Diannexin treatment decreases ischemia-reperfusion injury at the endothelial cell level of the microvascular bed in muscle flaps

Michal Molski, Anne Groth, Anthony C Allison, Mark Hendrickson, Maria Siemionow
Annals of Plastic Surgery 2009, 63 (5): 564-71
Ischemia-reperfusion injury (IRI) is a common and serious complication of reperfusion following vascular occlusion. We present a novel interpretation of the pathogenesis of IRI. According to this hypothesis, anoxia resulting from ischemia allows translocation of phosphatidylserine to the surface of endothelial cells (ECs), providing an attachment site for leukocytes and platelets. This attachment impedes blood flow through the microvasculature. During IRI mediators of increased vascular permeability are produced, resulting in edema. We have developed a recombinant homodimer of human Annexin V, Diannexin, to attenuate IRI. Annexin V (36 kDa) rapidly passes from the circulation into the urine. In Diannexin 2 annexin V molecules are joined by a short peptide linker to produce a 73 kDa protein, which exceeds the renal filtration threshold. Diannexin has a half-life of about 2.5 hours in the human circulation. Diannexin also has a higher affinity for phosphatidylserine on cell surfaces than the monomer has. Such binding inhibits leukocyte attachment to ECs, and inflammatory mediator formation, during IRI. The aim of the study now reported was to ascertain the effects of Diannexin on IRI in the rat cremaster muscle flap, as revealed by intravital microscopy. During IRI there was increased attachment of leukocytes to ECs, reduced blood flow and augmented vascular permeability. Administration of Diannexin before or just after ischemia prevented these effects. Diannexin inhibited transmigration of leukocytes during IRI. Edema complicates peripheral vascular surgery, stroke, and other clinical conditions. Diannexin has proven to be safe when administered to patients after major surgical operations, and it may be useful to prevent IRI associated with peripheral vascular surgery.

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