refludan and Syndrome

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: Administration, Oral; Anticoagulants; Arginine; Critical Care; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; International Normalized Ratio; Nurse's Role; Nursing Assessment; Partial Thromboplastin Time; Patient Selection; Pipecolic Acids; Platelet Count; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Sulfonamides; Syndrome; Thrombocytopenia; Time Factors

Heparin was first discovered in 1916 and at present is used in more than 12 million patients a year. In the 1950s, several physicians noticed an uncommon paradoxical phenomenon in which heparin appeared to function as a procoagulant instead of an anticoagulant. This phenomenon is now known as the immune-mediated heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS). Our understanding of this syndrome has evolved over the last 2 to 3 decades, and therapeutic options are arising. This article will focus on the most extensively studied therapy for HIT, which is the class of drugs known as the direct thrombin inhibitors. Specifically, we will focus on the mechanisms by which direct thrombin inhibitors may be useful in this syndrome, the evidence for their use, and the unique characteristics of the two FDA-approved agents in this class, lepirudin and argatroban.

Topics: Anticoagulants; Arginine; Binding Sites; Heparin; Hirudins; Humans; Models, Biological; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombocytopenia; Treatment Outcome

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).

Topics: Antibodies; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Gangrene; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Leg; Platelet Activation; Platelet Factor 4; Protein C Deficiency; Receptors, IgG; Recombinant Proteins; Retrospective Studies; Syndrome; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

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

Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconium-induced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60-70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response.

Topics: Antibodies, Monoclonal; CD11b Antigen; Complement Activation; Complement C5a; Complement System Proteins; Dose-Response Relationship, Drug; Flow Cytometry; Hirudins; Humans; Infant, Newborn; Inflammation; L-Selectin; Meconium; Meconium Aspiration Syndrome; Neutrophil Activation; Neutrophils; Oxidative Stress; Protein Binding; Recombinant Proteins; Respiratory Burst; Syndrome