refludan and Thrombosis

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

Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis. Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.

Topics: Anticoagulants; Antithrombins; Arginine; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombosis; Translational Research, Biomedical

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

The options for drug-controlled anticoagulation are becoming noticeably more manifold. In the area of anaesthesiology and intensive care, there are furthermore special disease patterns, such as heparin-induced thrombocytopenia (HIT) to be known, diagnosed and treated. This article gives a review of the substance groups of the direct thrombin inhibitors (DTI) as alternative anticoagulants for HIT in combination with cardiovascular diseases. For the administration of DTIs, experience and the correct dose are the keys to success and are the deciding factors for the two sides of haemostasis: thrombosis and haemorrhage.

Topics: Anesthesia; Anticoagulants; Cardiovascular Surgical Procedures; Critical Care; Hemorrhage; Hemostasis; Heparin; Heparin Antagonists; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; 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

To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients.. All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006.. HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients.. HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Extracorporeal Circulation; Heparin; Heparitin Sulfate; Hirudins; Humans; Intensive Care Units; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis

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

Heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis (HITT) ar rare complications associated with use of unfractionate heparin (UFH) or low-molecular-weight heparin (LMWH) HIT is a benign clinical condition characterized by a mil drop in platelet count with no clinical significance. HIT is an immune-mediated reaction associated with a wide spread "hypercoagulable" state resulting in arterial an venous thrombosis. There is a higher incidence of HIT with UFH use than with LMWH use. Orthopedic surger patients are at higher risk for developing HITT than are patients who receive prophylactic heparin for cardiovascular surgery or medical reasons. Therapy for patients suspected of having HITT should begin with immedi ate discontinuation of heparin in any form followed by pharmacologic inhibition with thrombin (e.g., recombinant hirudin [lepirudin], argatroban, danaparoid sodium).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Heparin; Heparitin Sulfate; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombosis; Warfarin

Recommendations for transitioning from therapy with heparin or a low-molecular-weight heparin preparation to therapy with an oral anticoagulant in patients with acute venous or arterial thromboembolism have undergone several changes during the last two decades. Physicians are now comfortable with beginning treatment with an oral anticoagulant once the diagnosis is confirmed, and loading doses are no longer considered to be necessary. Exceptions to early transition may be necessary in patients with an extensive iliofemoral or axillary-subclavian vein thrombosis or pulmonary embolism where thrombolytic agents may be indicated, or in individuals who require surgery or other invasive procedures, or if there are concerns about bleeding. The avoidance of early transition to oral anticoagulants in patients with acute heparin-induced thrombocytopenia also has been advised because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.

Topics: Administration, Oral; Anticoagulants; Arginine; Blood Coagulation; Blood Coagulation Factors; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Gangrene; Heparin; Heparitin Sulfate; Hirudins; Humans; Ischemia; Leg; Necrosis; Pipecolic Acids; Recombinant Proteins; Skin; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

Heparin-induced thrombocytopenia (HIT) is a pathology manifested as clinically induced destruction of platelets. There are 2 forms of HIT, type I and type II; type II is the more serious. HIT type I is a transient, non-immune-mediated form manifesting with mild thrombocytopenia. Type II is a drug-induced, immune-mediated syndrome that may cause life- or limb-threatening thromboembolic events. Induction of general anesthesia for a person with HIT type II is no different from that for a person in the general population. Treatment modalities vary only if heparin will be used during the case. The initial indicator of HIT is decreased platelet count, with or without thrombosis. Clinical criteria and advanced serological testing are available for the definitive diagnosis of HIT. Clinical suspicion of HIT remains key to early cessation of heparin (all routes) and initiation of alternative treatments.

Topics: Anesthesia, General; Anticoagulants; Arginine; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; Intraoperative Care; Nurse Anesthetists; Pipecolic Acids; Platelet Count; Recombinant Proteins; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin-induced thrombocytopenia (HIT) type II is an immune mediated reaction in which pathologic antibodies develop to a complex composed of heparin and the platelet-derived alpha granule protein, platelet factor 4 (PF4). HIT must be recognized quickly so as to eliminate all heparin exposure from a patient's clinical care. Thrombosis (HIT) may accompany thrombocytopenia resulting in limb and life-threatening complications. Despite a higher incidence of subclinically detectable heparin-PF4 antibody formation in the cardiac care setting, the development of the full clinicopathologic syndrome occurs in approximately 2% to 3% of patients, similar to the incidence in other clinical scenarios.

Topics: Anticoagulants; Arginine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heparin, Low-Molecular-Weight; Hirudins; Humans; Male; Pipecolic Acids; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Sulfonamides; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy that has a high rate of morbidity (thrombosis and amputation) and mortality. In the past, a number of different anticoagulants have been used to treat HIT in an attempt to prevent these complications. More recently, direct thrombin inhibitors have become popular. This systematic review summarizes the risk for thrombosis in HIT patients when heparin therapy is stopped; evidence of the efficacy of thrombin inhibitors in patients with HIT with and without thrombosis; evidence supporting the use of thrombin inhibitors in patients with a history of HIT who require a coronary intervention procedure; and the risk for bleeding when antithrombotic agents are used.

Topics: Anticoagulants; Arginine; Heparin; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Risk Assessment; Sulfonamides; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Aortic Valve Insufficiency; Arginine; Autoantibodies; Autoimmune Diseases; Female; Fingers; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Ischemia; Middle Aged; Necrosis; Pipecolic Acids; Platelet Activation; Platelet Factor 4; Postoperative Complications; Raynaud Disease; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Toes; Warfarin

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

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.

Topics: Anticoagulants; Antithrombins; Arginine; Blood Coagulation; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin induced thrombocytopenia thrombosis (HIT/T) is associated with a high morbidity and mortality. Diagnosis is essentially clinical and negative results of laboratory assays do not exclude the diagnosis. Treatment involves stopping all heparin immediately and giving an alternative thrombin inhibitor. The adoption of low molecular weight heparins is one reason for the reduced incidence of this disease in recent years.

Topics: Anticoagulants; Arginine; Heparin; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Platelet Count; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Epoprostenol; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that is associated with thrombotic events of the venous and arterial circulatory systems stemming from an intense and well-characterized prothrombotic triad of platelet activation, coagulation cascade stimulation and vascular endothelial cell injury. Although heparin (or other sulfated mucopolysaccharide compound) cessation represents a vital first step in management, patients remain susceptible to life-threatening thrombosis for up to several weeks, providing a strong rationale for a 'proactive approach' to care that includes prompt initiation of an alternative anticoagulant strategy throughout the high-risk period. The importance of alternative options for anticoagulation is most evident in clinical situations wherein treatment is a recognized standard of care and prerequisite for an optimal outcome. The following review highlights the use of recombinant hirudin (lepirudin) among patients with suspected HIT requiring precutaneous coronary interventions (PCI) and coronary arterial bypass grafting.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Blood Coagulation Tests; Coronary Artery Bypass; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Risk; Thrombocytopenia; Thrombosis

To determine whether lepirudin flushes are more effective than heparinized saline in preventing withdrawal occlusion of central venous access devices.. Randomized, double-blind clinical trial.. Research institution-tertiary referral center.. Forty-nine adults undergoing bone marrow transplantation for hematologic malignancies or metastatic solid tumors.. Twenty-four patients received heparin and 25 received lepirudin flushes. The heparin dose was 3 ml of porcine heparin 100 U/ml (300 U) per catheter lumen at least once/day; the lepirudin dose was 3 ml of lepirudin 100 microg/ml (300 microg) per catheter lumen at least once/day. After 3-4 weeks, all 49 patients received the heparin flushes.. Efficacy was assessed by the frequency with which the patients were treated with alteplase instillations for withdrawal occlusion of their central venous access devices during the first 4 months of catheterization. Three (12.5%) patients treated with heparin alone and five (20%) treated initially with lepirudin required alteplase instillations for an estimated relative risk with lepirudin versus heparin of 1.6 (95% confidence interval [CI] 0.40-13.86, p=0.70).. Lepirudin was not more effective than heparin, which may have been related to the conservative dose of lepirudin administered. However, higher lepirudin doses are likely to incur an unacceptable risk of systemic anticoagulation.

Topics: Anticoagulants; Bone Marrow Transplantation; Catheterization, Central Venous; Double-Blind Method; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Thrombosis; Tissue Plasminogen Activator

This analysis of 3 prospective multicenter trials in patients with laboratory-confirmed acute heparin-induced thrombocytopenia (HIT) without clinically evident thromboembolic complications (TECs), isolated HIT, assessed the combined individual end points of death, new TECs, and limb amputation. Patients with the same inclusion criteria who did not receive lepirudin or danaparoid served as a contemporaneous control group. Ninety-one patients were treated with lepirudin (intravenous infusion 0.10 mg/kg/h, no bolus, activated partial thromboplastin time [aPTT]-adjusted to 1.5-2.5 times baseline) for a median of 11.0 days (range, 1-68 days). During the observation period (median 24 days), 13 (14.3%) deaths, 4 (4.4%) new TECs, 3 (3.3%) limb amputations (combined 18 [19.8%]), and 13 (14.3%) major bleeding events occurred. In comparison to the control group (N = 47), the combined end point (P = .0281) and new TECs (P = .02) were reduced, and major bleeding was not significantly different between groups (P = .5419). In renal impairment, lepirudin did not reach its steady state within 4 hours, and additional monitoring every 4 hours after start of lepirudin until steady state is reached is recommended. Lepirudin seems to be effective in patients with isolated HIT. Dose reductions in renal impairment are important. Keeping the aPTT in the range corresponding to 600 to 700 microg/L lepirudin during treatment may minimize bleeding complications.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombin III; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Hydrolases; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome

We prospectively investigated lepirudin for further parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT).. Patients with confirmed HIT (n=112) received lepirudin according to need for 2 to 10 days (longer if necessary): A1, treatment: 0.4 mg/kg IV bolus, followed by 0.15 mg. kg(-1). h(-1) intravenous infusion, n=65; A2, treatment in conjunction with thrombolysis: 0.2 mg/kg, followed by 0.10 mg. kg(-1). h(-1), n=4; and B, prophylaxis: 0.10 mg. kg(-1). h(-1), n=43. Outcomes from 95 eligible lepirudin-treated patients were compared with those of historical control patients (n=120). Complete laboratory response (activated partial thromboplastin time ratio >1.5 with /=1 outcome (cumulative incidence 30.9% versus 52.1%; relative risk [RR] 0.71; P=0.12, log-rank test). Bleeding events were more frequent in the lepirudin group than the historical control group (cumulative incidence at 35 days, 44.6% versus 27.2%; RR 2.57; P=0.0001, log-rank test). No difference was observed in bleeding events requiring transfusion (cumulative incidence at 35 days, 12.9% versus 9.1%; RR 1.66; P=0.23, log-rank test); no intracranial bleeding was observed in the lepirudin group.. Lepirudin effectively prevents death, limb amputations, and new thromboembolic complications and has an acceptable safety profile in HIT patients. Treatment should be initiated as soon as possible if HIT is suspected.

Topics: Aged; Amputation, Surgical; Anticoagulants; Autoimmune Diseases; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Life Tables; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Recurrence; Safety; Survival Analysis; Thrombocytopenia; Thrombosis; Treatment Outcome

This study was performed to evaluate the efficacy of peri-interventional treatment with recombinant hirudin (r-hirudin [HBW 023]) compared with heparin in the prevention of troponin T release in patients with unstable angina.. Percutaneous transluminal coronary angioplasty in patients with unstable angina is associated with a high risk of acute thrombotic complications.. Serial troponin T measurements were performed in 61 patients with unstable angina during the 48-h observation period after coronary angioplasty of the ischemia-related lesion. Patients were randomly assigned to peri-interventional intravenous treatment with either r-hirudin (dosage group I: 0.3-mg/kg body weight bolus, 0.12 mg/kg per h for 24 h; dosage group II: 0.5-mg/kg bolus, 0.24 mg/kg per h for 24 h) or heparin (150-IU/kg bolus, 20 IU/kg per h for 24 h). All patients received acetylsalicylic acid before coronary angiography. After 24 h, patients received a constant low dose infusion of either hirudin (0.04 mg/kg per h) or heparin (7 IU/kg per h) for another 24 h. The power of the study to detect a decrease in abnormal troponin T levels from 60% (heparin group) to 20% (combined r-hirudin groups) was 88%.. Serial troponin T measurements revealed two peaks within the 48 h after coronary angioplasty in the heparin but not the hirudin groups. An elevated serum troponin T concentration (> 0.2 ng/ml) within 48 h of coronary angioplasty was found in 9 (24%) of 38 patients in the hirudin groups (5 [25%] of 20 in dosage group I; 4 [22%] of 18 in dosage group II) compared with 11 (58%) of 19 in the heparin group (p = 0.01). We observed major cardiac events (death, myocardial infarction, abrupt vessel closure) in 1 (4.8%) of 21 patients in dosage group I, 1 (5.3%) of 19 in dosage group II and 3 (14.3%) of 21 in the heparin group (p = 0.33).. In this pilot trial, hirudin appears to be superior to heparin in preventing troponin T release after coronary angioplasty.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Coronary Angiography; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardium; Necrosis; Pilot Projects; Premedication; Recombinant Proteins; Thrombosis; Troponin; Troponin T

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

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

Topics: Adolescent; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; beta 2-Glycoprotein I; Diagnosis, Differential; Disease Progression; Dose-Response Relationship, Drug; Down Syndrome; Enoxaparin; Female; Hirudins; Humans; Immunoglobulin M; Recombinant Proteins; Renal Veins; Thrombophlebitis; Thrombosis; Vena Cava, Inferior

A treatment strategy of a difficult and unusual problem is presented. We are reporting a case of a patient who had a documented allergy to heparin and required Cardiac surgery for an ASD closure. The anticoagulation regime used during cardiopulmonary bypass was lepirudin based. This report indicates that r-hirudin provides effective anticoagulation, however unless ECT is monitoring, post operative hemorrhage is encountered. Therefore this case is unique not only because of its rarity but also by the fact that it presents the caveats encountered when ECT is not available.

Topics: Adult; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Female; Fibrinolytic Agents; Follow-Up Studies; Heart Septal Defects, Atrial; Heparin; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Thrombosis

The present study aimed to assess whether the fibrin network structure is modified by the direct thrombin-inhibitors lepirudin, argatroban or bivalirudin and by the indirect Xa-inhibitor danaparoid. Using an in vitro assay that imitates the physiological process of coagulation from thrombin generation to fibrin formation, we examined a normal plasma pool spiked with one of the inhibitors. At concentrations considered to be the plasma levels observed during therapy, almost no influence was detected for lepirudin despite clear-cut effects on "clotting time". However, argatroban, bivalirudin and danaparoid increased the fibrin gel permeability (Ks) to a similar extent. At concentrations higher than the "therapeutic" levels, the dose-response curve in the Ks assay became very steep for lepirudin while those were shallow for the others. In parallel with the drug-induced increases of Ks, larger network pores in 3D-microscopic images and significant shortenings in "clot lysis time" induced by addition of rtPA were observed. Recombinant factor VIII (rFVIII) added to danaparoid-treated samples profoundly counteracted the increase of Ks but had only a slight or no effect on the other drugs. Thus, in vitro, argatroban, bivalirudin and danaparoid have comparable anticoagulating effects, rendering the fibrin network more permeable and less resistant to fibrinolysis. For lepirudin, the steep dose-response curve supports previous clinical findings, i.e. this thrombin inhibitor has a narrow therapeutic window. Furthermore, our data suggest that the haemostatic agent, rFVIII, might be effective in treatment of bleeding complications induced by danaparoid.

Topics: Antithrombins; Arginine; Chondroitin Sulfates; Chromatography, Gel; Dermatan Sulfate; Factor VIII; Factor Xa Inhibitors; Fibrin; Fibrinolysis; Heparinoids; Heparitin Sulfate; Hirudins; Humans; In Vitro Techniques; Microscopy, Confocal; Peptide Fragments; Pipecolic Acids; Plasma; Porosity; Protein Multimerization; Recombinant Proteins; Sulfonamides; Thrombosis; Tissue Plasminogen Activator

Topics: Aged; Anticoagulants; Hirudins; Humans; Male; Recombinant Proteins; Thrombosis

The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Blood Coagulation Tests; Chondroitin Sulfates; Citrates; Critical Care; Dermatan Sulfate; Diagnostic Errors; Dose-Response Relationship, Drug; Epoprostenol; Fondaparinux; Hemofiltration; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Iloprost; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sodium Citrate; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) represents a serious side effect caused by an atypical immune response to platelet factor 4 leading to platelet activation and thrombin formation. These patients are at high risk of thromboembolism, with a rapid drop in platelet count between days 5 and 14 after the initiation of heparin treatment. In single cases, especially after major surgery, platelet count reduction might be absent or hidden by preceding thrombocytosis. Different clinical manifestations of HIT include unspecific skin reactions with potential necrosis at the site of heparin injection, mostly after the application of unfractionated heparin but also with low molecular weight heparin. In heparin-induced skin necrosis, administration of unfractionated or low molecular weight heparin is contraindicated and heparin therapy should be stopped immediately. Instead, an alternative anticoagulant in the form of a direct thrombin inhibitor such as argatroban, and respectively lepirudin, or danaparoid sodium must be administered. Due to frequent misinterpretations of heparin-induced unspecific skin reactions, especially in the absence of thrombocytopenia, we present two case reports which should increase the awareness of HIT's various clinical pictures.

Topics: Adult; Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Drug Eruptions; Female; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Male; Pipecolic Acids; Platelet Count; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Time Factors

Heparin is commonly used in the intensive care unit for preventing and treating thromboembolic disease. One of its more significant complications is heparin-induced thrombocytopenia (HIT), an immune-mediated disorder which can provoke an extreme prothrombotic state. We describe an unusual presentation of HIT, where thrombocytopenia was absent.

Topics: Adult; Anticoagulants; Calcitonin; Female; Follow-Up Studies; Heparin; Hirudins; Humans; Intensive Care Units; Partial Thromboplastin Time; Platelet Count; Protein Precursors; Recombinant Proteins; Stroke; Thrombocytopenia; Thrombosis; Time Factors; Tomography, X-Ray Computed

The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRgamma-null mice (FcRgamma(-/-)) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl(3) injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl(3) injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRgamma(-/-) compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRgamma(-/-). These data indicate a significant role for GPVI in FeCl(3)-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl(3)-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRgamma(-/-) was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl(3)-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.

Topics: Animals; Chlorides; Ferric Compounds; Hirudins; Lasers; Mice; Mice, Knockout; Platelet Membrane Glycoproteins; Radionuclide Imaging; Receptors, IgG; Recombinant Proteins; Thrombosis

Topics: Anticoagulants; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Renal Artery Obstruction; Renal Insufficiency; Syndrome; Thrombocytopenia; Thrombosis

A 56-year-old man with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) received anticoagulation with recombinant hirudin (lepirudin) for emergency coronary artery bypass graft (CABG) surgery and aortic valve replacement. The patient experienced life-threatening refractory bleeding that was successfully treated with recombinant factor VIIa. He had a history of infective endocarditis that resulted in severe aortic insufficiency, three-vessel coronary artery disease, and acute renal failure requiring hemodialysis. The patient was transferred from another hospital for the emergency surgery, but before his transfer, he developed HITTS secondary to therapeutic heparin for a deep vein thrombosis of the lower extremity. The presence of HITTS, the urgent nature of the case, and the availability of the direct thrombin inhibitor led the surgical team to select lepirudin for anticoagulation to facilitate cardiopulmonary bypass. After separation from cardiopulmonary bypass, the patient was in a coagulopathic state due to the inability to reverse the lepirudin and the slowed elimination of the drug secondary to inadequate renal function. As a result, the patient experienced excessive generalized oozing that was unresponsive to traditional therapies and blood product transfusions. Recombinant factor VIIa 35 microg/kg was given as rescue therapy. The bleeding slowed, which allowed placement of chest tubes and closing of the sternum. The patient was transferred to the intensive care unit in stable condition with no evidence of thrombosis in the freshly placed bypass grafts or on the bioprosthetic valve. Recombinant factor VIIa appears to be a suitable option as salvage therapy in patients with refractory bleeding secondary to anticoagulation with a direct thrombin inhibitor during cardiac surgery.

Topics: Acute Kidney Injury; Anticoagulants; Coronary Artery Bypass; Factor VII; Factor VIIa; Heparin; Hirudins; Humans; Male; Middle Aged; Postoperative Hemorrhage; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombosis

Patients with heparin-induced thrombocytopenia urgently requiring surgery with cardiopulmonary bypass (CPB) present a unique management challenge that must be addressed by the use of alternative anticoagulants. Although clinical success with the direct thrombin inhibitor hirudin has been reported, there is sparse information in the literature supporting the efficacy of this drug as an anti-thrombotic to prevent fibrin formation during CPB. In this report, we describe the efficacy of this drug to prevent thrombin-mediated fibrin formation during CPB.

Topics: Adult; Anticoagulants; Cardiopulmonary Bypass; Chondroitin Sulfates; Contraindications; Dermatan Sulfate; Endarterectomy; Fibrinolytic Agents; Fibrinopeptide A; Heparin; Heparitin Sulfate; Hirudins; Humans; Hypertension, Pulmonary; Hypothermia, Induced; Male; Peptide Fragments; Postoperative Complications; Prothrombin; Pulmonary Embolism; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombectomy; Thrombin; Thrombosis

Topics: Adult; Anticoagulants; Female; Heparin; Hirudins; Humans; Injections, Subcutaneous; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Recombinant Proteins; Sarcoidosis; Skin Diseases; Thrombosis

There are few reports of the management of pediatric patients with heparin-induced thrombocytopenia (HIT) requiring cardiac surgery using currently available anticoagulants. We report a case of an infant with HIT requiring a bidirectional Glenn shunt who was successfully managed using lepirudin (r-hirudin, Refludan; Aventis, Bridgewater, NJ). Dosing and monitoring of anticoagulation were difficult, and we suggest caution in the use of lepirudin for cardiac surgery unless reliable monitoring of the degree of anticoagulation becomes available.

Topics: Anticoagulants; Blood Coagulation Tests; Cardiac Catheterization; Cardiac Surgical Procedures; Hemodynamics; Heparin; Hirudins; Humans; Hypoplastic Left Heart Syndrome; Infant; Male; Monitoring, Intraoperative; Partial Thromboplastin Time; Recombinant Proteins; Thrombocytopenia; Thrombosis

Topics: Afibrinogenemia; Aspirin; Blood Coagulation Tests; Drug Therapy, Combination; Heparin; Hirudins; Humans; Infant, Newborn; Male; Recombinant Proteins; Recurrence; Thrombosis

Many functions of the coagulation system have nonthrombotic effects. The indirect thrombin inhibitor heparin has been previously shown to be effective in limiting intimal hyperplasia (IH). We sought to study the effect of thrombin on IH by using two direct thrombin inhibitors (DTIs), argatroban and lepirudin. Sprague-Dawley rats underwent interposition vein grafting to the carotid artery. Vein grafts were treated with either saline (n = 6) or one of the two DTIs (n = 6 for both). At 30 days, the rats were sacrificed and vessels were perfusion fixed. Sections of the proximal carotid artery, graft, and both anastomoses were stained with both hematoxlyin/eosin and von Gieson's elastin stain. Sections were examined and compared for luminal area and intima-to-media (IM) ratio. The vessels treated with DTIs had less (p < 0.05) IH (IM ratio for proximal anastomosis: control 1.036 +/- 0.857, lepirudin 0.373 +/- 0.21, argatroban 0.182 +/- 0.118) and better lumen preservation than the control vessels (lumen area of proximal anastomosis: control 1.69 +/- 0.9, lepirudin 2.45 +/- 0.74, argatroban 2.81 +/- 0.78). There were no thromboses in the DTI-treated vessels. Dilatation of the graft segment was noted in the argatroban group. Thus, DTIs are effective at reducing IH in a small-animal model, suggesting that inhibition of thrombin has a protective role in IH. In addition, a difference of action between DTIs is suggested by the dilatation seen only in the argatroban-treated graft sections.

Topics: Anastomosis, Surgical; Animals; Carotid Artery, Common; Disease Models, Animal; Fibrinolytic Agents; Hirudins; Hyperplasia; Male; Models, Cardiovascular; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thrombin; Thrombosis; Tunica Intima; Veins

We report herein a patient with coronary artery disease that developed heparin-induced thrombocytopenia after coronary artery bypass graft with resulting thrombosis of multiple saphenous vein grafts and myocardial infarction after heparin exposure. The patient required lepirudin and a cardiac catheterization with placement of stents.

Topics: Angina Pectoris; Angioplasty, Balloon; Anticoagulants; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiac Catheterization; Coronary Artery Bypass; Coronary Restenosis; Drug Therapy, Combination; Eptifibatide; Heparin, Low-Molecular-Weight; Hirudins; Humans; Internal Mammary-Coronary Artery Anastomosis; Male; Middle Aged; Myocardial Infarction; Peptides; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Recurrence; Saphenous Vein; Stents; Thrombocytopenia; Thrombosis

Topics: Adult; Anticoagulants; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Trimester, First; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

A 50-year-old patient presented with clinical symptoms of heart failure with orthopnoe and edema (NYHA IV).. Echocardiography revealed a dilated left ventricle with severely reduced left ventricular function and biventricular floating thrombi, due to dilatative cardiomyopathy.. With a heart failure medication clinical symptoms reduced and body weight decreased > 10 kg in 3 weeks. Due to the high-risk constellation, anticoagulation was performed with lepirudin and the biventricular thrombi were dissolved within 17 days. At this point in time, the patient suffered from petechial bleedings, hemoptysis and gross hematuria. Despite breaking anticoagulation and substitution of PPSB with not measurable fibrinogen, subarachnoid hemorrhage occurred leading to exitus letalis.. Lepirudin is a highly effective anticoagulant, that can induce severe hemorrhagic side effects in individual cases. The present case report demonstrates an immunological reaction as a rare cause with activation of prothrombin and formation of fibrin.

Topics: Antibody Formation; Cardiomyopathy, Dilated; Dose-Response Relationship, Drug; Echocardiography; Fatal Outcome; Fibrinolytic Agents; Heart Failure; Heart Ventricles; Hematuria; Hemoptysis; Hirudins; Humans; Male; Middle Aged; Prothrombin Time; Purpura; Recombinant Proteins; Subarachnoid Hemorrhage; Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Glycine; Hirudins; Humans; In Vitro Techniques; Recombinant Proteins; Thrombin; Thrombosis

Appropriate management, as well as efficacy and safety, of heparin-induced thrombocytopenia (HIT) and prevention of severe consequences with argatroban and lepirudin are discussed. Heparin-induced thrombocytopenia, a serious immune-mediated drug reaction, can occur as an isolated incident (isolated HIT) or with acute thrombosis sometimes referred to as HIT and associated thrombosis syndrome (HITTS). Due to the severe consequences associated with HIT, appropriate management is critical. Argatroban and lepirudin, two direct thrombin inhibitors (DTIs), are currently FDA approved for use in patients with HIT. The clinical experience with these agents is critically examined in this article. The safety and efficacy of argatroban in management of HIT were the subject of a single published clinical trial. The study was designed to reflect conventional clinical practice, whereby treatment of patients with HIT was initiated upon clinical suspicion. In several of these patients, HIT antibodies could not be demonstrated. Compared to historical controls, argatroban demonstrated efficacy in patients with isolated HIT; however, no differences were observed in HIT patients with acute thrombosis. Rates of bleeding episodes did not differ between argatroban and control. The clinical efficacy and safety of lepirudin have been the subject of three clinical trials and one large drug monitoring program. Lepirudin has demonstrated benefit in HIT patients with or without existing thromboembolism. Bleeding rates were higher than in the historical control. However, bleedings requiring transfusion did not differ. Although no direct head-to-head comparison trials of argatroban and lepirudin have been conducted, parallels can be drawn between the agents based on careful review of published clinical trials. Consistently, rates of new thrombosis, limb amputation, and death appear to be lower in patients treated with lepirudin as compared with those treated with argatroban, whereas the risk for major bleeding per patient day seems to be similar with both DTIs.

Topics: Antithrombins; Arginine; Heparin; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; United States

Topics: Animals; Antibody Formation; Anticoagulants; Blood Coagulation Disorders; Dogs; Hirudins; Humans; Male; Rats; Recombinant Proteins; Swine; Thrombin; Thrombosis

Heparin-induced thrombocytopenia (HIT) is a common complication of heparin therapy. There are three types of HIT. In the majority of patients, thrombocytopenia is modest and resolves without sequelae (HIT I). In a smaller number of patients, the thrombocytopenia is severe (HIT II), and in still others, the thrombocytopenia is also associated with thrombosis (HITT). Administration of heparin to this latter group of patients causes platelet aggregation, thromboembolism, and thrombocytopenia. It is advisable that heparin not be administered in any form to patients with documented or suspected HIT II or HITT. This situation, of course, poses a problem for those patients requiring cardiopulmonary bypass (CPB) surgery. In this report, we summarize our experience with Lepirudin (Hoechst, Frankfurt Ammain, Germany), which is a recombinant hirudin (r-hirudin), as an alternative to heparin for systemic anticoagulation, as well as the use of the ecarine clotting time (ECT) for monitoring anticoagulation status during CPB.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cardiopulmonary Bypass; Female; Heparin; Hirudins; Humans; Male; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thrombosis

Lepirudin is a specific thrombin inhibitor that is used for anticoagulation in patients with heparin-induced thrombocytopenia who are also undergoing cardiopulmonary bypass (CPB). Monitoring of lepirudin during CPB has been carried out with activated clotting time and ecarin clotting time. Correlation is poor with the former method, whereas ecarin clotting time is not widely available. A patient is described with heparin-induced thrombocytopenia who underwent CPB, where coagulation monitoring was accomplished with the Thrombelastograph. This more widely available method may be useful in such patients.

Topics: Anticoagulants; Cardiopulmonary Bypass; Drug Monitoring; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Thrombelastography; Thrombocytopenia; Thrombosis

Treatment of critically ill patients who have heparin-induced thrombocytopenia and thrombosis (HITT) and also renal failure is a challenge. Recombinant hirudin (Refludan, Hoechst Marion Roussel) is a direct thrombin inhibitor indicated for anticoagulation in HITT and approved by the United States Food and Drug Administration. Because this drug is renally cleared, a single dose of hirudin may induce prolonged (up to one week) unpredictable anticoagulation in patients with renal insufficiency. There are a few case reports of patients with renal failure and suspected heparin-induced thrombocytopenia (HIT) in which patients were anticoagulated with Refludan for catheter thrombosis. There is no literature on the therapeutic use of Refludan to treat HITT in patients with diffuse thrombosis and renal failure. The authors report the case of a 44-year-old female dialysis patient with HITT and extensive life-threatening thrombosis. The patient developed common iliac vein occlusion extending to the right atrium with progressive right internal jugular vein thrombus developing while on heparin. Her platelet count dropped to 60,000/microL. She was lethargic and hemodynamically unstable. Refludan was initially given as a bolus of 0.2 mg/kg (total, 12 mg) at a 50% dose reduction based on the patient's ideal body weight. This dose was based on the published pharmacokinetics of Refludan in patients with renal failure. Only 2 additional boluses of 6 mg and 3 mg were needed to extend the duration of therapeutic anticoagulation (measured by PTT) to 140 hours. The patient improved both clinically and radiographically after the treatment with Refludan. There were no additional thromboembolic events or bleeding complications. The platelets returned to normal within a few days. The patient was transitioned to coumadin and discharged from the hospital. She remains stable at 1-year follow-up.

Topics: Adult; Anticoagulants; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

Topics: Anticoagulants; Cardiopulmonary Bypass; Fatal Outcome; Heart Valve Prosthesis Implantation; Heparin; Hirudin Therapy; Hirudins; Humans; Intraoperative Period; Male; Middle Aged; Mitral Valve; Multiple Organ Failure; Partial Thromboplastin Time; Postoperative Complications; Recombinant Proteins; Thrombocytopenia; Thrombosis

Topics: Ancrod; Anticoagulants; Antithrombins; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia; Thrombosis; Warfarin

Heparin-induced thrombocytopenia type II (HIT type II) is the most serious complication of heparin treatment apart from bleeding, which is the most common side effect. Eleven days after coronary bypass grafting, a 71 year old patient showed a posterolateral myocardial infarction and a thrombocytopenia of 80,000/microliter. This was considered a postoperative thrombocytopenia. Coronary angiography revealed closed venous bypass grafts. The right coronary artery (RCA) was revascularized by percutaneous transluminal coronary angioplasty (PTCA) and stent placement. During both coronary angiography and PTCA, heparin was administered to the patient. The platelet number did not change. Four days later the patient showed an inferior myocardial infarction and an AV-block III degrees and a syncope. The following coronary angiography revealed RCA stent occlusion. HIT type II was presumed and recanalization was carried out using Lepirudin (Refludan) as the anticoagulant. After placing the guide wire, thrombi could be seen in the proximal RCA. Abciximab (Reo pro), a monoclonal antibody against the glycoprotein IIb/IIIa receptor was additionally administered. Coronary angiography on the next day revealed only a small remaining thrombus. The AV-block disappeared immediately after revascularization. The diagnosis of HIT type II was confirmed through heparin-induced-platelet-activation-test (Hipa-test) and immunoassay (PF 4/heparin-ELISA). This case report illustrates the complicated diagnosis of HIT type II and the successful simultaneous use of Lepirudin (Refludan) and Abciximab (Reo pro). The number of platelets should be checked daily during heparin treatment. In the case of a thrombocytopenia, the treatment should be stopped immediately, and Hipa-test and PF 4/heparin-ELISA should be carried out.

Topics: Abciximab; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Coronary Artery Bypass; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Stents; Thrombocytopenia; Thrombosis

Topics: Catheters, Indwelling; Heparin; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Recurrence; Renal Dialysis; Thrombocytopenia; Thrombosis

A serious retroperitoneal bleeding occurred in a 56-year-old male patient receiving unfractionated heparin due to multiple pulmonary embolism. After reducing the heparin dose, the patient developed a new pulmonary embolism and a large thrombus in the right atrium. Concomitantly, the platelet count dropped to a value of 29 g/l. Heparin-induced thrombocytopenia (HIT) was confirmed by a functional assay, the heparin-induced platelet activation (HIPA) assay, whereas the results of a platelet factor 4/heparin complex ELISA were repeatedly negative. This indicated that the patient's HIT antibodies were directed towards an antigen other than platelet factor 4/heparin complexes. For treatment of the atrial thrombus, an ultra-low-dose lysis with rt-PA (2 mg/h, intravenously) was administered for a period of 52 h, overlapping with systemic treatment with recombinant hirudin (Lepirudin, Refludan, 0.06-0.14 mg/kg/h intravenously). The aim was to enhance lysis of the thrombus without increasing the haematoma, and at the same time keep the risk of fulminant pulmonary embolism due to thrombus fragmentation as low as possible. The cardiac thrombus disappeared within 48 h, without new signs of pulmonary embolism. Platelet counts normalized within nine days.

Topics: Anticoagulants; Arrhythmias, Cardiac; Autoimmune Diseases; Heart Atria; Heart Diseases; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phenprocoumon; Plasminogen Activators; Pulmonary Embolism; Recombinant Proteins; Retroperitoneal Space; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator; Vena Cava Filters

The study was composed of two parts, arterial and venous; the 24 rabbits in each arm were divided into three equal groups and treated with either saline (control) or 1 mg/kg body weight (bw) of a new recombinant hirudin HBW 023 given as a single dose or standard heparin 1 mg/kg bw followed by quarter doses of heparin every half hour. Both arms included a control group given equal volumes of saline. The study continued for 2 hours. The following parameters were evaluated: bleeding times from arteriotomy/venotomy, patency rates, and the weights of thrombotic materials. Plasma samples were taken for evaluation of anti-factor lla (anti-Flla), anti-factor Xa (anti-Fxa), and activated partial thromboplastin time (APTT). The bleeding times were significantly prolonged but were still within clinically acceptable levels, following both HBW 023 and heparin treatment. Patency rates were significantly improved in both the arterial and venous arms following HBW 023 and heparin treatment. A corresponding reduction in thrombotic materials was simultaneously registered in the arterial and venous arms following HBW 023 and heparin treatment. Hirudin (HBW 023) significantly improved the reduction compared with the heparin group in the venous study. Heparin treatment caused expected high levels of anti-FXa and prolonged APTT, but hirudin, being at least as effective in antithrombotic potency, changed the pre-treatment levels only slightly. Anti-Flla levels were immediately increased by both heparin and hirudin (the highest levels) but reached low levels after 2 hours of single-dose hirudin treatment, despite a simultaneously excellent antithrombotic effect. We conclude that the new recombinant hirudin HBW 023, like standard heparin, is a highly efficient antithrombotic agent in both small arteries and veins following severe vessel wall trauma. The bleeding times were simultaneously prolonged significantly (still within acceptable limits) following both heparin and HBW 023 treatment in the arterial arm but were only prolonged following heparin treatment in the venous arm. The advantage of r-hirudin HBW 023 was furthermore the single dose administration.

Topics: Animals; Anticoagulants; Antithrombins; Arteries; Blood Coagulation Tests; Drug Administration Schedule; Factor Xa; Heparin; Hirudin Therapy; Hirudins; Male; Partial Thromboplastin Time; Prothrombin; Rabbits; Random Allocation; Recombinant Proteins; Single-Blind Method; Sodium Chloride; Thrombosis; Vascular Patency; Veins

Intravenous recombinant (r)-hirudin has a potent antithrombotic effect in aspirin- and heparin-resistant platelet-dependent thrombus formation in baboon models. However, these thrombi reform when therapy is stopped after 60 minutes. To determine if 4 hours of therapy can produce a lasting antithrombotic effect, we investigated the extent of deposition of 111In-labeled platelets onto 0.5-cm2 segments of Dacron vascular grafts for 53 hours. These grafts had been incorporated into exteriorized permanent femoral arteriovenous shunts in baboons. Platelet deposition in eight untreated animals was generally sigmoidal. Maximum platelet deposition, 1.7% +/- 0.9% of injected labeled platelets, was reached after approximately 4 hours. Deposition then gradually decreased to 0.4% +/- 0.2% of injected labeled platelets after 53 hours. After a thrombus was allowed to form for 15 minutes in six animals, intravenous treatment with r-hirudin at a dose of 20 nmol (0.14 mg)/kg-min-1 (aPTT > 300 seconds) was started and maintained for 4 hours. Platelet deposition was interrupted during treatment. After infusion was stopped, platelets accumulated again, but not as much as in the untreated animals. Maximum platelet deposition, 0.7% +/- 0.2% of injected labeled platelets, was significantly less (P < .01), and was reached after approximately 23 hours. Thereafter, deposition decreased to 0.4% +/- 0.2% at 53 hours. The shunts in all of the untreated animals occluded at some stage during the study, while only one shunt occluded in the treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriovenous Shunt, Surgical; Femoral Artery; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Infusions, Intravenous; Male; Papio; Partial Thromboplastin Time; Platelet Adhesiveness; Polyethylene Terephthalates; Recombinant Proteins; Thrombin; Thrombin Time; Thrombolytic Therapy; Thrombosis; Time Factors