellitus referred for elective percutaneous coronary intervention were randomized in the Novel Approaches for Preventing or Limiting EventS (NAPLES) trial to receive bivalirudin monotherapy or UFH plus routine tirofiban. The primary composite end point (30-day composite incidence of death, urgent repeat revascularization, myocardial infarction, and all bleeding) was lower in the bivalirudin group than in the UFH plus tirofiban group (18.0% vs 31.5%, odds ratio 0.47, 95% confidence interval 0.28 to 0.79, p = 0.004). No death, urgent revascularization, or Q-wave myocardial infarction occurred. The rate of non-Q-wave myocardial infarction was similar in the 2 groups (10.2% in the bivalirudin group vs 12.5% in the UFH plus tirofiban group, p = 0.606). In contrast, fewer patients in the bivalirudin group experienced bleeding (8.4% vs 20.8%, odds ratio 0.34, 95% confidence interval 0.18 to 0.67, p = 0.002). This difference was mainly ascribed to the lower rate of minor bleeding (7.8% in the bivalirudin group vs 18.5% in the UFH plus tirofiban group, odds ratio 0.37, 95% confidence interval 0.19 to 0.74, p = 0.005), although the rate of major bleeding in the 2 groups was comparable (0.6% vs 2.4%, respectively; p = 0.371). In conclusion, in patients with diabetes mellitus undergoing elective percutaneous coronary intervention, the strategy of bivalirudin monotherapy compared to UFH plus routine tirofiban is safe and feasible and associated with a significant reduction of in-hospital bleeding.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Artery Disease; Diabetes Mellitus; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Prospective Studies; Recombinant Proteins; Retreatment; Thrombocytopenia; Tirofiban; Tyrosine

The coronary artery bypass grafting (CABG) heparin-induced thrombocytopenia thrombosis syndrome (HITTS) on- and off-pump safety and efficacy (CHOOSE-ON) trial was designed as a safety and efficacy trial of bivalirudin for use in anticoagulation during cardiopulmonary bypass (CPB) in patients with confirmed or suspected HIT and (or) antiplatelet factor 4/heparin (anti-PF4/H) antibodies.. In an open-label, multicenter trial, 50 patients were enrolled prospectively. The primary study endpoint was in-hospital acute procedural success, defined as the absence of death, Q-wave myocardial infarction (MI), repeat operation for coronary revascularization, and stroke at day seven after surgery or hospital discharge, whichever occurred first. The secondary study endpoints were procedural success, defined as the absence of death, Q-wave MI, repeat operation for coronary revascularization, and stroke, at 30 days and 12 weeks after surgery. Perioperative blood loss, transfusions, and the incidence of major bleeding events were also captured.. There were 49 patients treated with bivalirudin of which 43 had acute HIT and thrombosis syndrome (HITTS) with antibodies at time of surgery. Procedural success in-hospital or at 7 days was achieved in 46 (94%) patients. At day 30 procedural success was achieved in 42 (86%) patients, and after 12 weeks in 40 (82%) patients. Mean intraoperative blood loss was 575 +/- 524 mL, and mean 24-hour postoperative blood loss was 998 +/- 595 mL. Forty-one (84%) patients received transfusions before day 7 or discharge with a mean of 5.6 +/- 3.8 units of red blood cells, 8.6 +/- 7.2 units of platelets, and 6.0 +/- 4.7 units of fresh frozen plasma. No differences in outcome among bivalirudin-treated patients were observed between those in the overall group and those with moderately impaired renal function (n = 10).. The current investigation expands the experience of safe and effective anticoagulation with bivalirudin during CPB to patients with confirmed or suspected HIT and anti-PF4/H antibodies, including in the setting of impaired renal function.

Topics: Acute Disease; Aged; Aged, 80 and over; Antibodies; Anticoagulants; Blood Loss, Surgical; Cardiopulmonary Bypass; Erythrocyte Transfusion; Female; Heparin; Hirudins; Humans; Intraoperative Care; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Syndrome; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

This study assessed the use of bivalirudin as an alternative anticoagulant in patients with heparin-induced thrombocytopenia-thrombotic syndrome (HIT/TS) or antiplatelet factor four-heparin (anti-PF4/H) antibodies undergoing off-pump coronary artery bypass (OPCAB).. In a prospective, open-label, multicenter study, fifty-one patients with documented anti-PF4/H antibodies and (or) HIT/TS underwent OPCAB with bivalirudin anticoagulation (0.75 mg/kg i.v. bolus, 1.75 mg/kg/hour infusion). Procedural success (absence of death, Q-wave myocardial infarction, repeat revascularization, and stroke), bleeding, and transfusion at day seven/discharge, thirty days, and twelve weeks were assessed.. Thirty-five patients (67%) were included with positive anti-PF4/H antibodies and no thrombocytopenia or thrombosis, eleven patients (22%) had thrombocytopenia, and five patients had clinical HIT/TS (10%). Procedural success at seven days/discharge was achieved in forty-seven patients (92%), while procedural success at thirty days and twelve weeks was 88%. There were no deaths. Chest tube output over the first twenty-four hours was 936 +/- 525 mL and twenty-five patients received a red blood cell transfusion during their hospitalization. Two patients required reexploration for persistent postoperative hemorrhage.. Bivalirudin was an effective alternative anticoagulant for patients with HIT/TS or circulating anti-PF4/H antibodies undergoing OPCAB, with high rates of procedural success and an acceptable incidence of bleeding or transfusions.

Topics: Aged; Antibodies; Anticoagulants; Coronary Artery Bypass, Off-Pump; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Factor 4; Prospective Studies; Recombinant Proteins; Thrombocytopenia

Unfractionated heparin and its antidote, protamine sulfate, allow for rapid and reversible anticoagulation during cardiac surgery with cardiopulmonary bypass, yet limitations exist, including a variable dose-response, dependence on a cofactor for anticoagulant effect, and antigenic potential. This trial was performed to evaluate the safety and efficacy of bivalirudin as an alternative to heparin with protamine reversal in on-pump cardiac surgery.. We conducted a randomized, open-label, multicenter trial comparing heparin with protamine reversal to bivalirudin in patients undergoing cardiac surgery with cardiopulmonary bypass. The primary objective was to demonstrate comparable rates of in-hospital procedural success defined as freedom from death, Q-wave myocardial infarction, stroke, or repeat revascularization. Twenty-one institutions enrolled 101 patients randomized to bivalirudin and 49 patients to heparin treatment.. The primary end point of procedural success was not significantly different between the bivalirudin arm and the heparin/protamine arms at 7 days, 30 days, or 12 weeks' follow-up. Adequate anticoagulation was achieved in all patients. Secondary end points including mortality, 24-hour blood loss, overall incidence of transfusions, and duration of surgery were similar between the two arms.. Bivalirudin is a safe and effective anticoagulant for patients undergoing a wide range of cardiac surgical procedures with cardiopulmonary bypass. Procedural success rates with bivalirudin were similar to rates in patients receiving heparin anticoagulation, with no difference in mortality. Avoidance of blood stasis and attention to the intraoperative medical management of patients is critical for successful use of bivalirudin during cardiopulmonary bypass.

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Female; Heparin; Heparin Antagonists; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Protamines; Recombinant Proteins; Thrombocytopenia; Thrombosis

Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5.. This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding.. The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT.. Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.

Topics: Anticoagulants; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Sodium Bicarbonate; Thrombocytopenia; Tissue Plasminogen Activator; Treatment Outcome

Topics: Anticoagulants; Extracorporeal Membrane Oxygenation; Heparin; Humans; Peptide Fragments; Pulmonary Embolism; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Thrombosis

The present study aimed to comprehensively investigate the occurrence and risk factors of adverse events (AEs) or adverse drug reactions (ADRs) (especially for thrombocytopenia and bleeding) in Chinese female patients receiving bivalirudin during percutaneous coronary intervention (PCI).. A total of 918 female patients from 27 Chinese medical centers took bivalirudin as anticoagulant for PCI were enrolled in this prospective, multi-center, intensive monitoring study. Safety data (AEs, ADRs, thrombocytopenia and bleeding) were collected from admission to 72 h post bivalirudin administration; then, patients were followed up at the 30. One hundred and twenty (13.1%) patients occurred AEs, among which 7 (0.8%) cases experienced severe AEs, and 2 (0.2%) cases died. Besides, 40 (4.4%) patients occurred bivalirudin-related ADRs, in which 3 (0.3%) cases experienced severe ADRs, but 0 (0.0%) cases died. It was of note that 27 (2.9%) and 13 (1.4%) patients experienced thrombocytopenia and bleeding, respectively. Subsequent multivariate analyses observed that: clinical presentation of spontaneous coronary artery dissection (SCAD) (odds ratio (OR) = 3.191, P = 0.004), CRUSADE high risk (OR = 2.075, P = 0.031), multiple culprit vessel (OR = 2.328, P = 0.019) independently correlated with higher risk of bivalirudin-related ADRs; clinical presentation of SCAD (OR = 4.388, P = 0.002) and multiple culprit vessel (OR = 2.974, P = 0.010) independently linked with raised thrombocytopenia risk; history of diabetes mellitus (OR = 5.227, P = 0.007) and CRUSADE high risk (OR = 4.475, P = 0.016) were independent factor related to elevated bleeding risk.. Bivalirudin is well tolerated with low ADRs, thrombocytopenia and bleeding incidences in Chinese female patients undergoing PCI.

Topics: Aged; Antithrombins; China; Coronary Artery Disease; Female; Hemorrhage; Hirudins; Humans; Incidence; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Prospective Studies; Recombinant Proteins; Risk Assessment; Risk Factors; Sex Factors; Thrombocytopenia; Time Factors; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis.. The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

Topics: Acenocoumarol; Anticoagulants; Arginine; COVID-19; COVID-19 Drug Treatment; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Pipecolic Acids; Recombinant Proteins; SARS-CoV-2; Sulfonamides; Thrombocytopenia; Thrombosis

Unfractionated heparin is the most commonly utilized anticoagulant in extracorporeal membrane oxygenation (ECMO) due to clinician familiarity, ease of reversal, and low cost compared to alternative agents. However, heparin's anticoagulant effect can be unpredictable and its use accompanies a risk of heparin induced thrombocytopenia (HIT). Successful use of bivalirudin as an alternative to heparin in non-HIT ECMO patients has previously been described. However, there is a paucity of data regarding its utilization in patients with confirmed HIT on ECMO.. This single-center retrospective chart review at Cleveland Clinic Main Campus included 12 ECMO patients who were managed with bivalirudin for a new diagnosis of HIT. Descriptive statistical analyses were performed utilizing median with interquartile range and number with percent as appropriate.. Of the 12 patients included, median ECMO duration was 328.5 (218.8-502.1) h and venoarterial ECMO was the most common configuration. No patients experienced the primary outcome of in-circuit thrombosis while on bivalirudin. One patient developed a deep vein thrombosis 22.5 h after switching from heparin to bivalirudin. Major bleeding occurred during bivalirudin therapy in 8 (66.7%) patients.. Overall, our study results suggest that bivalirudin is effective for the management of HIT and did not show evidence of in-circuit thrombosis. A high incidence of major bleeding was observed with bivalirudin use within this study. Clinicians should view bivalirudin as an acceptable agent for the treatment of HIT in the ECMO population, but must consider bleeding risk given the lack of effective reversal agents.

Topics: Anticoagulants; Extracorporeal Membrane Oxygenation; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Thrombosis

This prospective, multi-center, intensive monitoring study aimed to systematically assess the occurrence of adverse events (AEs) and adverse drug reactions (ADRs), especially thrombocytopenia and bleeding, as well as their risk factors in Chinese ST-segment elevation myocardial infraction (STEMI) patients receiving bivalirudin as anticoagulant for percutaneous coronary intervention (PCI).. In total, 1244 STEMI patients undergoing PCI and receiving bivalirudin as anticoagulant were enrolled in the present study. Safety data were collected from hospital admission to 72 h after bivalirudin administration; in addition, patients were further followed up at the 30th day with safety data collected at that time.. AEs, severe AEs, ADRs and severe ADRs were reported in 224 (18.0%), 15 (1.2%), 49 (3.9%) and 5 (0.4%) patients, respectively. Importantly, 4 (0.3%) patients were submitted to hospitalization and 6 (0.5%) patients died due to AEs, while 1 (0.1%) patient was submitted to hospitalization but no (0.0%) patient died due to ADRs. Meanwhile, thrombocytopenia and bleeding occurred in 24 (1.9%) and 21 (1.7%) patients, respectively. Further multivariate logistic analysis identified several important independent factors related to AEs, ADRs, thrombocytopenia or bleeding, which included history of cardiac surgery and renal function impairment, high CRUSADE risk stratification, elective operation and combination with glycoprotein IIb/IIIa inhibitors. Moreover, 4 multivariate models were constructed based on the above-mentioned factors, which all showed acceptable predictive value for AEs, ADRs, thrombocytopenia and bleeding, respectively.. Bivalirudin is a well-tolerant anticoagulant in Chinese STEMI patients undergoing PCI procedure.

Topics: Anticoagulants; Antithrombins; China; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Prospective Studies; Recombinant Proteins; ST Elevation Myocardial Infarction; Thrombocytopenia; Treatment Outcome

Herein the case of a patient with a prior history of heparin-induced thrombocytopenia who underwent percutaneous mitral valve edge-to-edge repair that was followed by a tricuspid edge-to-edge repair two months later is presented. Recommendations exist for systemic anticoagulant alternatives for percutaneous mitral valve edge-to-edge repair with the MitraClip device (Abbott, Chicago, IL), but minimal guidance and experience are present regarding alternative systemic anticoagulation during the performance of right-sided interventions, including tricuspid edge-to-edge repair (TriClip; Abbott). Notably, there is no clear consensus regarding the use of an alternative anticoagulant in the catheter flush solution for the delivery systems used during these procedures, particularly for right-sided interventions.

Topics: Anticoagulants; Cardiac Catheterization; Heart Valve Prosthesis Implantation; Hirudins; Humans; Mitral Valve Insufficiency; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Treatment Outcome; Tricuspid Valve

Argatroban and bivalirudin are direct thrombin inhibitors (DTIs) used for the treatment of heparin-induced thrombocytopenia (HIT). The purpose of this study was to determine whether either agent offered an advantage in efficacy and ability to remain within the targeted therapeutic anticoagulation range.. This was a single-center, retrospective, observational cohort study at a large academic medical center. The primary efficacy outcome was time to therapeutic anticoagulation, defined as total number of hours to achieve 2 consecutive activated partial thromboplastin time (aPTT) values in goal range.. A total of 91 patients were included in the analysis. Average time to initial therapeutic anticoagulation was 4.71 hours and 9.8 hours for the argatroban and bivalirudin groups, respectively (. Argatroban may be advantageous compared to bivalirudin in achieving initial therapeutic anticoagulation goals among patients with suspected or confirmed HIT.

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Treatment Outcome

The use of systemic bivalirudin and an anticoagulant-free purge solution in a percutaneous left ventricular assist device (pVAD) is described in a patient with a history of heparin-induced thrombocytopenia (HIT). An 80-year-old man with a past medical history of severe aortic stenosis and HIT was transferred to our facility for cardiogenic shock. The patient was emergently taken to the cardiac catheterization laboratory for balloon valvuloplasty and Impella pVAD (Abiomed, Inc) implantation. Due to the history of HIT, bivalirudin was chosen as an alternative anticoagulant. The device representative suggested adding bivalirudin 20 mg/500 mL to the Impella purge solution. However, due to the negligible amount of bivalirudin this would provide in comparison to patient's systemic intravenous bivalirudin dose, we elected not to add bivalirudin to the purge solution. The patient remained on the Impella for 72 hours with intravenous bivalirudin without any evidence of pump thrombosis as evidenced by unchanging flows and stable purge pressures. Unfortunately, despite functional Impella pVAD support, care was withdrawn due to ongoing multi-organ failure. This patient case demonstrated the safe, effective, and practical use of an anticoagulant-free purge solution with systemic bivalirudin in a patient with 72 hours of Impella support.

Topics: Aged, 80 and over; Anticoagulants; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

The Impella device is a percutaneous ventricular assist devices that requires administration of heparin via a continuous purge solution. Patients on Impella device support may experience hemolysis with accompanying thrombocytopenia generating suspicion for heparin-induced thrombocytopenia (HIT). However, data and recommendations for use of non-heparin anticoagulants with Impella device are lacking. Therefore, we performed a retrospective cohort analysis of patients requiring bivalirudin during Impella device support to describe the safety and efficacy of bivalirudin as an alternative anticoagulant during Impella device support. Nine patients were included in the evaluation which analyzed Impella device purge flow and purge pressure along with bivalirudin dosing requirements, incidence of thrombosis, and incidence of pump failure. All patients had a positive platelet factor-4 IgG ELISA test, and the serotonin release assay was positive in four patients. After initiation of bivalirudin, the median (15th, 85th percentile) nadir purge flow decreased by 76% (5%, 88%) and the median (15th, 85th percentile) peak purge pressure increased by 86% (21%, 143%). At the time of bivalirudin discontinuation, the median final purge flow and pressure were 2.4 mL/h (74% decrease) and 969 mmHg (89% increase), respectively. Zero patients experienced catastrophic pump failure. Adding low concentration bivalirudin to the purge solution along with systemic bivalirudin may be a reasonable approach.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Drug Substitution; Female; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are routinely anticoagulated with heparin before the initiation of bypass. Heparin is contraindicated, however, in patients with acute HIT, and alternatives to routine practice are often used. While guidelines have recently been published addressing this topic 10, there remains variance between institutions in how these cases are treated. Our goal was to better delineate practice trends in the diagnosis and management of HIT patients requiring CPB.. We surveyed members of the Society of Cardiovascular Anesthesiologists (SCA) and the American Society for Extracorporeal Technology (AmSECT) using an online survey tool.. We received 304 completed surveys (5.8% response rate), 75% completed by an anesthesiologist, and 24% by a perfusionist. The majority of respondents used clinical history and/or antibody testing (71% and 63%, respectively) to diagnose HIT. Seventy-five percent of respondents reported using an institutional protocol for HIT-CPB cases. Most respondents (89%) reported having at least 1 case in the last 3 years, with a total case experience of at least 785 cases (785 = the minimum number of cases in each case volume category × the number of respondents choosing that category). The strategy recommended in published guidelines, bivalirudin, was the most commonly reported alternative anticoagulation strategy (75%) used by respondents in HIT cases, with most (83%) using the activated clotting time (ACT) to monitor anticoagulation.. Most responding SCA and AmSECT members reported that their institution used a protocol or guideline for HIT/CPB cases, and most guidelines directed the use of bivalirudin as an alternative anticoagulant. Various other methods such as plasmapheresis are also being used with success in this patient population. Further research, including comparison studies of alternative anticoagulant strategies, is required to elucidate the best approach to these difficult cases.

Topics: Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Contraindications, Procedure; Drug Monitoring; Drug Substitution; Guideline Adherence; Health Care Surveys; Heparin; Hirudins; Humans; Peptide Fragments; Plasmapheresis; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Risk Assessment; Risk Factors; Thrombocytopenia; Whole Blood Coagulation Time

Extracorporeal membrane oxygenation (ECMO) induces hemostatic alterations that may contribute to hematological complications. Unfractionated heparin (UFH) is the mainstay antithrombotic in ECMO and depends on antithrombin III (AT III) to exhibit its actions. However, it bears the risk for heparin-induced thrombocytopenia. Bivalirudin is a direct thrombin inhibitor and is inherently not dependent on AT III.. To assess the efficacy and safety profiles of UFH compared with bivalirudin during ECMO support.. We retrospectively reviewed 52 adult patients who were supported by ECMO from 1 January 2013 to 1 September 2018. Among them, 33 received UFH and 19 received bivalirudin. We analyzed their 7-day rate of composite thrombotic, bleeding, and mortality episodes while on anticoagulation.. There were no statistical differences in the 7-day rate of composite thrombosis (33.3% vs 26.3%; P = 0.60), major bleeding (18.2% vs 5.3%; P = .24), 30-day mortality, (42.4% vs 26.3%; P = .37), or in-hospital mortality (45.5% vs 36.8%; P = .58). The percentage of time activated partial thromboplastin time (aPTT) was within the therapeutic range was higher with bivalirudin (50% vs 85.7%; P = .007).. This study suggests that UFH and bivalirudin are associated with similar rates of thrombosis, major bleeding, and mortality events in patients supported by ECMO. However, it was observed that bivalirudin consistently maintained aPTT within the therapeutic range in comparison to UFH.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Extracorporeal Membrane Oxygenation; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Thrombosis; Young Adult

Bivalirudin, a direct thrombin inhibitor, is a treatment option for the management of heparin-induced thrombocytopenia (HIT) and other coagulation disorders. To date, no published studies have identified patients at risk for or the consequence of subtherapeutic bivalirudin therapy.. The primary objective was to identify factors associated with failure to achieve early therapeutic anticoagulation (ETA) with bivalirudin, defined as achievement of two consecutive therapeutic activated partial thromboplastin times (aPTTs) within 24 hours. Secondary objectives included evaluating whether failure to achieve ETA was a risk factor for clinical outcomes of interest including thromboembolism, hemorrhage, and mortality.. This was a retrospective cohort study. Patients between the ages of 18 and 89 years treated with bivalirudin for 24 hours or longer were identified and classified as either achieving or failing to achieve ETA.. Nonadherence to the dosing protocol (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.07-2.71) and creatinine clearance (CrCl) of 60 ml/min or greater (OR 2.99, 95% CI 1.12-7.97) were significantly associated with failure to achieve ETA in univariate analyses. Conversely, increasing age (OR 0.98, 95% CI 0.97-0.99) was significantly associated with achievement of ETA. Failure to achieve ETA was associated with a 4-fold increase in the odds of thromboembolism.. Younger age, normal renal function, and nonadherence to the dosing protocol when targeting therapeutic anticoagulation is associated with increased risk of failure to achieve ETA. This confers an elevated risk of thromboembolism when using bivalirudin for the management of HIT or other coagulation disorders.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anthropology, Medical; Antithrombins; Cohort Studies; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Risk Factors; Thrombocytopenia; Thromboembolism; Treatment Failure; Young Adult

Topics: Adrenal Gland Diseases; Aged; Anticoagulants; Atrial Fibrillation; Diabetic Angiopathies; Hemorrhage; Heparin; Hirudins; Humans; Hydrocortisone; Hypotension; Male; Non-ST Elevated Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Treatment Outcome; Vasoconstrictor Agents

Anticoagulation for cardiopulmonary bypass (CPB) is required to prevent acute disseminated intravascular coagulation and clot formation within the bypass circuit. Unfractionated heparin is the standard anticoagulant for CPB due to its many advantages and long history of successful use. However, heparin has the unique drawback of triggering Heparin-PF4 (PF4) antibodies potentially leading to heparin-induced thrombocytopenia (HIT). We have limited data regarding reformation of antibodies if a patient has had a prior (remote) antibody production or full HIT. Patients with antiphospholipid antibodies undergoing CPB with unfractionated heparin have a high complication rate, even in the absence of HIT. Antiphospholipid antibodies have a multifaceted, cumulatively inhibitory effect on the normal anticoagulation armamentarium in vivo. Even more concerning is the possibility that antiphospholipid syndrome and HIT may be synergistic. We report a patient with risk factors for both thromboembolic (remote history of HIT and antiphospholipid syndrome) and hemorrhagic complications who underwent an aortic valve replacement and coronary artery bypass grafting on CPB using bivalirudin. We discuss the complex decision making regarding anticoagulant for CPB, particularly with regard to American College of Chest Physicians guidelines.

Topics: Anticoagulants; Antiphospholipid Syndrome; Aortic Valve; Cardiopulmonary Bypass; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thromboembolism

Acute heparin-induced thrombocytopenia (HIT) patients present a myriad of anticoagulation management challenges, in clinical settings where unfractionated heparin (UFH) is the traditional drug of choice. UFH use in cardiac surgery is a known entity that has been subject to rigorous research. Research has, thus, led to its unparalleled use and the development of well-established protocols for cardiac surgery. In comparison to UFH, bivalirudin use for acute HIT patients requiring urgent cardiac surgery with cardiopulmonary bypass (CPB) is still in its infancy. We describe the tailored post-CPB management of refractory bleeding in a 65-year-old infective endocarditis, acute HIT patient with renal failure who underwent urgent aortic valve replacement and mitral valve repair with bivalirudin anticoagulation. A management approach that entailed a combination of continuous venovenous haemofiltration (CVVH), 4-Factor prothrombin complex concentrate (PCC) (Beriplex), recombinant factor VIIa (rFactor VIIa) and desmopressin (DDAVP) were consecutively used post-operatively in theatre. Based on this case study experience, two modifications to institutional protocols are recommended. The first is the use of CVVH in theatre to eliminate bivalirudin in renal failure patients or in patients where bivalirudin elimination is prolonged. Secondly, a 'rescue therapy/intervention' algorithm for the swift identification of refractory bleeding post-CPB is also recommended. Rescue therapy agents, such as a 4-Factor PCCs and rFactor VIIa, should be incorporated into the protocol after a robust evidence-based search and agreement with the haematologist. The aim of these recommendations is to reduce the risk of bleeding associated with bivalirudin use for inexperienced institutions and experienced institutions alike, until larger randomized, controlled studies provide more in-depth knowledge to expand our clinical practice.

Topics: Acute Disease; Aged; Anticoagulants; Aortic Valve; Blood Coagulation Factors; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Deamino Arginine Vasopressin; Factor VIIa; Hemorrhage; Hemostatics; Heparin; Hirudins; Humans; Male; Mitral Valve; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia

In patients with submassive pulmonary embolism, the use of catheter-directed thrombolysis (CDT), using low-dose alteplase is associated with improvement in overall hemodynamics. The data for use of CDT in patients with heparin-induced thrombocytopenia are limited. We report a case of CDT in a patient with HIT using bivalirudin anticoagulation. Data of the use of bivalirudin and argatroban for systemic anticoagulation with CDT are limited.

Topics: Anticoagulants; Antithrombins; Blood Coagulation; Drug Administration Schedule; Drug Substitution; Fatal Outcome; Fibrinolytic Agents; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments; Pulmonary Embolism; Recombinant Proteins; Thrombocytopenia; Thrombolytic Therapy; Tissue Plasminogen Activator; Tomography, X-Ray Computed; Treatment Outcome

The rate of heparin-induced thrombocytopenia (HIT) on a population basis is unknown. The objective of this study was to characterize the risk for HIT during antepartum, delivery, and postpartum hospitalizations in the United States.. A large administrative database was used to determine the risk of HIT in hospitalized obstetric patients who received unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Patients were presumed to have HIT if they were exposed to UFH or LMWH, received a diagnosis of HIT, and were administered a medication for the treatment of HIT including bivalirudin, argatroban, fondaparinux, or lepirudin. We queried severe complications of HIT including arterial thrombosis, limb amputation, heart failure, and death.. We identified 66,468 antepartum hospitalizations, 66,741 delivery hospitalizations, and 16,325 postpartum readmissions where women received pharmacologic prophylaxis. Of these, 10 antepartum admissions, 1 delivery admission, and 14 postpartum readmissions involved a diagnosis of HIT with treatment of bivalirudin, argatroban, fondaparinux, or lepirudin. There were no deaths and no diagnoses of arterial thrombosis, limb amputation, heart failure, and death.. Risk for HIT among hospitalized obstetric patients is low. In this cohort, no cases of death or severe complications were noted in relation to the diagnosis.

Topics: Adolescent; Adult; Arginine; Databases, Factual; Delivery, Obstetric; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Hospitalization; Humans; Middle Aged; Peptide Fragments; Pipecolic Acids; Postpartum Period; Pregnancy; Recombinant Proteins; Risk Assessment; Sulfonamides; Thrombocytopenia; United States; Young Adult

An 81-year-old woman presented with acute decompensated heart failure due to new-onset atrial fibrillation and a flail myxomatous mitral valve which necessitated surgical mitral valve repair. No atrial thrombi were noted on transoesophageal echocardiograms performed prior to surgery and intraoperatively. Immediately postoperatively, while treated with unfractionated heparin, the patient developed thrombocytopaenia with positive platelet factor 4 antibodies and an abnormal serotonin functional platelet assay, consistent with heparin-induced thrombocytopaenia. The anticoagulation therapy was changed to the direct thrombin inhibitor bivalirudin with an improvement in the platelet count. Despite bivalirudin therapy, a left atrial layering thrombus was revealed on transoesophageal echocardiogram performed in preparation for cardioversion of the symptomatic atrial fibrillation. Anticoagulation was changed to warfarin, and the patient was discharged without thromboembolic complications neither during her hospital stay nor the 3-year outpatient follow-up.

Topics: Aged, 80 and over; Anticoagulants; Antithrombins; Coronary Thrombosis; Echocardiography, Transesophageal; Female; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Warfarin

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin. Patients are at markedly increased risk of thromboembolism.. These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about diagnosis and management of HIT.. ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.. The panel agreed on 33 recommendations. The recommendations address screening of asymptomatic patients for HIT, diagnosis and initial management of patients with suspected HIT, treatment of acute HIT, and special situations in patients with acute HIT or a history of HIT, including cardiovascular surgery, percutaneous cardiovascular intervention, renal replacement therapy, and venous thromboembolism prophylaxis.. Strong recommendations include use of the 4Ts score rather than a gestalt approach for estimating the pretest probability of HIT and avoidance of HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score. Conditional recommendations include the choice among non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) for treatment of acute HIT.

Topics: Administration, Oral; Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Evidence-Based Medicine; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Recombinant Proteins; Renal Replacement Therapy; Sulfonamides; Thrombocytopenia; Venous Thromboembolism

Topics: Anticoagulants; Antithrombins; Blood Coagulation Tests; Cardiomyopathies; Cardiopulmonary Bypass; Disease Management; Female; Fibrinolytic Agents; Heart Transplantation; Heparin; Hirudins; Humans; Kidney Transplantation; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Insufficiency, Chronic; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) results in platelet consumption and a virulent thrombotic state, which generally responds to cessation of heparin and initiation of anticoagulation. Rarely, delayed HIT can occur and/or persist after heparin is discontinued.. A 47-year-old male developed delayed HIT with severe thrombocytopenia and thrombosis after cardiac surgery. Thrombocytopenia developed and persisted after heparin cessation and did not improve despite sequential use of argatroban followed by bivalirudin. Treatment with intravenous immunoglobulin (IVIg) was well tolerated and resulted in rapid resolution of thrombocytopenia.. There are few case reports on the management of delayed HIT with severe and prolonged thrombocytopenia. The risk for thrombosis and bleeding in the setting of an undefined time course increases uncertainty in management.. This case, along with others accumulating in the literature, suggest that IVIg may be effective in treating delayed HIT with persistent thrombocytopenia.

Topics: Arginine; Cardiac Surgical Procedures; Heparin; Hirudins; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Peptide Fragments; Pipecolic Acids; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

A patient scheduled for lung transplantation needed veno-venous extracorporeal membrane oxygenation (ECMO) and developed acute heparin-induced thrombocytopenia (HIT). After 21 days on ECMO support, lung transplantation was successfully performed using veno-arterial ECMO with bivalirudin anticoagulation. The target activating clotting time values of 160-180 s resulted in low bivalirudin infusion rates of 0.1 mg/kg/h. Diffuse bleeding stopped quickly after ending the continuous bivalirudin infusion.

Topics: Anticoagulants; Extracorporeal Membrane Oxygenation; Heparin; Hirudins; Humans; Lung Transplantation; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an uncommon problem in hemodialysis (HD) patients. There have been a few reports on the use of lepirudin, argatroban, or danaparoid in the management of extracorporeal thrombosis (ECT) during dialysis in these patients, because heparin is contraindicated. Here, we report the first long-term use of bivalirudin to prevent ECT. Our study was conducted at Fahd Bin Jassim Kidney Center in Doha, Qatar. All patients diagnosed with HIT were included. A bivalirudin treatment protocol was developed with the initial dosage and dosage adjustments based on the value of activated partial thromboplastin time (aPTT), the risk of bleeding, and the recurrence of ECT. Eight patients were positive for HIT AB. Among them, three were excluded: two due to the use of warfarin for atrial fibrillation and one due to a negative repeat HIT AB test with no ECT. Five patients who were positive for HIT AB and experienced recurrent ECT events during dialysis were included. These patients were monitored while on bivalirudin protocol for a mean of 4.6 ± 2 months, during which they received a mean number of HD treatments of 66 ± 24. There were no bleeding events or adverse reactions related to bivalirudin during the study. Here, we report the first long-term successful use of a bivalirudin protocol to prevent ECT in ambulatory HD patients with HIT. This protocol allowed for a simple dosing initiation with easy adjustment based on weight, aPTT, and recurrence of ECT events. The protocol provided excellent safety.

Topics: Adult; Aged; Antithrombins; Clinical Protocols; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombosis

A 6-year-old child developed heparin-induced thrombocytopenia while on extracorporeal life support. Hours after a difficult transition from heparin to argatroban for anticoagulation therapy, the child underwent heart transplantation. Intraoperative management was plagued with circuit thrombus formation while on cardiopulmonary bypass and subsequent massive hemorrhage after bypass. We review the child's anticoagulation management, clinical challenges encountered, and review current literature related to the use of argatroban in pediatric cardiac surgery.

Topics: Antithrombins; Arginine; Cardiopulmonary Bypass; Child; Exchange Transfusion, Whole Blood; Extracorporeal Membrane Oxygenation; Heart Transplantation; Heparin; Hirudins; Humans; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Bivalirudin use as a procedural anticoagulant in patients undergoing percutaneous coronary intervention (PCI) is associated with a lower incidence of thrombocytopaenia compared to other antithrombotic agents. We aimed to evaluate the prognostic impact of baseline thrombocytopaenia and early changes in platelet counts among patients undergoing PCI with exclusive use of bivalirudin.. We evaluated 7,505 patients who underwent PCI over a period of eight years. Patients who received unfractionated heparin and glycoprotein IIb/IIIa receptor inhibitors were specifically excluded. Eight hundred and fifty-eight (11.4%) patients had baseline thrombocytopaenia and 451 (6.0%) developed acquired thrombocytopaenia. After adjustment for potential covariates, moderate to severe acquired thrombocytopaenia was the strongest independent predictor (HR 4.34, 95% CI: 2.13-8.84; p<0.001) of in-hospital net adverse clinical events, which included major adverse cardiac events and major bleeding complications. Age, male gender, baseline platelet count and intra-aortic balloon pump (IABP) insertion were independent predictors of in-hospital acquired thrombocytopaenia. After a mean follow-up of 2.6±1.7 years, moderate to severe baseline thrombocytopaenia (HR 2.42, 95% CI: 1.79-3.29; p<0.001), moderate to severe acquired thrombocytopaenia (HR 2.37, 95% CI: 1.13-4.97; p=0.02) and severe changes in platelet count (>67 k) were significant predictors of mortality.. In patients undergoing PCI with bivalirudin, moderate to severe baseline and acquired thrombocytopaenia along with severe changes in platelet count are associated with higher long-term mortality.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

The direct thrombin inhibitor bivalirudin is an option for anticoagulation in patients with heparin induced thrombocytopenia (HIT) requiring cardiopulmonary bypass (CPB). There are a limited number of reports of pediatric patients in which bivalirudin has been used for anticoagulation for CPB. We present the case of an 11 year old male with acute onset heart failure secondary to idiopathic dilated cardiomyopathy that developed heparin induced thrombocytopenia with thrombosis (HITT). The patient was anticoagulated in the operating room with bivalirudin and placed on CPB for insertion of a HeartWare(®) Ventricular Assist Device (Heartware(®)). Modified techniques were utilized. This included use of the Terumo CDI 500 (Terumo Cardiovascular Systems, Inc.) in-line blood gas monitor which contains a heparin coated arterial shunt sensor. We flushed this sensor with buffered saline preoperatively and noted no significant decrease in platelet count postoperatively. The patient was successfully placed on the ventricular assist device and was subsequently listed for heart transplantation.

Topics: Anticoagulants; Cardiomyopathy, Dilated; Cardiopulmonary Bypass; Child; Heart Failure; Heart Transplantation; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis

Transition from bivalirudin to long-term warfarin therapy is often difficult to execute due to bivalirudin prolongation of the international normalized ratio (INR), and literature to help guide this transition is extremely limited.. To assess the transition from bivalirudin to warfarin after implementation of an institution-wide transition protocol.. In this retrospective quasiexperimental study, adult patients receiving bivalirudin directly followed by warfarin for nonprocedural systemic anticoagulation were evaluated to determine the frequency of successful transition to warfarin. Participants were compared before (preprotocol) and after (postprotocol) the implementation of the transition protocol.. A total of 39 patients met inclusion criteria and were included in the analysis (preprotocol = 19; postprotocol = 20). The percentage of patients achieving a successful transition was significantly higher in the postprotocol group compared with the preprotocol group (80.0% vs 42.1%, P = 0.015). Bleeding events were similar between the 2 groups (23.1% vs 16.7%, P = 0.689). Withholding of warfarin doses or the use of anticoagulant reversal agents or blood transfusions for supratherapeutic INR levels, surgical procedures, or drop in hemoglobin was numerically lower in the postprotocol group compared with the preprotocol group (16.7% vs 46.2%, P = 0.202).. Implementation of a simplistic bivalirudin-warfarin transition protocol significantly increased the frequency of therapeutic INR results on bivalirudin discontinuation. Additionally, patients treated according to this protocol were less likely to have warfarin doses withheld or require reversal agents. Larger studies testing this transition strategy are warranted.

Topics: Adult; Aged; Anticoagulants; Female; Hemorrhage; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Transitional Care; Warfarin

Argatroban is the only commercially available Food and Drug Administration (FDA)-approved anticoagulant for managing heparin-induced thrombocytopenia (HIT). However, bivalirudin may be an attractive alternative.. To assess the efficacy and safety of argatroban and bivalirudin in patients with suspected HIT.. This single-center, retrospective analysis included patients who received argatroban or bivalirudin for at least 24 hours between January 1, 2000, and June 30, 2012. The primary end point assessed anticoagulation goals, specifically time to therapeutic activated partial thromboplastin time (aPTT) goal and percentage of aPTT values within therapeutic range. Secondary end points included new thromboembolic events, bleeding, and mortality.. Of the 68 patients who met the inclusion criteria, 48 received argatroban and 20 received bivalirudin. Baseline characteristics were similar between the 2 groups except for age, percentage of patients with liver dysfunction, aPTT immediately prior to drug initiation, and the serotonin release assay results. The mean ± SD times to reach therapeutic aPTT goal for argatroban and bivalirudin were 14 ± 15 and 7 ± 8 hours, respectively (P = 0.024). The mean ± SD percentage of aPTT values within therapeutic aPTT goal was 69% ± 23% for argatroban and 84% ± 18% for bivalirudin (P = 0.005). Rates of thromboembolic events were similar between the 2 groups, as were the rates of bleeding and all-cause mortality.. Bivalirudin appears to reach therapeutic aPTT goal faster with more aPTT values within therapeutic aPTT goal while achieving similar clinical outcomes. Although not approved by the FDA for managing HIT, bivalirudin may be an attractive alternative anticoagulant.

Topics: Aged; Anticoagulants; Arginine; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

A pediatric patient requiring venovenous (VV) extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation developed heparin-induced thrombocytopenia. Unfractionated heparin was discontinued, and a bivalirudin infusion was started. During the lung transplant evaluation, he was found to have allosensitization, requiring treatment with plasma exchange along with pulse methylprednisolone, rituximab, bortezomib, and pooled immunoglobulin infusion. We describe our experience with successful plasma exchange for allosensitization during bivalirudin anticoagulation on VV ECMO in a pediatric patient.

Topics: Antithrombins; Extracorporeal Membrane Oxygenation; Fatal Outcome; Heparin; Hirudins; Humans; Infant; Lung Transplantation; Male; Peptide Fragments; Plasma Exchange; Preoperative Care; Recombinant Proteins; Thrombocytopenia; Thrombosis

Topics: Aged; Anticoagulants; Disease Management; Femoral Artery; Heparin; Hirudins; Humans; Intraoperative Care; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Transcatheter Aortic Valve Replacement

Topics: Heart Ventricles; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia

Topics: Aged, 80 and over; Antibodies; Anticoagulants; Blood Platelets; Dalteparin; Female; Fondaparinux; Hip Fractures; Hirudins; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Morpholines; Peptide Fragments; Platelet Count; Polysaccharides; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombocytopenia; Venous Thrombosis

The case of a patient with confirmed heparin-induced thrombocytopenia (HIT) and anticoagulation failure undergoing catheter-directed thrombolysis (CDT) with alteplase and bivalirudin for extensive thrombosis is reported.. A 48-year-old, morbidly obese Caucasian woman was admitted to a trauma-surgical intensive care unit (TSICU) after a motor vehicle accident. The patient suffered aortic and renal lacerations, multiple rib and spinal fractures, pleural effusion, bilateral subdural hematomas, and cerebral edema. An inferior vena cava (IVC) filter was placed on hospital day 3, and prophylactic enoxaparin was initiated. The patient was diagnosed with HIT on hospital day 10. Systemic bivalirudin was initiated, and the patient was transitioned to therapeutic fondaparinux on hospital day 13. The patient continued to improve and was transferred from the TSICU to a step-down unit a few days later; the IVC filter remained in place. On hospital day 20, the patient developed respiratory distress and was transferred back to the TSICU. Computed tomography angiography was performed and revealed a questionable pulmonary embolism and distended IVC and iliac veins. Lower-extremity Doppler ultrasound revealed extensive thrombosis. On hospital day 21, the patient underwent CDT with alteplase and bivalirudin infusions through two CDT sheaths for approximately 36 hours, after which most of the thrombus had dissipated. The IVC filter and drug administration sheaths were removed. After the procedure, the patient received bivalirudin and was later transitioned to warfarin.. A 48-year-old woman with HIT and anticoagulation failure possibly due to the presence of an IVC filter was successfully treated with CDT using alteplase and bivalirudin.

Topics: Anticoagulants; Catheterization; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Middle Aged; Obesity, Morbid; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombolytic Therapy; Tissue Plasminogen Activator

Topics: Aged; Aged, 80 and over; Antithrombins; Arginine; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Pipecolic Acids; Practice Guidelines as Topic; Prospective Studies; Recombinant Proteins; Sulfonamides; Survival Analysis; Thrombocytopenia; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated reaction in which heparin administration causes a person to enter a pathological and highly prothrombotic state. When patients with known HIT undergo coronary artery bypass and grafting procedures, they must be appropriately anticoagulated. The dangers of heparin administration in this population necessitate the use of an alternative anticoagulant. The case describes the successful use of bivalirudin for procedural anticoagulation during an off-pump coronary artery bypass and grafting.

Topics: Antithrombins; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

To evaluate the safety, effectiveness, and dosing of off-label bivalirudin to argatroban and lepirudin in patients with heparin-induced thrombocytopenia (HIT) using a new pharmacist driven protocol.. Retrospective cohort study of forty eight patients treated with lepirudin, argatroban, or bivalirudin from November 2010 to February 2012 for suspected HIT. Patients were excluded if the bivalirudin therapy was being used for acute coronary syndrome or if the treatment duration was less than 24 hours. The primary endpoint was time to therapeutic activated partial thromboplastin time (aPTT 50-90 seconds for argatroban and bivalirudin and 50-85 seconds for lepirudin). The secondary endpoints were elevation in international normalized ratio (INR), bleeding episodes, and percent time in aPTT target range.. Patients receiving bivalirudin reached a therapeutic aPTT more quickly than those receiving argatroban and lepirudin (3.7 hours vs. 14.2 hours vs. 14.7 hours, p <0.001). The INR was increased more in patients treated with argatroban than lepirudin and bivalirudin (1.3 vs. 0.3 vs. 0.4, p = 0.4). Clinically significant bleeding in patients treated with bivalirudin was significantly lower than that observed with argatroban or lepirudin (7% vs. 22% vs. 56%, p = 0.02). The average percentage of therapeutic aPTTs drawn was higher for patients treated with bivalirudin than those patients treated with argatroban and lepirudin (90% vs. 66% vs. 67%, p = 0.2).. A pharmacist-driven protocol for bivalirudin provided a significantly shorter time to therapeutic aPTT and lower bleeding rate for patients being treated for HIT when compared to lepirudin and argatroban. A larger study should be considered to confirm the results of this single center study.

Topics: Aged; Anticoagulants; Antithrombins; Arginine; Dose-Response Relationship, Drug; Female; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; Catastrophic Illness; Female; Heparin; Hirudins; Humans; Kidney Transplantation; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated response to unfractionated heparin and, less commonly, low molecular weight heparin. It is associated with a high thrombotic risk and the potential for limb and life-threatening complications. Argatroban is the only approved and currently available anticoagulant for HIT treatment in the USA.. To report safety and efficacy outcomes with bivalirudin for HIT treatment.. We retrospectively examined records from our registry of patients with a suspected, confirmed or previous history of HIT and who had received bivalirudin for anticoagulation in a single tertiary-care center over a 9-year period.. We identified 461 patients who received bivalirudin: 220 (47.7%) were surgical patients, and 241 (52.3%) were medical patients. Of this population, 107 (23.2%) were critically ill, and 109 (23.6%) were dialysis-dependent. Suspected, confirmed and previous history of HIT were reported in 262, 124 and 75 patients, respectively. Of 386 patients with suspected or confirmed HIT, 223 patients (57.8%) had thrombosis at HIT diagnosis. New thrombosis was identified in 21 patients (4.6%) while they were on treatment with therapeutic doses of bivalirudin. No patient required HIT-related amputation. Major bleeding occurred in 35 patients (7.6%). We found a significant increase in major bleeding risk in the critically ill population (13.1%; odds ratio 2.4, 95% confidence interval 1.2-4.9, P = 0.014). The 30-day all-cause mortality rate was 14.5% (67 patients), and eight of 67 (1.7%) deaths were HIT-related.. Bivalirudin may be an effective and safe alternative option for the treatment of both suspected and confirmed HIT, and appears to reduce the rate of HIT-related amputation.

Topics: Adult; Aged; Anticoagulants; Antithrombins; Arginine; Female; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Male; Middle Aged; Odds Ratio; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Treatment Outcome

Optimal anticoagulation plays a pivotal role in successful outcome of extracorporeal membrane oxygenation (ECMO). Heparin has been the anticoagulant of choice owing to its advantages like easy monitoring and reversibility. However, if heparin resistance is encountered, one has to decide whether to treat heparin resistance with fresh-frozen plasma or antithrombin concentrates or to choose one of the heparin alternatives for anticoagulation. We report a case of heparin resistance resulting from antithrombin III deficiency in a patient on venovenous ECMO, in which anticoagulation was managed with bivalirudin. The dose of bivalirudin for anticoagulation in ECMO has not been standardized and different authors have reported different doses. We found a bivalirudin dose of .1-.2 mg/kg/h to be adequate to maintain a target activated clotting time of 200-220 seconds. Platelet counts were stable throughout and no major bleeding or thrombotic complications took place. We found bivalirudin to be a feasible and effective anticoagulant and safe to use for long durations in ECMO without any major complications.

Topics: Antithrombins; Extracorporeal Membrane Oxygenation; Hemofiltration; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome

Parenteral direct thrombin inhibitors (DTIs) may be used in pediatric patients with contraindications to heparin therapy, such as heparin-induced thrombocytopenia. Few data exist regarding the use of DTIs in pediatric patients.. To characterize the use of DTIs in pediatric patients, including monitoring strategies and bleeding complications.. A retrospective descriptive study was designed and the Pediatric Health Information System database was queried from 2004 to 2011 for pediatric patients receiving a parenteral DTI. Patient demographic and hospital data, mortality, disease state, and procedure information (from International Classification of Diseases, Ninth Revision codes) were collected from the query. DTI monitoring information was also collected. Patients were divided into 2 time periods (2004-2007, 2008-2011) to evaluate trends.. Two hundred eight patients met study criteria (50.9% male, 64.4% white), and children (2-12 years of age) represented 34.6% of the population. Congenital heart disease was present in 43.8% and cardiovascular surgical procedure occurred in 28.4%. Argatroban was most commonly used (73.1%) and bivalirudin use increased (P < .001). Bleeding complications were present in 37.9% of patients and mortality was 19.7%. Bleeding complications were associated with lepirudin (62.5%) and argatroban (41.7%) more often as compared with bivalirudin (18.8%) (P < .001). Activated partial thromboplastin time and prothrombin time were used more often in patients receiving argatroban and lepirudin in comparison with bivalirudin, and thrombin time was used more often in patients receiving lepirudin (P < .001). Activated clotting time use increased over time (5.1% versus 17.5%, P = .02).. Pediatric use of DTIs is infrequent and occurs in patients with high morbidity and mortality.

Topics: Adolescent; Age Factors; Antithrombins; Arginine; Child; Child, Preschool; Databases, Factual; Female; Health Information Systems; Hemorrhage; Hirudins; Humans; Incidence; Infant; Infant, Newborn; Infusions, Parenteral; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Young Adult

We report the case of a 27-year-old woman with signs of heparin-induced thrombocytopenia and thrombosis (HITT) and left heart failure presenting for urgent implantation of a left ventricular assist device (LVAD). HITT can occur in 4.2-6.1% of patients with LVADs. If the patient remains hemodynamically stable, implantation can be delayed for several months until the heparin/PF-4 antibodies decline allowing the use of heparin on cardiopulmonary bypass, However, in most cases related to cardiogenic shock, surgery cannot be delayed. We present the case of a patient who underwent implantation of a HeartMate II LVAD and discuss management strategy using bivalirudin during cardiopulmonary bypass.

Topics: Adult; Anticoagulants; Antithrombins; Cardiopulmonary Bypass; Combined Modality Therapy; Female; Heart Diseases; Heart Ventricles; Heart-Assist Devices; Heparin; Hirudins; Humans; Peptide Fragments; Prosthesis Implantation; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia is a well-recognized complication of anticoagulation with heparin. We present the case of a patient with recent heparin-induced thrombocytopenia who subsequently needed surgery on an emergency basis for acute type A aortic dissection. This article reports the successful use of bivalirudin, a direct thrombin inhibitor, as an alternative to heparin throughout cardiopulmonary bypass and deep hypothermic circulatory arrest. We contend that bivalirudin is a safe alternative to heparin when performing surgery for aortic dissection and should be considered as an option for use in patients who present with heparin-induced thrombocytopenia.

Topics: Aged, 80 and over; Anticoagulants; Aortic Aneurysm; Aortic Dissection; Blood Vessel Prosthesis Implantation; Cardiopulmonary Bypass; Circulatory Arrest, Deep Hypothermia Induced; Contraindications; Drug Administration Schedule; Emergencies; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Risk Factors; Thrombocytopenia; Treatment Outcome

After on-pump coronary artery bypass graft surgery, a patient had acute heparin-induced thrombocytopenia with thoracic arterial and venous thrombus formations. Complex emergency surgery with cardiopulmonary bypass and deep hypothermic circulatory arrest using bivalirudin anticoagulation was performed.

Topics: Aged; Anticoagulants; Antithrombins; Blood Coagulation; Cardiopulmonary Bypass; Circulatory Arrest, Deep Hypothermia Induced; Coronary Artery Bypass; Coronary Artery Disease; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombectomy; Thrombocytopenia; Thrombosis

Here we present our attempt at off pump HeartMate II left ventricular assist device (LVAD) implantation using the anticoagulant bivalirudin in a patient with heparin induced thrombocytopenia, which resulted in thrombosis within the LVAD device. This required that our procedure be converted to on pump, and a new HeartMate II LVAD device to be implanted. In our view, this thrombotic event may have been caused by a number of factors that include bivalirudin's (1) short half-life of about 20 minutes, (2) decreased activity with blood stasis, (3) inability to prevent clot propagation, and (4) uncertainty with real-time monitoring of therapeutic levels. To prevent future thrombotic events, it may be beneficial to immediately deair the LVAD device prior to the coring of the left ventricle during off pump LVAD placement. In addition, a solution other than blood may be used for priming. If blood is used for priming of the LVAD device, the duration of blood stasis should not exceed 20 minutes when bivalirudin is being used for anticoagulation. Furthermore, this case emphasizes the importance of having a backup LVAD device available and ready to use during surgical procedures.

Topics: Aged; Anticoagulants; Antithrombins; Blood Coagulation; Female; Heart Ventricles; Heart-Assist Devices; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thoracic Surgical Procedures; Thrombocytopenia; Thrombosis

In patients with acute heparin-induced thrombocytopenia (HIT) needing urgent cardiac surgery, bivalirudin is recommended as a first-line strategy for intraoperative anticoagulation. However, due to the unique elimination process of bivalirudin, careful adjustment of the perfusion and surgical strategy is mandatory as blood stasis in the circuit or prolonged interruption of areas or compartments containing blood from the systemic circulation may result in thrombus formation. We report here a modified surgical strategy for the implantation of the HeartWare™ left ventricular assist device, which avoids prolonged disconnection of the blood-filled device from the systemic blood flow, so that bivalirudin can be safely used as anticoagulant.

Topics: Anticoagulants; Blood Coagulation; Heart Failure; Heart-Assist Devices; Heparin; Hirudins; Humans; Peptide Fragments; Prosthesis Design; Prosthesis Implantation; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome; Ventricular Function, Left

A simplified dosing nomogram to assist nurses in adjusting the rate of i.v. bivalirudin administration in cases of heparin-induced thrombocytopenia (HIT) is described.. To facilitate the availability of bivalirudin [corrected] as an alternative direct thrombin inhibitor (DTI) for patients with HIT at The Ohio State University Wexner Medical Center (OSUWMC), a team of clinical pharmacists developed a nomogram designed to simplify infusion dosage adjustments by nurses. In contrast to bivalirudin nomograms requiring patient-specific, percentage-based dose adjustments, the nomogram developed at OSUWMC specifies fixed adjustments (0.005 or 0.01 mg/kg/hr) according to the current activated partial thromboplastin time (aPTT) value relative to aPTT goals. During pilot testing over three years, the nomogram was used to guide dosage adjustments in 65 adult patients receiving continuous infusions of bivalirudin for suspected or confirmed HIT in intensive care units. Overall, the use of the nomogram resulted in adequate anticoagulation, with 53.7% of all measured aPTT values in the target range; 30.5% of aPTT values were below target, and 15.8% of values were above target. The median time to steady state was 11.0 hours (range, 5.0-31.8 hours), and bleeding rates were consistent with those reported in the literature. Nurse adherence to the nomogram was 100%, and no dosing errors occurred during a total of 487 dosage changes. Based on the pilot study results, the nomogram was refined to improve initial dosing for patients with creatinine clearance values of >30 mL/min; other refinements were made to enhance the safety of bivalirudin therapy for HIT in patients with severe renal impairment.. A nurse-driven, sliding-scale nomogram for bivalirudin therapy in patients with HIT provided a simple dosing protocol and resulted in a high rate of adherence by nurses.

Topics: Aged; Disease Management; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Nomograms; Nurse's Role; Peptide Fragments; Pilot Projects; Program Development; Recombinant Proteins; Thrombocytopenia

Bivalirudin is a direct thrombin inhibitor that has been approved for use in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention. The efficacy of bivalirudin has been well documented in the setting of percutaneous coronary intervention, but there are only few data on its use in chronic dialysis-dependent patients. Bivalirudin is mainly eliminated enzymatically (80%) and to a lesser extent renally (20%). Nevertheless, in patients with chronic kidney disease a substantial increase in coagulation time and bleeding complications has been reported. Therefore, dosage adjustments may be necessary in patients with renal impairment. Dosing and monitoring recommendations in dialysis patients have not yet been established. We describe the case of a 77-year-old man with non-ST-elevation acute coronary syndrome complicated by heparin-induced thrombocytopenia and acute renal failure requiring dialysis treatment. During percutaneous coronary intervention, anticoagulant therapy with bivalirudin was administered at non-standard doses, though already documented in the literature.

Topics: Aged; Antithrombins; Heparin; Hirudins; Humans; Male; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins; Renal Dialysis; Risk Factors; Thrombocytopenia

Bivalirudin, a direct thrombin inhibitor, is indicated for patients with suspected heparin-induced thrombocytopenia (HIT) with anticipated percutaneous coronary intervention (PCI). Data is limited on dose selection among patients with renal insufficiency, particularly with prolonged infusion durations. The study cohort comprised 73 patients with renal dysfunction who received bivalirudin for suspected HIT with or without acute coronary syndrome. We reviewed individual pharmacy and medical records for laboratory and bivalirudin dosing information, medical comorbidities, and adverse clinical outcomes during administration. When estimated glomerular filtration rate (eGFR) was calculated by the Cockcroft-Gault (CG; ml/min) formula, the average bivalirudin dose (mg/kg/h) achieving a therapeutic activated partial thromboplastin time (aPTT) was 0.07 ± 0.04, 0.15 ± 0.08, and 0.16 ± 0.07 for patients with eGFR between 15-30, 31-60, and >60, respectively. When eGFR was calculated by the modification of diet in renal disease (MDRD; ml/min/1.73 m(2)) formula, the average bivalirudin dose achieving a therapeutic aPTT was 0.07 ± 0.04, 0.12 ± 0.07, and 0.20 ± 0.07 for patients with eGFR between 15-30, 31-60, >60, respectively. The difference between the dose achieving a therapeutic aPTT for patients with eGFR >60 when calculated by MDRD versus CG was completely abolished when obese patients were excluded from the CG cohort. The results of our series of patients with renal dysfunction receiving prolonged duration of bivalirudin in the setting of acute coronary syndrome (ACS) suggests that dose adjustment is safe and should be considered for patients with moderate to severe renal impairment (eGFR < 60 ml/min/1.73 m(2)).

Topics: Aged; Aged, 80 and over; Cohort Studies; Dose-Response Relationship, Drug; Drug Evaluation; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Retrospective Studies; Thrombocytopenia

To compare dosing strategies using total body weight (actual measured body weight), adjusted body weight, and ideal body weight when starting bivalirudin for the treatment for heparin-induced thrombocytopenia (HIT) in obese patients, and to compare differences in dosing requirements and clinical outcomes between obese and nonobese patients.. Retrospective medical record review.. Academic tertiary care medical center.. One hundred thirty-five medical and surgical patients who were treated with bivalirudin for HIT between June 1, 2004, and October 1, 2009.. The 135 patients were separated into two groups based on body mass index (BMI): 46 patients had a BMI greater than 30 kg/m(2) and were classified in the obese group; the nonobese group consisted of 89 patients with a BMI less than 30 kg/m(2) . The mean BMI in the obese group was 37.7 kg/m(2) (range: 30.1-56.2 kg/m(2) ). Weight-standardized doses that achieved activated partial thromboplastin time (aPTT) goal were compared in the obese group. The mean ± SD doses that achieved aPTT goal with total (actual), adjusted, and ideal body weights in this group were 0.1 ± 0.07, 0.11 ± 0.08, and 0.14 ± 0.09 mg/kg/hour, respectively. Of the three weight-based dosing approaches, total body weight followed by adjusted body weight provided the closest correlation to rates observed at the target aPTT goal. The secondary analysis compared initial doses of bivalirudin, doses required to reach goal aPTT, time to achieve goal aPTT, and clinical outcomes (number of patients not achieving goal, new thrombosis, major bleeding, and 30-day all-cause mortality) between the obese and nonobese groups. A significant difference in initial dose was noted between groups; however, no significant differences in dose required to achieve goal aPTT, time to achieve goal aPTT, and clinical outcomes were noted between the obese and nonobese groups.. This study provides evidence that the dosing strategy for bivalirudin based on total body weight is the most accurate predictor of achieving aPTT goal in obese patients with HIT. The study also suggests that there are no clinical differences that warrant different dosing strategies between obese and nonobese patients. Further prospective studies are needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Female; Heparin; Hirudins; Humans; Ideal Body Weight; Male; Middle Aged; Obesity; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Young Adult

Patients with heparin-induced thrombocytopenia (HIT) that require anticoagulation for cardiovascular procedures represent a challenging and high-risk group. Bivalirudin and argatroban have been successfully used as alternative anticoagulants in adult patients with HIT. There have been few experiences published involving the pediatric population and controversy exists regarding the properties and optimal dosing of these drugs. This report describes the experience of managing two pediatric patients with HIT that underwent cardiovascular procedures requiring anticoagulation. Bivalirudin was used in both cases for anticoagulation during cardiopulmonary bypass, while argatroban was used without complications during cardiac catheterization. A description of perfusion and anticoagulation protocols is included.

Topics: Antithrombins; Arginine; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Infant; Infant, Newborn; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

The clinical outcomes of patients receiving renal replacement therapy (RRT) and treated with direct thrombin inhibitors (DTIs) for the management of heparin-induced thrombocytopenia (HIT) were compared.. A retrospective evaluation of clinical outcomes of patients receiving RRT with a presumed diagnosis of HIT treated with lepirudin, argatroban, or bivalirudin was conducted. Inpatients at the University of Pittsburgh Medical Center from January 1, 1995, through March 1, 2008, were included if they were receiving either continuous or intermittent RRT and argatroban, bivalirudin, or lepirudin; were exposed to heparin within the preceding 100 days (including a heparin-treated pulmonary artery catheter) or had a documented heparin allergy; and had at least one of following: (1) an absolute platelet count of <150,000 cells/μL, (2) a decline in platelets of >50% from baseline before exposure to heparin, or (3) a documented diagnosis of thrombocytopenia. The primary outcome assessed was a triple composite endpoint of thrombosis, hemorrhage, and inhospital mortality. A secondary assessment compared the pharmacodynamic relationship between activated partial thromboplastin time and the triple composite.. For the primary endpoint, there was no statistically significant difference observed among DTIs. In patients receiving RRT, a lack of a previous heparin allergy, the degree of International Normalized Ratio elevation, and lower serum albumin were significantly correlated with increased morbidity and the occurrence of the composite endpoint.. No differences in adverse events or other clinical outcomes were observed in this retrospective evaluation of DTI use in patients receiving RRT with presumed HIT.

Topics: Adult; Aged; Anticoagulants; Antithrombins; Arginine; Female; Heparin; Hirudins; Humans; International Normalized Ratio; Male; Middle Aged; Peptide Fragments; Pipecolic Acids; Platelet Count; Recombinant Proteins; Renal Replacement Therapy; Retrospective Studies; Serum Albumin; Sulfonamides; Thrombocytopenia

The impact of a collaborative drug therapy management (CDTM) agreement enabling pharmacist-managed direct thrombin inhibitor (DTI) therapy was evaluated.. A retrospective chart review was conducted to compare selected outcome measures between cohorts of adults who received argatroban or bivalirudin therapy for suspected heparin-induced thrombocytopenia (HIT) before (n = 25) and after (n = 25) the implementation of an institutional DTI protocol under which properly trained and credentialed pharmacists have a primary role in dosing and monitoring DTI infusions. The primary endpoints were the mean time to attainment of activated partial thromboplastin time (aPTT) values in a specified therapeutic range and the proportion of total inpatient treatment time during which aPTT values were in that range. Secondary endpoints included the incidence of major and minor bleeding and the incidence of medication errors.. After implementation of the DTI protocol, therapeutic aPTT values were achieved more rapidly (a mean of 3.4 hours in the postimplementation cohort versus a mean of 7.7 hours in the preimplementation cohort, p = 0.009) and maintained more consistently. Rates of bleeding and overall mortality were similar in the two groups; the frequencies of documented medication errors were 12% and 40% in the postimplementation and preimplementation cohorts, respectively (p = 0.05).. A pharmacist-driven DTI program resulted in improved effectiveness and safety outcomes, as demonstrated by improved attainment of target aPTT values and a decreased frequency of medication errors.

Topics: Adult; Aged; Antithrombins; Arginine; Cohort Studies; Cooperative Behavior; Drug Monitoring; Female; Hemorrhage; Heparin; Hirudins; Humans; Inpatients; Male; Medication Errors; Middle Aged; Outcome Assessment, Health Care; Partial Thromboplastin Time; Peptide Fragments; Pharmacists; Pharmacy Service, Hospital; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Time Factors

Thrombin inhibition is an important objective in the prevention and treatment of thrombosis. A new molecule, dabigatran etexilate or Pradaxa(®), has been recently licensed for thromboprophylaxis in major orthopedic surgery in several countries but not in the USA. In contrast, the FDA has approved it for prevention in patients with non-valvular atrial fibrillation. This new orally active anticoagulant is being developed for the treatment of venous thromboembolism and acute coronary syndromes in patients with non-valvular atrial fibrillation. Dabigatran is a reversible inhibitor of free thrombin and clot-bound thrombin. An oral thrombin inhibitor melagatran is no longer available due to hepatic toxicity. Several other thrombin inhibitors are used via parenteral administration: lepirudine and desirudine, bivalirudine and argatroban. They are mostly given to patients with heparin-induced thrombocytopenia (HIT). Bivalirudine is used for acute coronary syndrome in patients undergoing percutaneous interventions. The main pharmacologic characteristics of thrombin inhibitor agents are presented focusing on dabigatran etexilate and including the main results of clinical trials.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; Contraindications; Dabigatran; Drug Interactions; Heparin; Hirudin Therapy; Hirudins; Humans; Orthopedic Procedures; Peptide Fragments; Postoperative Complications; Pyridines; Recombinant Proteins; Thrombocytopenia; Thrombosis; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin-platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of o Ther causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.

Topics: Aged; Anticoagulants; Arginine; Cardiac Catheterization; Cardiac Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Vascular Surgical Procedures; Vitamin K; Young Adult

Anticoagulation therapy for cardiopulmonary bypass in patients with recently diagnosed heparin-induced thrombocytopenia can be particularly challenging. Although heparin is the standard of care, in these situations anticoagulation is achieved with alternative agents such as direct thrombin inhibitors. Therapeutic concentrations are difficult to assess with direct thrombin inhibitors, and their use is riddled with bleeding and thrombotic complications. We report the successful use of a specific chromogenic antifactor IIa assay in a patient with heparin-induced thrombocytopenia who received anticoagulation therapy with bivalirudin during cardiopulmonary bypass for coronary artery bypass graft surgery.

Topics: Aged; Antithrombins; Cardiopulmonary Bypass; Coronary Artery Bypass; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Monitoring, Intraoperative; Myocardial Infarction; Peptide Fragments; Peripheral Vascular Diseases; Preoperative Care; Radiography; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) occurs in both the pediatric and adult populations after exposure to heparin. Bivalirudin has been used as an alternative to heparin for adults undergoing cardiac surgery and cardiopulmonary bypass, but has only been used minimally in children for this purpose. We report the successful use of bivalirudin for anticoagulation during cardiopulmonary bypass in a small child with HIT, using novel techniques not previously described.

Topics: Anticoagulants; Cardiopulmonary Bypass; Equipment Design; Heparin; Hirudins; Humans; Infant; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15-0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear.. To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis.. A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30-60 mL/min (n = 26), and CrCl <30 mL/min (n = 16).. Compared with patients with normal renal function (CrCl >60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30-60 and <30 mL/min) required lower doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p < 0.001). Patients on dialysis (IHD, SLEDD, CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl <30 mL/min.. Patients with renal dysfunction require a reduced dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Creatinine; Drug Monitoring; Female; Heparin; Hirudins; Humans; Male; Medical Records; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Severity of Illness Index; Thrombocytopenia; Young Adult

To evaluate steady-state bivalirudin dosing requirements in patients with a wide range of kidney function who were being treated for heparin-induced thrombocytopenia (HIT)-related disorders.. Retrospective medical record review.. Academic medical center.. Sixty-four adults with varying degrees of renal function who were receiving bivalirudin for at least 48 hours for HIT-related disorders between March 2007 and May 2010.. Steady-state conditions were defined as a constant bivalirudin infusion dose for at least 12 hours, with serum creatinine concentration varying less than 20% for 48 hours (for patients not receiving renal replacement therapy) and at least two therapeutic activated partial thromboplastin time (aPTT) values (60-80 sec). Patients were assigned to five groups based on Cockcroft-Gault-estimated creatinine clearance (Clcr) of less than 30, 30-60, or greater than 60 ml/minute, or by type of renal replacement therapy-intermittent hemodialysis or continuous venovenous hemofiltration (CVVH). For Clcr greater than 60 ml/minute, the median bivalirudin dose was 0.15 mg/kg/hour (interquartile range [IQR] 0.11-0.15 mg/kg/hr), which was greater than median doses for Clcr 30-60 ml/minute (0.10 mg/kg/hr, IQR 0.06-0.13 mg/kg/hr, p=0.004), Clcr less than 30 ml/minute (0.08 mg/kg/hr, IQR 0.04-0.1 mg/kg/hr, p=0.001), CVVH (0.06 mg/kg/hr, IQR 0.03-0.10 mg/kg/hr, p=0.046), and hemodialysis (0.04 mg/kg/hr, IQR 0.03-0.05 mg/kg/hr, p=0.0001). Bivalirudin doses correlated with Clcr (Spearman r = 0.58, p<0.01). The median aPTT value of 70 seconds (IQR 63-74 sec) was similar in all groups. Thrombosis was present before bivalirudin therapy in 18 (28%) of 64 patients, and two patients (3%) developed thromboemboli during bivalirudin therapy. Clinically significant bleeding related to bivalirudin and leading to discontinuation of bivalirudin occurred in four patients (6%). The median international normalized ratio increased from 1.5 (IQR 1.3-1.7) before bivalirudin therapy to 1.9 (IQR 1.8-2.1) during bivalirudin therapy (p=0.002) in 11 patients who were not receiving warfarin.. Bivalirudin dosing requirements increased with increasing Clcr values. The high degree of variability suggests that dosing in individual patients will require careful titration to achieve adequate anticoagulation.

Topics: Aged; Aged, 80 and over; Antithrombins; Creatinine; Dose-Response Relationship, Drug; Female; Heparin; Hirudins; Humans; Infusions, Intravenous; International Normalized Ratio; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Renal Replacement Therapy; Retrospective Studies; Thrombocytopenia

We present the case of a man with heparin-induced thrombocytopenia (HIT) and acute idiopathic decompensated cardiomyopathy who underwent successful heart transplantation with the use of bivalirudin as anticoagulant.

Topics: Adult; Anticoagulants; Blood Transfusion, Autologous; Cardiomyopathies; Cardiopulmonary Bypass; Heart Transplantation; Heparin; Hirudins; Humans; Immunosuppressive Agents; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Transplantation, Homologous; Treatment Outcome

Infants with heparin-induced thrombocytopenia (HIT) represent a challenging and high-risk group of patients when they require cardiopulmonary bypass (CPB). Bivalirudin offers many potential pharmacologic advantages over other nonheparin anticoagulants for such patients. We describe our protocol for the use of bivalirudin in a 5-month-old infant undergoing stage 2 Norwood for hypoplastic left heart syndrome. The patient was a 5- month-old, 6-kg infant who developed HIT after a bowel resection complicating initial Norwood stage 1. After sternotomy and dissection had been redone, the child received an initial dose of bivalirudin of 1.0 mg/kg and 0.5 mg/kg 5 min later. The CPB circuit was primed with 50 mg/kg bivalirudn/400 cc volume. With the initiation of CPB, a continuous infusion of 2.5 mg/kg bivalirudin was begun. Activated clotting time (ACT) was targeted for over 400 s, with an examination prior to bypass and each 15 min thereafter. Bivalirudin was discontinued with separation from bypass and during modified ultrafiltration (MUF). The ACT was 286 s after the initial 1 mg/kg bolus and 597 s after the second 0.5 mg/kg bolus and initiation of CPB. At a rate of 2.5 mg/kg/min, ACT ranged between 461 and 597 s. At the completion of MUF, the ACT was 316 s. The ACT was 214 s 20 min after MUF. No clots were noted in the CPB circuit, and good hemostasis was achieved within 10 min after MUF was completed. Incision to closure time was 160 min; time from completion of MUF to sternal closure was 30 min. Post-MUF, 60 cc of processed cell saver blood was reinfused, and no clotting factors were required. Chest tube output was 10, 10, 3, and 4 ccs, respectively, at hours 1-4 post operation. Bivalirudin provides effective anticoagulation in infants requiring CPB in the presence of HIT. Bivalirudin's efficacy is effectively monitored by ACT, and, after CPB, its short half-life and ability to be ultrafiltered facilitate the ability to achieve hemostasis in a timely fashion.

Topics: Anticoagulants; Cardiopulmonary Bypass; Clinical Protocols; Heparin; Hirudins; Humans; Hypoplastic Left Heart Syndrome; Infant; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Direct thrombin inhibitors are heparin alternatives for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. We report a case of a large thrombus forming in the venous reservoir while using bivalirudin. We suggest that blood stasis associated with the full venous reservoir maintained in this case led to formation of a large thrombus at the top of the venous canister. Furthermore, activated clotting times may not accurately reflect the magnitude of anticoagulation when using direct thrombin inhibitors.

Topics: Anticoagulants; Antithrombins; Cardiomyopathy, Dilated; Fibrinolysis; Heart Transplantation; Heparin; Hirudins; Humans; Intra-Aortic Balloon Pumping; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Failure; Whole Blood Coagulation Time

Current guidelines recommend using bivalirudin, a direct thrombin inhibitor,as a preferred alternative to unfractionated heparin in patients with heparin induced thrombocytopenia (HIT) for percutaneous coronary intervention, as well as for cardiac and vascular surgery. Anticoagulation during radiofrequency catheter ablation (RFA) procedures may be another potential use for bivalirudin in the setting of HIT. Radiofrequency catheter ablation procedures involving left atrial or left ventricular access are increasingly employed as a method to treat cardiac arrhythmias. Because stroke risk is a serious complication of RFA, anticoagulation is required during this procedure. We describe the first report, to our knowledge, of successful use of bivalirudin anticoagulation during RFA procedures in two patients with a history of clinically diagnosed HIT that precluded the use of unfractionated heparin or low-molecular-weight heparin. One of the patients underwent RFA for ventricular tachycardia, the other for pulmonary vein isolation for the treatment of atrial fibrillation. In both patients, bivalirudin was administered as a 0.75-mg/kg intravenous bolus, followed by a 1.75-mg/kg/hour infusion.Activated clotting time (ACT) was measured after the initial bolus in each patient. However, no dosage adjustment was made based on the ACT, and the infusion rate of bivalirudin remained fixed during the procedures. Both procedures were completed without any embolic events. No bleeding or clotting events were noted; one patient experienced minor access site oozing that was not felt to be clinically important. Bivalirudin is a therapeutic option for anticoagulation during left-sided catheter RFA procedures in patients with a history of HIT.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Catheter Ablation; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Tachycardia, Ventricular; Thrombocytopenia; Treatment Outcome

To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin-induced thrombocytopenia (HIT).. Single-center, retrospective analysis.. Large tertiary care academic medical center.. A total of 138 adults who received either bivalirudin (92 patients) or argatroban (46 patients) for at least 24 hours for known or suspected HIT between January 2007 and July 2008. MEASUREMENTS AND MAIN RESULTS. Data regarding demographics, direct thrombin inhibitor (DTI) dosing and monitoring, and related clinical outcomes were collected; statistical analysis was performed to compare results for patients receiving bivalirudin versus those receiving argatroban. Duration of DTI use ranged from 24-658 hours. At the time of DTI initiation, 108 patients (78%) were in an intensive care unit, with the highest proportion (61/138 [44%]) in the cardiothoracic surgery intensive care unit. The median (interquartile range [IQR]) DTI doses at the time of first reaching therapeutic goal were bivalirudin 0.06 mg/kg/hour (0.04-0.08 mg/kg/hr) and argatroban 1.0 μg/kg/minute (0.5-2.0 μg/kg/min). The median percentage of activated partial thromboplastin time (aPTT) values within therapeutic range while patients were receiving DTI therapy were similar for bivalirudin and argatroban (75% and 70%, respectively, p=0.238). A greater percentage of aPTT values were supratherapeutic with argatroban versus bivalirudin treatment (18% vs 8%, p=0.046). Median time to therapeutic goal was similar for bivalirudin (5.50 hrs [IQR 4-14.5 hrs]) and argatroban (5.75 hrs [IQR 3-17.7 hrs], p=0.499). New thromboembolic events occurred in seven patients (8%) receiving bivalirudin and two (4%) receiving argatroban (p=0.718). Bleeding events occurred at similar rates in both groups (9% for bivalirudin vs 11% for argatroban, p>0.999).. Bivalirudin and argatroban were similar in achieving and maintaining therapeutic anticoagulation goals, clinical outcomes, and safety. This study suggests that bivalirudin represents an alternative in the management of HIT, but prospective studies are needed.

Topics: Antithrombins; Arginine; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombocytopenia; Time Factors

We report a combined carotid endarterectomy and coronary revascularization surgery with cardiopulmonary bypass using bivalirudin for systemic anticoagulation in a patient with a positive titer for the heparin-platelet factor 4 antibody. The patient experienced procedural success for both the carotid and coronary surgeries. Increased blood and blood product transfusion was required postoperatively.

Topics: Anticoagulants; Autoantibodies; Blood Coagulation; Cardiopulmonary Bypass; Carotid Stenosis; Coronary Artery Bypass; Coronary Artery Disease; Endarterectomy, Carotid; Heparin; Hirudins; Humans; Intraoperative Care; Male; Middle Aged; Peptide Fragments; Platelet Factor 4; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Topics: Animals; Anticoagulants; Antithrombins; Clinical Trials as Topic; Heart Valve Prosthesis; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombocytopenia; Thromboembolism

Prevention of valve thrombosis in patients after prosthetic mechanical heart valve replacement and heparin-induced thrombocytopenia (HIT) is still an open issue. The aim of the present in-vitro study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves. Blood (230 ml) from healthy young male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion. Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anticoagulated blood samples. To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment. Mean thrombus weight in group 1 (UFH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p-value <0.001). Electron microscopy showed increased rates of thrombus formation in groups 2 and 3. Argatroban and bivalirudin were as effective as UFH in preventing thrombus formation on valve prostheses in our in-vitro investigation when they were administered continuously. We hypothesise that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa.

Topics: Anticoagulants; Arginine; Diagnostic Techniques, Cardiovascular; Drug Therapy, Combination; Feasibility Studies; Heart Diseases; Heart-Assist Devices; Heparin; Hirudins; Humans; In Vitro Techniques; Infusion Pumps; Male; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Antithrombins; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation; Recombinant Proteins; Thrombocytopenia

To describe a case of successful bivalirudin use as a prefilter anticoagulant in continuous venovenous hemofiltration (CVVH).. A 30-year-old male was brought to the hospital by ambulance with an anterior communicating artery subarachnoid hemorrhage, signs of intraparenchymal hemorrhage, and hydrocephalus. During the patient's complicated hospital course, he developed acute renal failure requiring CVVH, as well as hepatic insufficiency (Child-Pugh class B). Unfractionated heparin was used as a prefilter anticoagulant. After he had a positive heparin-induced thrombocytopenia (HIT) antibody test, prefilter heparin was discontinued in favor of bivalirudin. Filter survival and systemic activated partial thromboplastin time (aPTT) values were compared between prefilter heparin (n = 5) and bivalirudin (n = 4). Filter survival was similar (median 26 h with heparin vs 37 h with bivalirudin; p = 0.52). Prefilter bivalirudin 1-2.5 mg/hour (0.009-0.023 mg/kg/h) was effective in maintaining systemic aPTTs that were 1-1.4 times the reference range. Serotonin release assay and subsequent HIT antibodies were negative. The patient's renal function improved and CVVH was discontinued.. Critically ill patients requiring CVVH often need regional or systemic anticoagulation to prevent filter occlusion. In some patient populations, such as those with HIT or liver failure, prefilter heparin and regional citrate, respectively, may not be options. Alternative anticoagulants may be needed to avoid complications of frequent filter occlusions. The direct thrombin inhibitors (DTIs) lepirudin and argatroban have been used to maintain hemofilter patency, in small studies. Bivalirudin may have pharmacokinetic advantages over other DTIs when used in patients with hepatic and renal impairment. In our patient, bivalirudin provided a safe alternative to heparin therapy and was effective in maintaining hemofilter patency during CVVH.. Prefilter bivalirudin may be an option to prevent filter occlusion in patients requiring continuous renal replacement therapy. Future studies are needed to validate the safety and efficacy of bivalirudin as a prefilter anticoagulant.

Topics: Acute Kidney Injury; Adult; Anticoagulants; Hemofiltration; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin which significantly confers risks of thrombosis and devastating outcomes. Once diagnosed, it requires immediate cessation of heparin and therapy with an alternative anticoagulant. No data are available in the literature on the pathophysiology and clinical implications of performing prolonged extracorporeal membrane oxygenation with a heparin-coated system in a patient with acute HIT treated with bivalirudin.

Topics: Acute Disease; Aged; Antibodies; Anticoagulants; Extracorporeal Membrane Oxygenation; Female; Heparin; Hirudins; Humans; Mitral Valve Insufficiency; Peptide Fragments; Platelet Count; Recombinant Proteins; Thrombocytopenia

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

Topics: Anticoagulants; Arginine; Biological Availability; Chondroitin Sulfates; Dermatan Sulfate; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Infusions, Parenteral; Injections, Subcutaneous; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Topics: Aged; Anticoagulants; Blindness, Cortical; Brain Infarction; Heparin; Hirudins; Humans; Male; Mesenteric Arteries; Occipital Lobe; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis; Tomography, X-Ray Computed; Treatment Outcome

Type II heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that may arise in a time-dependent manner following heparin therapy, placing patients at significant risk for thromboembolic events. Therapy includes anticoagulation with a direct thrombin inhibitor and avoidance of heparin. We report a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia who presented for orthotopic liver transplant and required postoperative anticoagulation with bivalirudin. During the post-transplant graft function improvement, we observed a significant dose-effect alteration manifested by an increased bivalirudin dose requirement as factor V activity increased. This observation is an important consideration in the attempt to maintain an optimal balance between effective anticoagulation and a reduced risk of postoperative bleeding.

Topics: Adult; Anticoagulants; Blood Coagulation; Budd-Chiari Syndrome; Dose-Response Relationship, Drug; Factor V; Heparin; Hirudins; Humans; Liver; Liver Transplantation; Male; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis

To evaluate the safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia (HIT).. Retrospective cohort study.. University-affiliated hospital.. Thirty-seven adults with a diagnosis or history of HIT who were treated with bivalirudin between January 1, 2004, and March 31, 2007.. Patients had a mean +/- SD age of 50 +/- 16 years and weighed 80 +/- 20 kg; 62% were male, 73% were Caucasian, and 95% were treated in the intensive care unit. Patients were divided into three renal function groups for assessment of bivalirudin dosing requirements: creatinine clearance (Cl(cr)) greater than 60 ml/minute (12 patients, group 1); Cl(cr) 30-60 ml/minute (11 patients, group 2); and Cl(cr) lower than 30 ml/minute or receiving continuous renal replacement therapy ([RRT] 14 patients, group 3). Except for renal function, baseline demographic characteristics were similar among groups. A total of 19 (51%) of the 37 patients achieved goal activated partial thromboplastin time (aPTT) with initial mean +/- SD bivalirudin doses of 0.14 +/- 0.04 (median 0.15), 0.1 +/- 0.07 (median 0.08), and 0.05 +/- 0.05 (median 0.05) mg/kg/hour in groups 1, 2, and 3, respectively. Doses remained similar over the study period and were 0.13 +/- 0.04 (median 0.15), 0.1 +/- 0.06 (median 0.1), and 0.04 +/- 0.02 (median 0.03) mg/kg/hour for groups 1, 2, and 3, respectively. The mean +/- SD aPTT value after achieving goal range was 64 +/- 9 seconds (all patients). Bivalirudin dosing requirements correlated with Cl(cr) (r(2) = 0.37, p<0.0001). Therapy duration was a mean +/- SD of 11 +/- 13 days (median 7 days). Systemic thrombosis and bleeding while receiving bivalirudin were also evaluated. Thrombosis occurred in one patient; clinically significant bleeding occurred in two patients.. Bivalirudin dosing requirements correlated with renal function; therefore, dosage reduction is required in patients with moderate or severe renal dysfunction. Starting bivalirudin at 0.15 mg/kg/hour in patients with Cl(cr) greater than 60 ml/minute, 0.08-0.1 mg/kg/hour in patients with Cl(cr) 30-60 ml/minute, and 0.03-0.05 mg/kg/hour in patients with Cl(cr) below 30 ml/minute or receiving continuous RRT is effective at achieving goal aPTT values in most patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Creatinine; Dose-Response Relationship, Drug; Female; Heparin; Hirudins; Humans; Kidney Function Tests; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Treatment Outcome; Young Adult

Thromboembolism in children is typically treated with unfractionated heparin (UH) or low molecular weight heparin (LMWH). Both rely on antithrombin (AT) for their action. In addition, heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin use in children. Bivalirudin or other direct thrombin inhibitors may be a useful alternative to heparins in treating thrombosis in children.. We report a retrospective review to assess the efficacy and safety of bivalirudin in pediatric patients with thrombosis.. Sixteen children received bivalirudin for thrombosis or prevention of thrombosis at the Children's Hospital of Illinois from January 2005 to January 2007. Patients received a bolus dose of 0.25 mg/kg followed by a continuous infusion (0.16 +/- 0.07 mg kg(-1) hr(-1)) titrated to 1.5-2.5 times the baseline activated partial thromboplastin time (aPTT). Positive correlation between the bivalirudin average infusion rate and aPTT was observed in twelve patients. Ultrasonographic evidence of thrombus regression was noted at 72 hr in 10 of 10 patients. One patient experienced hematuria after catheterization of the urethra.. Bivalirudin was effective and well-tolerated in these patients. Further studies should be conducted to better define safety and efficacy of bivalirudin in pediatric patients.

Topics: Adolescent; Anticoagulants; Antithrombins; Child; Child, Preschool; Female; Heparin; Hirudins; Humans; Infant; Infant, Newborn; Male; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening, adverse effect of heparin therapy. Patients with this complication require an alternative approach to anticoagulation. Bivalirudin is a direct thrombin inhibitor with an efficacy comparable to that of heparin, a short half-life, and reduced bleeding complications in adults. We present the case of a 2-year-old boy with HIT Type II who underwent recanalization of an occluded superior vena cava and stent placement, utilizing bivalirudin as anticoagulant.

Topics: Angioplasty, Balloon; Anticoagulants; Child, Preschool; Heart Defects, Congenital; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Recurrence; Stents; Superior Vena Cava Syndrome; Thrombocytopenia

A patient with myocardial failure after repair of an acute type A aortic dissection had acute heparin-induced thrombocytopenia develop during extracorporeal membrane oxygenation. Heparin was discontinued and the anticoagulant was switched to the direct thrombin inhibitor bivalirudin given with a bolus of 0.5 mg/kg followed by a continuous infusion of 0.5 mg/kg/h. Using this protocol, activated clotting time values ranged from 200 to 220 seconds. After prolonged extracorporeal membrane oxygenation support and recovery of left ventricular function, a right ventricular assist device was implanted during extracorporeal membrane oxygenation support with bivalirudin anticoagulation. For this procedure an additional bolus of 0.25 mg/kg bivalirudin was given, and the infusion rate increased to 1 mg/kg/h to achieve activated clotting time values of 300 to 350 seconds. Surgery was successfully performed with moderate intraoperative and postoperative blood loss and transfusion requirements.

Topics: Adult; Anticoagulants; Aortic Aneurysm; Aortic Dissection; Cardiac Surgical Procedures; Extracorporeal Membrane Oxygenation; Female; Heart Failure; Heart-Assist Devices; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Topics: Antibodies; Anticoagulants; Coronary Artery Bypass, Off-Pump; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Factor 4; Recombinant Proteins; Thrombocytopenia

To describe the successful use of bivalirudin as the primary procedural anticoagulant in a patient with suspected heparin-induced thrombocytopenia (HIT) undergoing carotid endarterectomy (CEA).. A 73-year-old white man presented for an elective CEA 3 weeks after emergent, on-pump coronary artery bypass grafting. Bivalirudin was used for procedural anticoagulation because of seropositivity for heparin-PF4 antibodies and a clinical history consistent with HIT. The dose was administered as a 0.75 mg/kg bolus and 1.75 mg/kg/h infusion as reported in percutaneous coronary intervention, based on review of the available bivalirudin literature. The dosage was adjusted for the patient's renal dysfunction. The outcome was successful, with the patient discharged home in 8 days without significant complications.. During active HIT, when thrombocytopenia and heparin-PF4 antibodies are present, heparin therapy must be avoided. In patients with subacute HIT, when platelet counts have recovered but HIT antibodies are still present, it is also prudent to avoid heparin administration. In the case of a patient in whom anticoagulation is necessary but heparin use is contraindicated, a direct thrombin inhibitor, such as bivalirudin, may offer a viable alternative. Bivalirudin is not immunogenic and does not cross-react with the heparin-PF4 antibodies associated with HIT. To our knowledge, as of January 20, 2006, this is the first report of the use of bivalirudin for procedural anticoagulation during CEA in a patient with HIT antibodies and recent exposure to heparin.. Further investigation is warranted to clarify the clinical benefits of bivalirudin for patients undergoing vascular surgery of the carotids, including potential advantages for vulnerable patient populations such as those with diagnosed or suspected HIT as well as those with renal dysfunction.

Topics: Aged; Antibodies; Anticoagulants; Endarterectomy, Carotid; Heparin; Hirudins; Humans; Male; Peptide Fragments; Platelet Count; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Coronary Artery Bypass, Off-Pump; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Syndrome; Thrombocytopenia

Topics: Anticoagulants; Cardiopulmonary Bypass; Contraindications; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Factor 4; Recombinant Proteins; Sulfonamides; Thrombocytopenia

To evaluate the safety, effectiveness, and dosing of bivalirudin for treatment of heparin-induced thrombocytopenia (HIT) in critically ill patients with hepatic and/or renal dysfunction.. Retrospective cohort study.. University-affiliated medical center. Eighteen patients older than 18 years who were admitted to the intensive care unit (ICU), had hepatic and/or renal dysfunction, and were treated with bivalirudin for the diagnosis of HIT between January 1, 2004, and March 31, 2005.. Patient records were reviewed for dosage and duration of bivalirudin therapy, occurrence of thrombosis, and clinically significant adverse effects. Of the 18 patients identified, 12 had both hepatic and renal dysfunction (group 1), four had hepatic dysfunction (group 2), and two had renal dysfunction (group 3). Demographics were similar among the groups. Mean +/- SD age was 54 +/- 15 years and weight was 82 +/- 14 kg, 67% were male, 83% were Caucasian, and 56% were receiving renal replacement therapy. Mean bivalirudin doses were 0.06 +/- 0.15 mg/kg/hour (median 0.03 mg/kg/hr), 0.14 +/- 0.05 mg/kg/hour (median 0.14 mg/kg/hr), and 0.05 +/- 0.01 mg/kg/hour (median 0.05 mg/kg/hr) for patients in groups 1, 2, and 3, respectively. Ten patients receiving continuous venovenous hemofiltration with or without dialysis received a mean dose of 0.04 +/- 0.03 mg/kg/hour (median 0.03 mg/kg/hr). In the 18 patients, mean bivalirudin duration was 15 +/- 17 days, activated partial thromboplastin time (aPTT) was 69 +/- 22 seconds, and international normalized ratio was 2.2 +/- 0.8. Supratherapeutic aPTTs were most common on days 1 (22%) and 2 (28%) when bivalirudin doses were highest. Clinically significant bleeding did not occur in any patient. Thrombosis occurred in one patient (6%) while receiving bivalirudin.. Patients in the ICU who have hepatic and/or renal dysfunction require low doses of bivalirudin to achieve aPTT values 1.5-2.5 times baseline. Bivalirudin can be safely started at 0.14 mg/kg/hour in patients with hepatic dysfunction, 0.03-0.05 mg/kg/hour in those with renal or combined hepatic and renal dysfunction, and 0.03-0.04 mg/kg/hour in patients receiving continuous renal replacement therapy.

Topics: Adult; Aged; Anticoagulants; Cohort Studies; Critical Illness; Female; Heparin; Hirudins; Humans; Intensive Care Units; Kidney Diseases; Liver Diseases; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombin; Thrombocytopenia

To evaluate the efficacy, safety, and associated costs of anticoagulation with argatroban, bivalirudin, and lepirudin for managing patients with heparin-induced thrombocytopenia (HIT) or presumed HIT.. Retrospective medical record review.. University-affiliated teaching hospital.. Forty-two patients who were hospitalized between January 1 and December 31, 2004, and who were treated with bivalirudin, argatroban, or lepirudin for at least 24 hours.. The primary outcome was the time to reach the desired goal for activated partial thromboplastin time (aPTT). Secondary outcomes were the number of aPTT measurements within the therapeutic range, costs, treatment duration, clinical outcomes, and adverse events. Of the 42 patients who met the inclusion criteria, 24 received bivalirudin, 13 received argatroban, and 5 received lepirudin. Patients receiving bivalirudin who reached therapeutic aPTTs attained them sooner than those receiving either argatroban or lepirudin (8.5 vs 14 and 24 hrs, respectively, p=0.124). Average percentage of therapeutic aPTTs/patient was greatest in the argatroban group (62%), followed by the bivalirudin (57%) and lepirudin (29%) groups (p=0.062). Average drug cost/day/patient was greater in the lepirudin group than the other groups, whereas average laboratory costs were similar among groups. Treatment duration was longer with argatroban than with bivalirudin or lepirudin. Bleeding rates were similar in the argatroban and bivalirudin groups, but higher than in the lepirudin group. A composite of clinical outcomes (deep vein thrombosis, nonfatal myocardial infarction, nonfatal stroke, limb amputation, and all-cause mortality) were similar among the three groups.. All three drugs were effective as anticoagulants for patients with HIT or presumed HIT. Based on average use and average wholesale price, bivalirudin cost less per day than the other two agents. Although not yet approved by the United States Food and Drug Administration for management of HIT, bivalirudin appears to be a viable treatment alternative for anticoagulation therapy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arginine; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Retrospective Studies; Sulfonamides; Thrombin; Thrombocytopenia; Time Factors; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a potentially serious syndrome. Since there are some alternatives to treatment with heparin in patients who develop HIT, the decision as to which to use should be based on renal and hepatic function, drug availability and the available monitoring resources. We report a patient who received heparin for mechanical aortic valve replacement. Her clinical course was complicated by HIT, which was treated initially by danaparoid. The syndrome progressed with new thrombotic complications, and eventually was treated successfully by bivalirudin (Angiomax; Medison Pharma Ltd, Petach Tikva, Israel) for 9 days. We propose that treatment with bivalirudin for several days is a safe and effective alternative to heparin therapy in patients who develop HIT.

Topics: Anticoagulants; Aortic Valve; Fatal Outcome; Female; Follow-Up Studies; Heart Valve Prosthesis; Heparin; Hirudins; Humans; Middle Aged; Peptide Fragments; Platelet Count; Recombinant Proteins; Syndrome; Thrombocytopenia

Heparin-induced thrombocytopenia is a potentially limb- and life-threatening response to heparin exposure. Direct thrombin inhibitors (DTIs) have been reported to provide anti-coagulation for cardiopulmonary bypass; however, clot formation within the cardiopulmonary bypass circuit has been reported after the administration of DTIs. We present a case of thrombosis of the cardiopulmonary bypass circuit and, ultimately, death after argatroban administration. An in vitro thrombelastographic assessment of the effects of DTIs on clot kinetics was consequently performed to determine potential causes for this complication.. Normal human plasma was unmodified or exposed to heparin (1, 2, 3 U/ml), argatroban (5, 10, 50 microg/ml), bivalirudin (12, 20, 120 microg/ml), or lepirudin (3, 6, 10 microg/ml) before activation with tissue factor/kaolin in a thrombelastograph. Clot initiation (R, reaction time), propagation (MTG, maximum thrombus generation), and strength (MG, maximum elastic modulus) were determined. Analysis of variance was performed, with p < 0.05 considered significant.. Compared with unmodified plasma, heparin significantly prolonged R and essentially reduced MTG and MG to the limits of detection in an activity-dependent fashion. In general, the DTIs tested prolonged R in a concentration-dependent fashion but did not diminish MTG or MG nearly as well as heparin. The only exception was 10 microg/ml lepirudin, which eliminated coagulation.. DTIs demonstrated a significant prolongation of clot initiation but poor attenuation of propagation and strength. Further in vitro and clinical investigations to design a heparin-equivalent regimen to provide anti-coagulation for patients with heparin-induced thrombocytopenia are indicated.

Topics: Anticoagulants; Antithrombins; Arginine; Cardiopulmonary Bypass; Child; Dose-Response Relationship, Drug; Fatal Outcome; Female; Fibrinolytic Agents; Heart Transplantation; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Recombinant Proteins; Sulfonamides; Thrombelastography; Thrombocytopenia; Treatment Failure; Whole Blood Coagulation Time

Unfractionated heparin has been a near universal anticoagulant for cardiac surgery; however it is contraindicated in heparin-induced thrombocytopenia type II. Alternative anticoagulants such as bivalirudin (a direct thrombin inhibitor) are being utilized. Bivalirudin was successfully used in an immunologically complex patient (diagnoses of heparin-induced thrombocytopenia type II, systemic lupus erythematosus, antiphospholipid syndrome, and dialysis-dependent renal failure) requiring cardiopulmonary bypass. Thrombotic events are common in antiphospholipid syndrome patients undergoing cardiac surgery utilizing high-dose heparin. This may represent unrecognized heparin-induced thrombocytopenia type II. Our patient did not experience perioperative thrombotic or bleeding complications. The possible cross-reactivity between heparin induced thrombocytopenia type II and antiphospholipid syndrome has not been investigated.

Topics: Adult; Antibody Specificity; Anticoagulants; Antiphospholipid Syndrome; Autoantibodies; Cross Reactions; Drug Evaluation; Drug Therapy, Combination; Female; Heart Failure; Heparin; Hirudins; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Mitral Valve Insufficiency; Peptide Fragments; Platelet Count; Platelet Factor 4; Recombinant Proteins; Renal Dialysis; Thrombocytopenia; Thrombophilia; Warfarin

Giant-cell myocarditis (GCM) is a rare, idiopathic disorder of young adults with high rates of morbidity and mortality. We describe a unique case of giant cell myocarditis associated with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS). Our patient responded to therapy with bivalirudin, but later succumbed to complications from multiorgan failure. To our knowledge, this is the first reported case of GCM associated with HITTS, which was treated with bivalirudin (Angiomax; The Medicines Company; Parsippany, NJ).

Topics: Adult; Anticoagulants; Fatal Outcome; Giant Cells; Heparin; Hirudins; Humans; Male; Multiple Organ Failure; Myocarditis; Necrosis; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis

A patient with chronic lymphocytic leukemia and thrombocytopenia who underwent percutaneous coronary intervention (PCI) and stenting is presented. Patients with these concomitant diseases who require invasive cardiac procedures are at increased risk for ischemic and bleeding complications and the choice of anticoagulation in these patients is critical. In the present case, anticoagulation was achieved with the direct thrombin inhibitor bivalirudin. No complications were reported, and the patient tolerated the procedure well. This case suggests that bivalirudin may be safely used in patients who are at an increased risk of bleeding undergoing PCI.

Topics: Aged; Cardiac Catheterization; Clopidogrel; Hirudins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Ticlopidine

Bivalirudin, a direct thrombin inhibitor, has recently emerged as a promising option for anti-coagulation during cardiopulmonary bypass in patients who cannot receive heparin. There is limited experience with the use of bivalirudin in children. We present the case of a child with heparin-induced thrombocytopenia with thrombosis (HIT Type II) who underwent successful orthotopic cardiac transplantation using bivalirudin as the primary anti-coagulant for cardiopulmonary bypass.

Topics: Anticoagulants; Cardiopulmonary Bypass; Child, Preschool; Dose-Response Relationship, Drug; Female; Heart Transplantation; Heparin; Hirudins; Humans; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Blood Coagulation Tests; Endopeptidases; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time

Heparin-induced thrombocytopenia (HIT) is an increasingly common clinical finding in patients presenting for cardiac transplantation. Bivalrudin, a reversible direct thrombin inhibitor, is a molecular anti-coagulant with short half-life and the potential for removal by intraoperative hemofiltration. Herein we describe the dosing and intraoperative management of bivalrudin anti-coagulation in a patient undergoing urgent cardiac transplantation in the context of recently diagnosed HIT.

Topics: Adult; Anticoagulants; Cardiomyopathy, Dilated; Combined Modality Therapy; Dose-Response Relationship, Drug; Heart Failure; Heart Transplantation; Hemofiltration; Heparin; Hirudins; Humans; Intraoperative Care; Male; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombocytopenia

The use of heparin in patients with heparin-induced thrombocytopenia (HIT) may result in severe complications or death. The diagnosis of HIT is frequently uncertain, however. Alternative anticoagulants in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass remain problematic. The novel short-acting, direct-thrombin inhibitor bivalirudin is the only alternative to heparin/protamine being used in elective non-HIT patients during CPB.. Four patients with severe thrombocytopenia after heparin exposure and suspected acute HIT underwent on-pump coronary artery bypass grafting surgery with preemptive use of bivalirudin. A continuous bivalirudin infusion was used during cardiopulmonary bypass, and activated clotting times were used to monitor anticoagulation.. Anticoagulation with bivalirudin during cardiopulmonary bypass was effective and uncomplicated. Duration of operation was not prolonged, and perioperative blood loss and transfusion rates were acceptable. Activated clotting times were helpful for monitoring anticoagulation in these patients.. These data provide further evidence of the feasibility of bivalirudin for anticoagulation during on-pump coronary artery bypass graft surgery in urgent clinical situations.

Topics: Aged; Anticoagulants; Coronary Artery Bypass; Coronary Artery Disease; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Topics: Aged; Anticoagulants; Coronary Artery Bypass; Coronary Artery Disease; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

To describe the perioperative management in a heparin-induced thrombocytopenia (HIT) positive patient who had prosthetic valve endocarditis and an aortic root abscess. The patient underwent high-risk cardiac re-operation with the use of the alternative anticoagulant, bivalirudin.. A 62-yr-old patient who underwent stentless tissue aortic valve replacement with a Toronto-SPV valve in 1998, was admitted to hospital with symptoms of stroke. A heparin infusion was started and further investigation revealed positive blood cultures. The patient developed HIT which was confirmed by laboratory tests. Echocardiographic examination performed one month later showed vegetations on the aortic tissue valve and a small aortic root abscess. The patient still tested positively for the presence of HIT antibodies and was treated conservatively with antibiotics. A repeat echocardiographic examination showed progression of the aortic root abscess and it was decided to proceed with urgent redo aortic valve surgery. Anticoagulation for cardiopulmonary bypass (CPB) was achieved with the use of a direct thrombin inhibitor (DTI), bivalirudin. Following an uneventful wean from CPB, hemostasis was achieved within 40 min. The postoperative course was uncomplicated and the patient was discharged from hospital on the seventh postoperative day.. Bivalirudin is a DTI, which can be used as an alternative anticoagulant for CPB in HIT positive patients. This case report showed a favourable outcome with bivalirudin for urgent complex redo cardiac surgery requiring CPB.

Topics: Abscess; Anticoagulants; Cardiopulmonary Bypass; Echocardiography; Endocarditis, Bacterial; Female; Heparin; Hirudins; Humans; Middle Aged; Peptide Fragments; Prosthesis-Related Infections; Recombinant Proteins; Thrombocytopenia

Bivalirudin is a short-acting direct thrombin inhibitor that has been used in cardiac surgical patients with heparin-induced thrombocytopenia (HIT) or suspected HIT. Although no direct thrombin inhibitor is indicated for anticoagulation during cardiac surgery in patients with heparin-induced thrombocytopenia (HIT) or suspected HIT, use of heparin-alternatives are increasing as the awareness of HIT increases. Reports of anticoagulation with bivalirudin are sporadic, however, with variable dosing and management strategies. In this report, we describe our management techniques for cardiopulmonary bypass with bivalirudin based upon our personal experience. Although the reported clinical experience with bivalirudin in cardiac surgery is reviewed, operative techniques for the perfusionist/surgeon team are discussed in detail. We recognize that the use of bivalirudin during cardiopulmonary bypass is evolving and modifications of technique will undoubtedly occur as further data and experience accumulate.

Topics: Anticoagulants; Antithrombins; Cardiopulmonary Bypass; Drug Monitoring; Extracorporeal Circulation; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody-positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.

Topics: Amino Acid Sequence; Antibody Specificity; Binding Sites; Cross Reactions; Epitopes; Heparin; Hirudins; Humans; Molecular Sequence Data; Peptide Fragments; Protein Conformation; Recombinant Proteins; Thrombocytopenia

We treated persistent hemorrhage after cardiopulmonary bypass in a heart transplant recipient who had received anticoagulation with the direct thrombin inhibitor bivalirudin by a combination therapy aimed at reducing the plasma concentration of the thrombin antagonist (hemodialysis and modified ultrafiltration), increasing the concentration of thrombin at bleeding sites (recombinant factor VIIa), and increasing the plasma concentration of other coagulation factors (fresh frozen plasma and cryoprecipitate). The bleeding was controlled, and there was no thrombotic complication.. A combination of modified ultrafiltration, hemodialysis, and the administration of recombinant factor VIIa, fresh frozen plasma, and cryoprecipitate may reverse the anticoagulant effect of bivalirudin.

Topics: Adult; Antithrombins; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a problem of growing significance and concern, affecting an estimated 1-3% of patients among those receiving an estimated 10 million heparin exposures annually in the United States. The prevalence of heparin antibodies has been reported as at least 12.7% in the general cardiac surgery population before surgery and 42% following surgery. Various management techniques for anticoagulation in these patients have been proposed. Many of these alternative agents present additional risks for bleeding and efficacy and, furthermore, require the use of nonconventional monitoring assays to assess the level of anticoagulation achieved adequately. We report here the successful use of bivalirudin anticoagulation on pump, with no additional morbidity, and the first reported use of the plasma-modified ACT (activated clotting time) test, a simple modification of the standard ACT assay, to monitor the anticoagulant effect of bivalirudin.

Topics: Anticoagulants; Blood Coagulation; Cardiopulmonary Bypass; Drug Monitoring; Heparin; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Whole Blood Coagulation Time

Cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia poses significant challenges. Inadequate pharmacokinetic profiles, monitoring, reversibility, and availability often limit alternative anticoagulation strategies. Bivalirudin, a semisynthetic direct thrombin inhibitor, was recently approved for use in patients undergoing percutaneous coronary interventions. Its unique properties, including a relatively short half-life, an anticoagulation effect that closely correlates with activated clotting time, and an alternate metabolic pathway for elimination, make bivalirudin an attractive agent for cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia. We report our experience using bivalirudin in 2 patients undergoing coronary artery bypass grafting.

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Female; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Heparin is widely used as the anticoagulant of choice for cardiopulmonary bypass. However, some patients exposed to heparin therapies develop heparin-induced thrombocytopenia (HIT). Severe complications of HIT-induced thrombosis may lead to end-organ dysfunction and death. Bivalirudin, a hirudin analog, is an alternative anticoagulant that may be used in the patient with HIT without inducing thrombotic disorders. This case report provides a look at the successful use of bivalirudin as the sole anticoagulant in a patient diagnosed with HIT undergoing minimally invasive cardiothoracic surgery requiring cardiopulmonary bypass for severe mitral insufficiency. An 80-year-old male presented to the operating room for a minimally invasive mitral valve repair. Past medical history included mitral valve prolapse, atrial fibrillation, hypertension, and congestive heart failure. Preoperative evaluation noted the existence of HIT with heparin exposure 2 months prior. The decision was made to use bivalirudin as the sole anticoagulant for the operative procedure. Anticoagulation evaluation was performed with both high-does thrombin time (HiTT) and Celite activated clotting time tubes for comparison using a Hemochron device. Cardiopulmonary bypass was initiated, and the patient's mitral valve was repaired using a 34-mm annuloplasty ring. The patient was successfully weaned from bypass. No complications or evidence of HIT exacerbation were noted in the postoperative course.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cardiopulmonary Bypass; Contraindications; Drug Monitoring; Heparin; Hirudins; Humans; Male; Minimally Invasive Surgical Procedures; Mitral Valve Insufficiency; Peptide Fragments; Recombinant Proteins; Thrombin Time; Thrombocytopenia

Topics: Anesthetics, Intravenous; Anticoagulants; Aortic Valve Insufficiency; Cardiopulmonary Bypass; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Peptide Fragments; Propofol; Recombinant Proteins; Renal Insufficiency; Sufentanil; Thrombocytopenia; Whole Blood Coagulation Time

Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prospective Studies; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Heparin is the standard agent used for systemic anticoagulation during cardiopulmonary bypass in cardiac operations. Alternatives are needed when patients with heparin-induced thrombocytopenia type II are encountered. We present a patient with a clinical picture of heparin-induced thrombocytopenia type II who was effectively anticoagulated with bivalirudin, a direct thrombin inhibitor, during cardiopulmonary bypass for a cardiac operation.

Topics: Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Hirulog is a thrombin catalytic site inhibitor which exhibits specificity for the anionic binding exosite of alpha thrombin. Here, we have evaluated the effect of Hirulog (1, 5 and 10 mg/kg, 30 min pretreatment) in a rat model of endotoxemia. Intravenous injection of lipopolysaccharide from E. coli (25 mg/kg; serotype 0127:B8) caused decreases in blood pressure which were significantly reduced (about 60%) in animals pretreated with Hirulog. Rat survival to endotoxin was significantly increased in Hirulog pretreated group (5 and 10 mg/kg) up to 24 hours. Hirulog at the dose of 10 mg/kg inhibited both endotoxin-induced leukopenia at 30 and 60 minute points and thrombocytopenia at 30 minute point but not at 90 and 120 minute points. Fibrinogen levels were significantly reduced after 2 hours following endotoxin administration. Pretreatment with Hirulog (5-10 mg/kg i.v.) 30 min prior to administration of endotoxin prevented changes in fibrinogen plasma levels. These results demonstrate that Hirulog-induced inhibition of thrombin is effective in reducing toxic and lethal effects of endotoxin.

Topics: Animals; Antithrombins; Evaluation Studies as Topic; Fibrinogen; Hirudins; Hypotension; Leukopenia; Lipopolysaccharides; Male; Peptide Fragments; Rats; Rats, Wistar; Recombinant Proteins; Shock, Septic; Thrombin; Thrombocytopenia; Toxemia

Heparin-associated thrombocytopenia is a serious medical problem, especially when the patient requires continued anticoagulation. Hirulog is an immediate-acting intravenous anticoagulant that can be substituted for heparin. A new use of Hirulog in the treatment of life-threatening heparin-associated thrombocytopenia with thrombosis (HATT) is presented. Two patients suffering from the HATT syndrome were successfully treated with Hirulog to prevent further thrombosis. A third patient had developed heparin-associated thrombocytopenia after coronary artery bypass surgery in the past and was subsequently treated with Hirulog during a peripheral angioplasty procedure. Hirulog was an effective and predictable anticoagulant for these patients and was free from adverse effects.

Topics: Aged; Angioplasty, Balloon; Anticoagulants; Coronary Artery Bypass; Coronary Thrombosis; Heparin; Hirudin Therapy; Hirudins; Humans; Injections, Intravenous; Male; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombocytopenia

Topics: Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombophlebitis