Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin-antithrombin complex (TAT), and d-dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis-associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis-associated DIC.
Enoxaparin, a complex, biologically derived low-molecular-weight heparin, is approved for a range of clinical indications. This study was carried out to compare the potency profile and pharmacodynamic responses of branded enoxaparin (Lovenox; Sanofi, US) with a generic enoxaparin (enoxaparin sodium injection, USP). Five batches of each product were tested. Although the average molecular weight, anti-factor Xa, and anti-factor IIa potencies were similar for the two products, differences were observed in the in vitro thrombin generation and kinetics of clot formation (P = .01) and in the ex vivo pharmacodynamics regarding thrombin generation inhibition (P = .029), tissue factor pathway inhibitor release (P = .006), and inhibition of the active form of thrombin-activated fibrinolysis inhibitor (P = .023). These findings suggest that simple analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in biological performance between the branded and the generic enoxaparin.
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.
During the period of November 2007 to January 2008, an increased prevalence of adverse reactions to heparin was noted. These adverse events have been attributed to the presence of purposeful contaminant, oversulfated chondroitin sulfate (OSCS) from April 2007 to May 2008. An analysis of dialysis patients' plasma obtained in 2006 and 2007 consistently had a low (5%) prevalence of AHPF4 antibodies. Blood samples from 78 patients on maintenance hemodialysis, who were potentially exposed to OSCS-contaminated heparin, were analyzed for the presence of all AHPF4 antibodies using a commercially available ELISA kit from GTI. Although there was no change in the platelet count of these patients, 15 of 78 patients (19.2%) studied had an increased prevalence of AHPF4 antibodies. Subtyping of the all platelet factor 4 (PF4) antibodies documented showed a higher prevalence of immunoglobulin G antibodies as compared to their previously determined antibodies. These observations suggest that the OSCS contaminant in the recalled heparin triggers an immunogenic response not seen with OSCS-contaminated free heparin.
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