THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP) MEDIATES CLEARANCE OF COAGULATION-FACTOR XA IN-VIVO

Blood coagulation factor X plays a pivotal role in the clotting cascad e, When administered intravenously to mice, the majority of activated factor X (factor Xa) binds to alpha(2)-macroglobulin (alpha(2)M) and i s rapidly cleared from the circulation into liver. We show here that t he low-density lipoprotein receptor-related protein (LRP) is responsib le for factor Xa catabolism in vivo. Mice overexpressing a 39-kD recep tor-associated protein that binds to LRP and inhibits its ligand bindi ng activity displayed dramatically prolonged plasma clearance of I-125 -factor Xa. Preadministration of alpha(2)M-proteinase complexes (alpha (2)M) also diminished the plasma clearance of I-125-factor Xa in a do se-dependent fashion. The clearance of preformed complexes of I-125-fa ctor Xa and alpha(2)M was similar to that of I-125-factor Xa alone and was also inhibited by mice overexpressing a 39-kD receptor-associated protein. These results thus suggest that, in vivo, factor Xa is metab olized via LRP after complex formation with alpha(2)M. (C) 1998 by The American Society of Hematology.