ABSTRACT
Activation of the complement cascade is an important mechanism for antiphospholipid antibody-mediated thrombosis. We examined the effects of rEV576 (coversin), a recombinant protein inhibitor of complement factor 5 activation, on antiphospholipid antibody-mediated tissue factor up-regulation and thrombosis. Groups of C57BL/6J mice (n=5) received either IgG from a patient with antiphospholipid syndrome (APS) or control IgG from normal human serum (NHS). Each of these groups of mice had IgG administration preceded by either rEV576, or phosphate buffer control. For each of the four treatment groups, the size of induced thrombus, tissue factor activity in carotid homogenates, anticardiolipin and anti-ß2glycoprotein I (anti-ß2GPI) levels were measured 72 h after the first injection. Mice treated with IgG-APS had significantly higher titers of anticardiolipin antibodies and anti-ß2GPI at thrombus induction compared with those treated with IgG-NHS. The IgG-APS/phosphate buffer treatment induced significantly larger thrombi and tissue factor activity compared with other groups. Mice treated with IgG-APS/rEV576 had significantly smaller thrombi and reduced tissue factor activity than those treated with IgG-APS/phosphate buffer. The data confirm involvement of complement activation in antiphospholipid antibody-mediated thrombogenesis and suggest that complement inhibition might ameliorate this effect.
Subject(s)
Antibodies, Antiphospholipid/immunology , Complement C5/antagonists & inhibitors , Thrombosis/prevention & control , Animals , Mice , Mice, Inbred C57BL , Recombinant Proteins/pharmacology , Thromboplastin/analysis , Thrombosis/etiology , beta 2-Glycoprotein I/immunologyABSTRACT
The speed with which horseflies (Diptera: Tabanidae) obtain a bloodmeal suggests they have potent vasodilators. We used isolated perfused rat heart to examine the vasoactivity of salivary gland extracts (SGEs) of three horsefly species, Hybomitra bimaculata Macquart, Tabanus bromius Linnaeus and Tabanus glaucopis Meigen. Administration of horsefly SGEs to the heart produced biphasic coronary responses: a decrease and subsequent increase in coronary flow (CF), characterized by initial vasoconstriction followed by prolonged vasodilation of coronary vessels. However, although SGEs of H. bimaculata induced a significant decrease in left ventricular pressure (LVP), the effect on changes in CF was not significant except at the highest dose tested. The ability to reduce LVP without significantly lowering CF, or affecting heart rate and rhythm, represents a unique set of properties that have considerable therapeutic potential if they can be reproduced by a single molecule.
