cgp-39393 and 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

Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.

Topics: Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Partial Thromboplastin Time; Recombinant Proteins; Thrombin; Thrombocytopenia; Tissue Distribution; Venous Thrombosis

Topics: Anticoagulants; Antithrombins; Arginine; Chondroitin Sulfates; Clinical Trials as Topic; Critical Pathways; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Because of an extreme risk for thromboemboli, patients with suspected heparin-induced thrombocytopenia (HIT) require immediate initiation of an alternative anticoagulant. The only therapies approved by the Food and Drug Administration require intravenous infusion of expensive direct thrombin inhibitors. This prospective, randomized, open-label, exploratory study compared the clinical and economic utility of subcutaneous desirudin vs argatroban, the most frequently used agent for suspected or immunologically confirmed HIT, with or without thrombosis. Sixteen patients were randomized to treatment with fixed-dose desirudin (15 or 30 mg) every 12 hours or activated partial thromboplastin time-adjusted argatroban by intravenous infusion. Arm A included 8 patients naive to direct thrombin inhibitor therapy, whereas Arm B included 8 patients on argatroban for at least 24 hours before randomization. The primary efficacy measure was the composite of new or worsening thrombosis (objectively documented), amputation, or death. Other end points included major and minor bleeding while on drug therapy, time to platelet count recovery, and pharmacoeconomics. No amputations or deaths occurred. One patient randomized to argatroban had worsening of an existing thrombosis. Major bleeding occurred in 2 patients on argatroban and in none during desirudin treatment. There was 1 minor bleed in each treatment group. The average medication cost per course of treatment was $1688 for desirudin and $8250 for argatroban. Desirudin warrants further study as a potentially cost-effective alternative to argatroban in patients with suspected HIT.

Topics: Adolescent; Adult; Aged; Anticoagulants; Arginine; Disease Progression; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Pilot Projects; Pipecolic Acids; Platelet Count; Postoperative Complications; Postoperative Period; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis; Treatment Outcome; Young Adult

Desirudin, a bivalent direct thrombin inhibitor (DTI), is approved by the US Food and Drug Administration for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective hip replacement surgery. It became available in the United States in March 2010.. The goal of the present article was to provide an overview of the rationale and design of the PREVENT-HIT study, a randomized, prospective, open-label, active drug-controlled, exploratory trial comparing the clinical and economic utility of desirudin versus argatroban in patients with suspected heparin-induced thrombocytopenia (HIT), with or without thrombosis.. The PREVENT-HIT study was designed to enroll approximately 120 patients from 20 to 25 US centers. All eligible patients were required to be aged >or=18 years. Patients with suspected HIT with or without thrombosis were divided into 2 treatment arms and randomized to receive treatment with desirudin or argatroban in a 1:1 ratio using a block randomization method. Arm A comprised patients who were naive to DTI therapy; arm B included patients whose condition was previously stabilized with intravenous argatroban. Desirudin was administered as a fixed-dose injection (15 or 30 mg SC q12h in patients without or with thrombosis, respectively). Argatroban was administered by continuous intravenous infusion in accordance with approved prescribing information or institutional prescribing guidelines at each study site. The primary efficacy outcome measure included the occurrence of any of the following up to 30 days after study drug discontinuation: new-onset or worsening thrombosis requiring discontinuation of study drug; amputation; or all-cause mortality. Other outcomes that were assessed included platelet recovery, bleeding, and pharmacoeconomic parameters. In addition, adverse events and other safety parameters were evaluated. Study enrollment began in November 2008 and ended in December 2009 due to slow enrollment (N = 16). The study results will be published separately.. The results from the PREVENT-HIT study should enhance understanding of the comparative clinical and economic utility of desirudin and argatroban in patients with HIT with or without thrombosis. ClinicalTrials.gov identifier: NCT00787332.

Topics: Anticoagulants; Arginine; Female; Heparin; Hirudins; Humans; Male; Pilot Projects; Pipecolic Acids; Prospective Studies; Recombinant Proteins; Research Design; Sulfonamides; Thrombocytopenia; Thrombosis

Recombinant hirudin has been found to be immunogenic in patients treated with lepirudin following heparin-induced thrombocytopenia (HIT). We assessed the incidence of immunoglobulin G (IgG) antihirudin antibodies by enzyme-linked immunosorbent assay in 112 patients enrolled in a dose-finding study with desirudin. Patients received desirudin subcutaneously following orthopedic hip surgery at 10 mg twice a day (n = 17), 15 mg twice a day (n = 75), and 20 mg twice a day (n = 20). Of 112 patients, 11 (9.8%) developed antihirudin antibodies independently of the dose. The rate of immunization did not differ from that observed in HIT patients treated with lepirudin (P =.113). Plasma concentrations of desirudin did not differ between antihirudin antibody-positive and -negative patients. Antihirudin antibodies had no impact on incidences of deep vein thrombosis and/or pulmonary embolism, allergic reactions, and hemorrhage. However, the total number of immunized patients observed was low and so infrequent (but severe) effects of antihirudin antibodies cannot be excluded.

Topics: Antibodies; Anticoagulants; Arthroplasty, Replacement, Hip; Hirudin Therapy; Hirudins; Humans; Incidence; Injections, Subcutaneous; Recombinant Proteins; Thrombocytopenia; Thrombosis; Treatment Outcome

Recombinant hirudins (desirudin, lepirudin) are direct thrombin inhibitors administered as anticoagulants for heparin-induced thrombocytopenia (HIT) and venous thromboembolism (VTE) prophylaxis. Although these small polypeptides are widely used, concern exists over reports of antigenicity. In the largest study of r-hirudin immunogenicity to-date, we evaluated the prevalence, quantity and specificity of IgG immune responses to desirudin (15 mg SC q12h for as long as clinically required) in 245 surgical and medically-ill subjects enrolled in DESIRABLE, a multicenter, open-label, clinical trial of hospitalized patients requiring VTE prophylaxis. Sera obtained before and 30 days after desirudin administration were analyzed for IgG anti-desirudin by immunoenzymetric assay using immobilized desirudin to bind desirudin-reactive antibody and peroxidase conjugated monoclonal-anti-human IgG Fc to detect bound IgG antibody. Of 245 study subjects, 19 (7.7%) were antibody "responders" (>2-fold increase in IgG antibody levels with >50% inhibition by desirudin 30 days post-treatment). There were no differences between responders and non-responders in incidence of clinical outcomes or bleeding-related adverse events. Forty-six patients had detectable desirudin-reactive IgG antibody prior to treatment, with no significant increase in antibody levels after exposure and no increase in clinical events. The origin of pre-existing hirudin-reactive IgG antibody requires further investigation involving suspected anti-thrombin-thrombin interactions. These results indicate a low potential for immunogenicity, with <8% of patients developing IgG antibodies after desirudin administration for VTE prophylaxis. In contrast to reports on lepirudin, production of anti-hirudin antibodies to desirudin has no apparent effect on clinical events.

Topics: Aged; Antibodies; Antibodies, Monoclonal; Antibody Specificity; Antithrombins; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoenzyme Techniques; Immunoglobulin G; Male; Middle Aged; Recombinant Proteins; Reproducibility of Results; Thrombin; Thrombocytopenia; Time Factors; Venous Thromboembolism

Patients with a history of heparin-induced thrombocytopenia (HIT) and antibodies to hirudin were re-exposed to recombinant (r)-hirudin for prophylaxis of thromboembolism. Four patients were re-exposed to 2 x 25 mg of subcutaneous r-hirudin for 8-27 d. Two patients were re-exposed once, one patient twice and one four times. Re-exposure was well tolerated in all patients and no thromboembolism occurred. Antihirudin IgG (4/4 patients), IgA and IgM (1/4 patients) antibody levels increased. Baseline ecarin clotting times showed high variability. Patients with antibodies to hirudin may be re-exposed but anticoagulant monitoring is mandatory.

Topics: Adult; Aged; Antibodies; Anticoagulants; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Immunoglobulin A; Immunoglobulin G; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia; Thromboembolism; Whole Blood Coagulation Time

Heparin-induced thrombocytopenia (HIT) is the most common drug-related thrombocytopenia. Thromboembolic complications occur in approximately 50% of patients with HIT and result in limb amputation and death in up to 20% and 30% respectively. Because patients with a history of HIT may require future intravenous anticoagulation but have a high-risk of thromboembolism if re-challenged with heparin, alternative therapies are necessary when further anticoagulation is indicated. The use of direct thrombin inhibitors in HIT patients who also require thrombolytic therapy offers unique challenges to anticoagulant monitoring and safety. We present a case of progressive ileofemoral deep venous thrombosis in a patient with a history of HIT in order to review the combined use of hirudin and thrombolysis in this setting.

Topics: Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phlebography; Recombinant Proteins; Thrombocytopenia; Thrombolytic Therapy; Treatment Outcome; Venous Thrombosis

Topics: Animals; Cardiopulmonary Bypass; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombin; Thrombocytopenia; Thrombosis