Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity.

Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator. BACKGROUND: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaß and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaß and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaß enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. METHODS: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. RESULTS: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaß. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaß, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. CONCLUSION: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaß in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.

Laboratory confirmation of Amanita smithiana mushroom poisoning.

CONTEXT: Here we present a case of Amanita smithiana poisoning resulting in acute kidney injury requiring dialysis, and highlight laboratory methods used to confirm the diagnosis. Identification of Amanita smithiana toxin using thin-layer chromatography can provide greater diagnostic certainty than history and renal function tests alone. CASE DETAILS: A 63-year-old male presented to hospital with anuria and gastrointestinal symptoms, two days after consuming a soup of wild mushrooms he had picked. He was found to be in acute renal failure, requiring hemodialysis. After nine days of supportive treatment, he recovered renal function, and was discharged in good health 15 days post-ingestion. The patient provided a sample of leftover soup, and examination of cooked mushroom fragments by a mycologist provided preliminary identification of A. smithiana. Thin-layer chromatography revealed the presence of A. smithiana toxin in the soup, confirming this identification. DISCUSSION: A. smithiana is a nephrotoxic mushroom that can be easily mistaken for the edible and highly prized Pine mushroom (Tricholoma magnivelare). It causes initial gastrointestinal symptoms, followed by acute renal failure. Treatment includes dialysis and supportive care until the patient recovers renal function. The chemical structure of the A. smithiana toxin is unknown, but it can be identified as a characteristic spot on thin-layer chromatography.

Quetiapine-associated cholestasis causing lipoprotein-X and pseudohyponatraemia.

A case of intrahepatic cholestasis secondary to treatment with quetiapine in combination with lamotrigine and zopiclone, resulting in severe hypercholesterolaemia without overt lactescence of the plasma, is presented. Abundant lipoprotein-X was seen on lipoprotein electrophoresis. The patient was diagnosed and treated for hyponatraemia which was likely factitious and caused by hypercholesterolaemia. Cholestasis and hypercholesterolaemia resolved over a period of several months after the discontinuation of quetiapine.

Nephrogenic systemic fibrosis: the story unfolds.

The purpose of this Commentary is to briefly summarize the current knowledge of nephrogenic systemic fibrosis in order to promote better understanding of the complexity of chronic kidney disease and its associated conditions.

Preliminary evidence of psychological distress among reservists in the Persian Gulf War.

This study was conducted as a preliminary investigation into the presence and nature of psychological distress among military reserve personnel as a result of their participation in the Persian Gulf War. Eleven months after cessation of hostilities in the Gulf War, a self-report survey was mailed to the home of each of the 1090 members who had been assigned to the study Air National Guard unit during this period. After unit activation in December 1990, 517 of these individuals were deployed to the Persian Gulf as participants in Operation Desert Storm. The remainder of the unit participated in their military service during this period without being deployed to the Persian Gulf. The survey consisted of a demographic section, the Mississippi Scale for Combat Related Posttraumatic Stress Disorder (M-PTSD), the revised Symptom Checklist 90 (SCL-90-R), and an anecdotal response section; 46% of those surveyed responded. The major finding of the study was that 6.8% of the respondents who served in the combat theater had elevated M-PTSD scores. This was a statistically significant finding compared with the 1.7% of those surveyed who had elevated M-PTSD scores having served at home (chi2 = 6.25, df = 1, p = .01). These elevated M-PTSD scores were found despite low levels of traditional combat stressors and strong levels of perceived public support. SCL-90-R scores were also higher in deployed versus nondeployed respondents. Although the clinical presence of PTSD was not established by this study, the preliminary finding of elevated M-PTSD scores in the deployed group is suggestive of the possibility of clinical PTSD. This finding supports the need for further PTSD research among reservists who are exposed to nontraditional combat stressors. Elevated SCL-90-R scores in the deployed group also suggest that other forms of psychological distress may have developed in a significant number of combat veterans of the Persian Gulf War.

Cell surface oligosaccharide modulation during differentiation: III. Lectin affinity class distributions.

In previous studies we showed that the onset of the morphological phenotype of cellular senescence (IMR-90) in vitro is preceded by complex cell surface changes. Using fluorescently conjugated lectins these studies showed: (1) quantitative PDL-dependent decreases in cell surface mannosyl, galactosyl, and N-acetyl-glucosamine residues; (2) these changes were correlated with changes in ligand/lectin membrane mobility, suggesting a functional relationship for the quantitative changes. To further investigate the biological significance of these observations we have developed a synthetic ligand competition assay to analyze the lectin binding event itself. The results of these analyses show that: (1) the number of binding affinity class distributions is highly restricted; (2) the PDL-dependent mannosyl change is due to the loss of a high-affinity class distribution without significant change in the low-affinity site; and (3) PDL-dependent changes in both galactosyl and N-acetyl glucosamine binding events are the result of changes in the affinity class distributions. These results are interpreted in terms of the potential available energy to act as the basis for signal transduction at the cell surface.

Cell surface oligosaccharide modulation during differentiation: IV. Normal and transformed cell growth control.

In previous studies it was shown that cell surface oligosaccharide affinity class distributions and binding capacities were down-regulated as normal cells approach senescence. Using a sensitive, amplified, lectin/specific-ligand competition analysis three other growth regulation states were compared to that of cellular senescence. Non-senescent and senescent low-density and contact-induced growth inhibition was compared with neoplastic cell growth control. Non-senescent human fetal lung fibroblasts (IMR-90) down-regulated their mannosyl and galactosyl specificities in response to both low-density and contact-induced growth inhibition. Senescent IMR-90 down-regulate their mannosyl residues in response to contact conditions while they up-regulate their galactosyl residues under the same conditions. Growth-transformed transplantable canine glioma cells did not show density-dependent regulation of their cell surface oligosaccharide structures. Modulation of the CG cells with a specific alpha-mannosidase II inhibitor, Ricinus communis a galactosyl specific lectin, and pokeweed mitogen a cellular differentiating agent resulted in an altered growth phenotype and up-regulation of the mannosyl and galactosyl surface oligosaccharides. These data indicate a controller function for the cell surface oligosaccharides and a general influence on growth control.