Studies of a Second Family With the Quebec Platelet Disorder: Evidence That the Degradation of the α-Granule Membrane and Its Soluble Contents Are Not Secondary to a Defect in Targeting Proteins to α-Granules

Abstract

AbstractWe recently described a Quebec family with an autosomal dominant bleeding disorder characterized by mildly reduced-low normal platelet counts, an epinephrine aggregation defect, multimerin deficiency, and proteolytic degradation of several, soluble α-granular proteins. Similar clinical features led us to investigate a second family with an unexplained, autosomal dominant bleeding disorder. The affected individuals had reduced to normal platelet counts, absent platelet aggregation with epinephrine, and multimerin deficiency. Their platelet α-granular proteins factor V, thrombospondin, von Willebrand factor, fibrinogen, fibronectin, osteonectin, and P-selectin were proteolyzed and comigrated with the degradation products found in patients from the other family. However, their platelet albumin, IgG, external membrane glycoproteins, CD63 (a lysosomal and dense granular protein), calpain, and plasma von Willebrand factor were normal, indicating restriction in the proteins proteolyzed. Electron microscopy studies indicated preserved α-granular ultrastructure, despite degradation of soluble and membrane α-granular proteins. Immunoelectron microscopy studies of the patients' platelets indicated that fibrinogen, von Willebrand factor, P-selectin, multimerin, and factor V were within α-granules, with normal to reduced labeling for these proteins. Pathologic proteolysis of α-granular contents, rather than a defect in targeting proteins to α-granules, may be the cause of the protein degradation in the Quebec platelet disorder.