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Essentials Reversal of anticoagulant effects of dabigatran may occur despite application of idarucizumab. Monitoring of dabigatran level after antidote application is crucial to detect rebound. Repeated doses of idarucizumab may be necessary in cases of massive dabigatran accumulation. Combination of antidote application and renal replacement therapy may offer additional benefit. Summary Idarucizumab is a monoclonal antibody fragment designed for reversing the anticoagulant effects of dabigatran. Administration is recommended as two intravenous boluses of 2.5 g within 15 min of each other or as a single 5 g bolus. However, in certain situations a second dose of the drug could be necessary. We report the case of a 77-year-old man, treated with dabigatran for paroxysmal atrial fibrillation. He presented at our department with acute renal failure, concomitant massive dabigatran accumulation and subsequent acute gastrointestinal bleeding. Fifty minutes after the administration of idarucizumab, the dabigatran plasma concentration decreased from a peak of 1630 ng ml-1 to a level below the detection limit of 30 ng ml-1 and bleeding stopped. Eight hours after administration, the dabigatran plasma level started to increase up to 1560 ng ml-1 (96% of the maximum value obtained), accompanied by a further drop in hemoglobin. Concomitant hemodialysis and hemofiltration led to a continuous decrease in dabigatran plasma levels. However, sepsis and multiorgan failure ensued, which led to death. With this case report we raise the question of whether massive dabigatran accumulation requires repeated doses of idarucizumab, or alternatively, if the combination of antidote with hemodialysis/renal replacement therapy is advisable in order to remove circulating levels of dabigatran.

Dose-dependent effect of parenteral iron therapy on bleomycin-detectable iron in immune apheresis patients. Background Iron deficiency and anemia are commonly encountered in patients with autoimmune diseases undergoing immune apheresis. This makes erythropoietin and iron substitution necessary in most patients. However, intravenous iron therapy may result in an increase of potentially toxic nontransferrin-bound iron. Methods We examined the effect of 50 mg or 100 mg of iron (III) sucrose on bleomycin-detectable iron (BDI) in immune apheresis patients. Six patients with autoimmune disorders and normal kidney function were enrolled. Before and after the injection of 50 mg or 100 mg of iron (III) sucrose, BDI was measured in serum samples at five different time points. Results There was no BDI traceable before injection of iron (III) sucrose. BDI was present in serum of all patients after the administration of 100 mg of iron (III) sucrose in concentrations up to 0.49 μmol/L. In contrast, only one patient showed BDI at a concentration of 0.16 μmol/L after the administration of 50 mg of iron (III) sucrose. Conclusion We conclude that if parenteral iron is administered after apheresis treatment, despite the equal tolerability, use of 50 mg of iron (III) sucrose is superior to 100 mg of iron (III) sucrose in avoiding the formation of potentially toxic nontransferrin-bound iron.

Endothelial cell adhesion molecule and PMNL response to inflammatory stimuli and AGE-modified fibronectin. Background Atherosclerotic vascular disease is the leading cause of death in patients with diabetes mellitus and end-stage renal disease. Advanced glycation end products (AGEs) are strongly suggested to be involved in the pathogenesis of atherosclerosis in these patients who also frequently experience infectious complications. We hypothesized that the interaction of AGEs and inflammatory mediators contributes to the up-regulation of endothelial cell activation. Methods We investigated the effect of advanced glycated fibronectin in the presence or absence of inflammatory stimuli on the endothelial cell surface and mRNA expression of cell adhesion molecules. Furthermore, the influence of advanced glycated fibronectin on the transendothelial migration pattern of polymorphonuclear cells was analyzed. Results Exposure to advanced glycated fibronectin together with inflammatory stimuli such as interleukin (IL)-1α, tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) led to a significant increase in the surface expression of the cell adhesion molecules E-selectin, ICAM-1, VCAM-1 and PECAM-1 on endothelial cells. Soluble AGEs in combination with advanced glycated fibronectin significantly enhanced the endothelial cell surface expression of ICAM-1, VCAM-1 and PECAM-1, whereas this was not the case for E-selectin. At the transcriptional level short-time exposure of endothelial cells to advanced glycated fibronectin and inflammatory mediators resulted in an increased expression of E-selectin, ICAM-1 and VCAM-1 mRNA levels, whereas PECAM-1 repeatedly showed a significant decrease of gene transcript levels. An increase of mRNA levels was also observed for E-selectin, ICAM-1, VCAM-1 and PECAM-1 following incubation with a combination of advanced glycated fibronectin and soluble advanced glycation end-products. Furthermore, polymorphonuclear cells responded with a sevenfold increase in transendothelial migration following exposure of endothelial cells to advanced glycated fibronectin and inflammatory mediators. Conclusions These results suggest that the combination of matrix glycation and inflammation up-regulates the activation of the endothelial cell adhesion cascade, a mechanism that might contribute to the increased burden of atherosclerotic morbidity and mortality in patients suffering from diabetes mellitus or chronic renal failure.