Indermohan Thethi

Old Versus New Oral Anticoagulants: Focus on Pharmacology

Since the discovery of heparin nearly a century ago, there have been large gaps in the development of anticoagulants. The discovery of warfarin was the first step toward using oral anticoagulants, but warfarin use has been associated with its own challenges from the perspectives of the prescribing physician and the patient. Warfarin, along with other coumarins, has a narrow therapeutic index, requires frequent monitoring, exhibits interindividual response variations, and is associated with several adverse effects. Frequent drug and food interactions contribute to potential safety and efficacy compromise. The indications for use of oral anticoagulants have increased, as these drugs are used not only for thrombosis management but also for cardiovascular indications, producing more challenges for oral anticoagulant use. Factor Xa and thrombin targeting has provided a rational approach to develop new oral anticoagulants with improvements over warfarin. In this review, the pharmacology of warfarin and the pharmacology of the newly developed oral anti-Xa and antithrombin agents are discussed.

Simple scoring system for early management of heparin-induced thrombocytopenia.

This study was performed to develop a simple scoring system to aid in the early clinical management of patients suspected of heparin-induced thrombocytopenia (HIT) with regard to decisions for continued heparin therapy. The system was designed to arrive at low (0) or possible (1) probability scores without knowledge of laboratory test results (except platelet counts) to avoid delays. As the safest clinical approach is to discontinue heparin, intermediate and high scores were combined. Critically ill VA hospital patients (n = 100) with a ≥30% fall in platelet count were assessed by platelet aggregation (PA), 14C-serotonin release assay (14C-SRA), and GTI ELISA. In this population, 53% were scored 1 and of these 43% were positive by laboratory test. Emphasizing the decision to discontinue heparin, the clinical signs of HIT were paramount for the immediate determination of a diagnosis of HIT without dependence on a positive laboratory test.

Vascular disease: obesity and excess weight as modulators of risk

Coronary artery diseases leading to heart attacks and cerebral artery disease leading to stroke rank number one and two respectively, in causing acute vascular events. Thrombosis of the veins and pulmonary embolism are major causes of hospital-associated acute vascular events. Increased bodyweight at all stages of life, from the very beginning of life (intrauterine growth), to adulthood, promote risks that are associated with vascular disease. An increase in bodyweight promotes risk factors for developing acute vascular events by a variety of mechanisms. In this article, we briefly describe some of the major risks associated with vascular diseases leading to vascular injury, and the modulatory role that increased bodyweight plays in promoting these risks.

Review: Contaminants in Heparin: Review of the Literature, Molecular Profiling, and Clinical Implications

Background: The contaminant isolated from contaminated heparin was oversulfated chondroitin sulfate (OSCS). Other possible contaminants should be evaluated. Methods: Contaminants were isolated from recalled contaminated heparin and were compared to OSCS from animal sources and to heparin by-products synthetically persulfated. Results: A great variability in molecular weight was observed in the isolated contaminants. Dermatan sulfate with high-molecular-weight in addition to OSCS was detected. Oversulfated chondroitin sulfate from different sources as well as heparin by-products produced activation of prekallikrein to kallikrein at variable rates as measured by the generation of kallikrein. All agents produced activation of the complement system. All compounds formed complexes with platelet factor 4 (PF4) and all produced 14C serotonin release in the heparin-induced thrombocytopenia (HIT) analysis. The agents also exhibited variable anticoagulant responses that were mostly mediated via heparin cofactor II. Conclusion: These results suggest that heparin contaminants represent a heterogeneous group of oversulfated glycosaminoglycans (OSGAGs) which may mediate multiple pathophysiologic responses.

Ischemic Stroke in the Setting of Chronic Immune Thrombocytopenia in an Elderly Patient—A Therapeutic Dilemma

Chronic immune thrombocytopenia (ITP) carries a poor prognosis in the elderly patients. Increasing evidence proposes that a subgroup of patients with chronic ITP may be more susceptible to ischemic stroke. An 84-year-old Caucasian man with multiple ischemic stroke risk factors presented with acute onset of slurred speech, confusion, and unsteady gait. Physical examination and neurologic imaging were consistent with a new left thalamic infarct. Platelet counts ranged between 40 000 × 109/L and 65 000 × 109 /L. Antiplatelet therapy for his newly acquired stroke was not initiated considering his low platelet counts and for mildly symptomatic thrombocytopenia, and the patient was discharged home. Both hematologic and neurologic guidelines for the management of chronic ITP and stroke have contradictory goals. Although anticoagulation is mandated in acute stroke, ITP causes low platelet counts that increase bleeding complications.

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism

BackgroundThe prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available.MethodsMEDLINE and EMBASE databases were searched to identify relevant original articles.ResultsLow-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding.ConclusionsParenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.

Generic Versus Branded Enoxaparin in the Prevention of Venous Thromboembolism Following Major Abdominal Surgery: Report of an Exploratory Clinical Trial

Introduction: Several generic low-molecular-weight heparins (LMWHs) have recently become available worldwide, including the United States. Companies have filed for regulatory approval of generic versions in many countries, based only on compound biochemical characteristics or its immunogenicity. Methods: Prospective study to evaluate the comparative effect of 2 enoxaparins (Sanofi-Aventis branded enoxaparin [SAe] vs eurofarma-enoxaparin [Ee], a generic version) as prophylaxis for venous thromboembolism (VTE) following major abdominal surgery. A total of 200 patients were randomized in a 1:1 ratio either to receive 40 mg of SAe or Ee subcutaneously (sc) once daily (od) postoperatively for 7 to 10 days. Compressive ultrasound was performed on day 10 + 4. Results: No statistically significant differences between the 2 groups were detected. In all, 2 SAe patients presented deep vein thrombosis ([DVT] 2.1%), none of the Ee group. No major bleeding events occurred. Conclusions: This exploratory trial suggests that the generic LMWH is probably as safe and as effective as the branded enoxaparin (Lovenox, Brazil) in the prophylaxis of VTE in this population.

Metabolic differences of current thienopyridine antiplatelet agents

Introduction: Antithrombotics are one of the most commonly prescribed classes of medication around the world. The thienopyridines are an integral part of antithrombotic therapy and are prescribed for various indications including acute coronary syndrome, peripheral vascular disease and cerebrovascular disease. These drugs have distinct metabolic pathways, which lead to the formation of active metabolites that produce both observed clinical differences as well as pharmacokinetic and pharmacodynamic differences in response. Areas covered: The authors describe the pharmacokinetic and pharmacodynamic behavior of three of the currently available thienopyridines, namely ticlopidine, clopidogrel and prasugrel. The authors also describe and discuss the drug interaction and pharmacogenomic factors which may impact safety and drug efficacy. Expert opinion: P2Y12-ADP receptor antagonism has proven to be effective at preventing thrombosis. Differences in the activation of these drugs, cytochrome metabolism, concomitant drug use and pharmacogenomics have an impact on thienopyridine use. Clopidogrel remains the thienopyridine drug with the most approved indications for use. Prasugrel has proven to be efficacious but is associated with a higher bleeding risk in comparison to clopidogrel and therefore has to be used in appropriate clinical indications.

Upregulation of Surrogate Markers of Inflammation and Thrombogenesis in Patients With ESRD: Pathophysiologic and Therapeutic Implications

Patients with end-stage renal disease (ESRD) undergoing regular hemodialysis have high annual mortality rate of around 15%. The most predominant cause of death is cardiovascular, which is not entirely explainable with conventional cardiac risk factors present in these patients. It has been postulated that ESRD is a chronic inflammatory and hypercoagulable condition with marked elevation of several markers that may explain this high mortality. In the current study, patients with ESRD on a stable regimen of hemodialysis were studied for the inflammatory and thrombogenesis markers to explain this phenomenon. The parameters studied were of thrombogenesis—thrombin-antithrombin III complex (TAT), prothrombin fragment (F1.2), D-dimer, and fibrinopeptide A (FPA) and inflammation—CD40 ligand, myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and nitric oxide (NO), and compared to control group comprised of 100 healthy volunteers. Our study shows that ESRD patients exhibit activation of the coagulation and inflammatory processes.

An Open Label, Non-randomized, Prospective Clinical Trial Evaluating the Immunogenicity of Branded Enoxaparin Versus Biosimilars in Healthy Volunteers

Introduction: Compositional variations among biosimilar enoxaparin could lead to a differential immunogenic response between these preparations. Methods: Enoxaparin (Clexane, n = 110) and a biosimilar version (Cutenox, n = 110) were administered to healthy volunteers in Brazil, 40 mg subcutaneous (SQ), daily, for 10 days. Blood was collected at baseline, days 1 and 10, and analyzed for antiheparin/PF4 antibody (AHPF4 antibodies) titers and subtypes by enzyme-linked-immunosorbent serologic assay (ELISA). Results: Low-molecular-weight heparin (LMWH) treatment resulted in AHPF4 antibodies generation, with differences on day 10 (P < .05). Antibody subtyping (immunoglobulin [Ig] G, IgA, IgM) demonstrated different profiles between LMWH with statistical significance for IgG (Clexane 10 = 0.21 ± 0.06, Cutenox 10 = 0.28 ± 0.10, P < .0001) and IgA (Clexane 10 = 0.15 ± 0.02, versus Cutenox 10 = 0.13 ± 0.02, P < .0001) on day 10, with a significant drug effect (P < .0001) and significant time by drug interaction (P = .0009). All antibody titers were stated in terms of optical density (OD) units. Conclusion: LMWHs immunogenic potential varies to generate AHPF4 antibodies and subtypes and cross-reactivity with preformed antibodies. Such parameters may be useful in defining the biosimilar LMWHs bioequivalence. Future studies evaluating the immunogenicity of biosimilar drugs are warranted.