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Lepirudin-driven network of inflammation
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
Despite a growing understanding of the pathogenesis of sepsis induced disseminated intravascular coagulation (DIC), infusion of low doses of heparin remains the only specific therapeutic option available. The use of heparins, however, is hampered by functional limitations, which may have precluded their widespread use. These limitations include the necessity of sufficient plasma levels of antithrombin III (AT III, node in orange) as an endogenous cofactor and the risk of heparin-induced thrombocytopenia. Furthermore, heparin does not effectively inactivate clot-bound thrombin and its anticoagulant efficacy may be decreased by the release of endogenous inhibitors like platelet factor 4 and lactoferrin, which are increasingly released during systemic inflammation.
Hirudin is devoid of heparin's limitations. Hirudin, in contrast to heparin, has not been reported to activate platelets, and thus carries a lower risk for drug-induced thrombocytopenia, which is difficult to differentiate from platelet consumption during DIC. The latter could be particularly important in DIC where platelet counts are frequently low.
The theoretical advantages of lepirudin have fueled a number of animal studies on its effects in lipopolysaccharide (LPS, red hexagonal node)-induced DIC. Lepirudin prevented fibrin deposition in kidney and liver of rats and decreased mortality of rabbits from 70% to less than 20%. Furthermore, lepirudin inhibited the expression of tissue factor (TF) on endothelial cells and media at the sites of angioplasty in rabbits and pigs.
The therapeutic implications of lepirudin-based complement inhibition are visualized by antagonizing several phagocytotic interactions (left section, nodes with gray background). Granulocyte and monocyte oxidative burst is complement dependent and is reduced by 85% and 70%, respectively, by the CD3 binding peptide compstatin. A similar reduction has been found by inhibition of C5, C5a, and C5a receptor (C5aR/CD88). Opsonization and phagocytosis are completely inhibited by blocking of C5aR or CR3, whereas blocking of the Fc gamma receptors (CD16, CD32, CD64) has no effect. In contrast to oxidative burst and phagocytosis, cytokine secretion is largely complement independent.
In conclusion, the present network is particularly useful for studying complement, antithrombolytics, inflammation and DIC. If human complement is considered a primary inducer of inflammation, a network of inflammation can be build focusing on the thrombin-specific hirudin analog lepirudin as an anticoagulant, which, in contrast to heparin, does not interfere with complement activation.
Hirudin is devoid of heparin's limitations. Hirudin, in contrast to heparin, has not been reported to activate platelets, and thus carries a lower risk for drug-induced thrombocytopenia, which is difficult to differentiate from platelet consumption during DIC. The latter could be particularly important in DIC where platelet counts are frequently low.
The theoretical advantages of lepirudin have fueled a number of animal studies on its effects in lipopolysaccharide (LPS, red hexagonal node)-induced DIC. Lepirudin prevented fibrin deposition in kidney and liver of rats and decreased mortality of rabbits from 70% to less than 20%. Furthermore, lepirudin inhibited the expression of tissue factor (TF) on endothelial cells and media at the sites of angioplasty in rabbits and pigs.
The therapeutic implications of lepirudin-based complement inhibition are visualized by antagonizing several phagocytotic interactions (left section, nodes with gray background). Granulocyte and monocyte oxidative burst is complement dependent and is reduced by 85% and 70%, respectively, by the CD3 binding peptide compstatin. A similar reduction has been found by inhibition of C5, C5a, and C5a receptor (C5aR/CD88). Opsonization and phagocytosis are completely inhibited by blocking of C5aR or CR3, whereas blocking of the Fc gamma receptors (CD16, CD32, CD64) has no effect. In contrast to oxidative burst and phagocytosis, cytokine secretion is largely complement independent.
In conclusion, the present network is particularly useful for studying complement, antithrombolytics, inflammation and DIC. If human complement is considered a primary inducer of inflammation, a network of inflammation can be build focusing on the thrombin-specific hirudin analog lepirudin as an anticoagulant, which, in contrast to heparin, does not interfere with complement activation.
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