refludan and Acute-Disease

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

The numerous drugs to which the acutely ill are exposed place these patients at a significant risk of developing drug-induced thrombocytopenia. Such patients tend to have preexisting hemostatic defects that place them at additional risk of complications as a result of the drug-induced thrombocytopenia. The clinical challenge is to provide rapid identification and removal of the offending agent before clinically significant bleeding or, in the case of heparin, thrombosis results. Drug-induced thrombocytopenic disorders can be classified into three mechanisms: bone marrow suppression, immune-mediated destruction, and platelet aggregation. Clinical characteristics, preliminary laboratory findings, and drug history specific to the mechanisms can assist clinicians in rapidly isolating the causative drug.

Topics: Acute Disease; Anticoagulants; Antineoplastic Agents; Chondroitin Sulfates; Critical Care; Dermatan Sulfate; Disease Management; Drug Combinations; Fibrinolytic Agents; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Interleukin-11; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

Antithrombotic and antiplatelet agents, particularly unfractionated heparin and aspirin, are longstanding therapeutic mainstays for acute coronary syndromes such as unstable angina and non-Q-wave myocardial infarction (MI). Early studies demonstrated that aspirin reduces the risk of mortality or nonfatal MI by 50-70% in patients presenting with unstable angina or non-Q-wave MI. Added to aspirin, heparin regimens further diminish the incidence of these myocardial ischemic events in the acute setting. Three major clinical studies demonstrated that such enhanced risk reductions can be achieved without significant increases in bleeding complications. The low-molecular-weight (LMW) heparin, dalteparin, proved superior to placebo but not unfractionated heparin in diminishing the incidence of (1) death or MI; (2) death, MI, or recurrence of angina; or (3) frequency of revascularization procedures. On the other hand, another LMW heparin, enoxaparin, did reduce these events at 14 and 30 days, as well as 1 year after treatment. The principal biophysical limitation of heparins, however, is that they cannot inactivate clot-bound thrombin, which probably contributes to morbidity and mortality in acute coronary syndromes. The natural leech-derived polypeptide hirudin and its derivatives (e.g., lepirudin) inactivate both fibrin-bound and free thrombin. Lepirudin has been approved in certain countries for the treatment of heparin-induced thrombocytopenia and is now being evaluated in the clinical management of acute myocardial ischemic syndromes. The well-documented pathophysiologic foundation for acute coronary syndromes is partial or intermittent thrombotic occlusion of a coronary artery as the result of atherosclerosis. Although a stable atherosclerotic plaque may not be clinically problematic, plaque rupture, which occurs under a variety of stimuli, touches off a cascade of enzymatic and cellular responses that frequently culminate in thrombotic occlusion. In the coronary circulation, such an occlusion may cause transmural MI, unstable angina, or non-Q-wave MI. Because the pathogenetic mechanisms of atherosclerosis with thrombotic complications have been elucidated, this knowledge can be translated into a rational clinical approach using antithrombotic therapies.

Topics: Acute Disease; Angina, Unstable; Anticoagulants; Aspirin; Clinical Trials as Topic; Coronary Disease; Dalteparin; Enoxaparin; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Recombinant Proteins

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

Bacterial endotoxins can induce the synthesis and release of vascular endothelial growth factor (VEGF), which may alter vascular permeability and cause vascular leakage.. The effect of acute systemic inflammation on VEGF concentration was measured in healthy males after an intravenous bolus infusion of Escherichia coli endotoxin (lipopolysaccharide, LPS, 20 IU kg-1) in a double-blind, placebo-controlled parallel group study. LPS administration was followed by an infusion of lepirudin (bolus 0.1 mg kg-1, continuous infusion of 0.1 mg kg-1 h-1, n = 12) or saline (n = 12).. Plasma VEGF increased from a mean of 15.1 pg mL-1 to 74.6 pg mL-1 5 h after LPS (P < 0.003). Body temperature, pulse rate, leukcytes, prothrombin fragment 1 + 2 (F1 + 2) and lactoferrin increased and platelets decreased after LPS (P < 0.05). The LPS-induced increase in VEGF was paralleled by the neutrophil cell degranulation marker lactoferrin but not by F1 + 2, and was not affected by lepirudin, which blunted F1 + 2 formation (P < 0.05).. Inflammation-induced activation of leukcytes rather than platelets plays a role in the marked increase in VEGF, which cannot be abrogated by antithrombotic therapy.

Topics: Acute Disease; Adult; Anticoagulants; Blood Coagulation; Blood Platelets; Double-Blind Method; Endothelial Growth Factors; Endotoxins; Escherichia coli; Hirudins; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leukocytes; Lymphokines; Male; Recombinant Proteins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The purpose of this pilot study was to determine the effect of recombinant hirudin (r-hirudin) on coagulopathy and the relationship between concentrations of thrombin-antithrombin III (ATIII) complex (TAT) and thrombin-hirudin complex (THC) in patients with disseminated intravascular coagulation (DIC). Five patients with haematological malignancy associated with DIC were studied. r-Hirudin was administered by continuous intravenous infusion at a dose of 0.005 mg/kg/h for 4-9 days to each patient. Fibrin/fibrinogen degradation products (FDP), D-dimer, TAT and plasmin-alpha 2 antiplasmin complex (PAP) concentrations decreased after treatment with r-hirudin in four patients studied. However, in one patient, serum creatinine increased to 1.7 mg/dl and aPTT was prolonged to 74.4s. Statistical analysis disclosed significant positive correlations between plasma concentrations of hirudin and THC, and between concentrations of THC and TAT. The concentrations of THC were much higher than those of TAT. In conclusion, these findings indicate that r-hirudin more strongly inhibited thrombin than did ATIII without heparin, and that administration of r-hirudin to renal insufficiency required individual adjustment of dosage. The present findings also suggest that r-hirudin can be considered a new agent for the treatment of DIC.

Topics: Acute Disease; Adult; Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Blast Crisis; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Hirudin Therapy; Hirudins; Humans; Infusions, Intravenous; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Middle Aged; Peptide Hydrolases; Pilot Projects; Recombinant Proteins; Treatment Outcome

Acute coagulopathy is a serious complication of traumatic brain injury (TBI) and is of uncertain etiology because of the complex nature of TBI. However, recent work has shown a correlation between mortality and abnormal hemostasis resulting from early platelet dysfunction. The aim of the current study was to develop and characterize a rodent model of TBI that mimics the human coagulopathic condition so that mechanisms of the early acute coagulopathy in TBI can be more readily assessed. Studies utilizing a highly reproducible constrained blunt-force brain injury in rats demonstrate a strong correlation with important postinjury pathological changes that are observed in human TBI patients, namely, diminished platelet responses to agonists, especially adenosine diphosphate (ADP), and subarachnoid bleeding. Additionally, administration of a direct thrombin inhibitor, preinjury, recovers platelet functionality to ADP stimulation, indicating a direct role for excess thrombin production in TBI-induced early platelet dysfunction.

Topics: Acute Disease; Adenosine Diphosphate; Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Brain; Brain Injuries; Hirudins; Kinetics; Male; Partial Thromboplastin Time; Platelet Aggregation; Prothrombin; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Subarachnoid Hemorrhage; Thrombelastography; Thrombin; Wounds, Nonpenetrating

Topics: Acute Disease; Anticoagulants; Arginine; Blood Coagulation; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Pipecolic Acids; Platelet Count; Polysaccharides; Recombinant Proteins; Research Design; Sulfonamides; Thrombin; Thrombocytopenia; Treatment Outcome; Venous Thrombosis; Warfarin