Quantitative Assay of a Plasma Factor Deficient in von Willebrand's Disease that is Necessary for Platelet Aggregation. RELATIONSHIP TO FACTOR VIII PROCOAGULANT ACTIVITY AND ANTIGEN CONTENT

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Abstract

In a previous paper, we showed that the abnormality of ristocetin-induced platelet aggregation in platelet-rich plasma in 10 patients with von Willebrand's disease could be corrected by a factor in normal plasma that was present in the same fractions as factor VIII procoagulant activity (antihemophilic factor, AHF, VIIIAHF) when prepared by chromatography on Bio-Gel 5 M (Bio-Rad Laboratories, Richmond, Calif.). This observation suggests that patients with this disorder are deficient in a plasma factor, associated with the factor VIII molecule, that is necessary for normal platelet function. In the present paper, we describe, an assay for this factor, the von Willebrand factor (VIIIVWF), based on the observation that a log-log relationship exists between the amount of ristocetin-induced aggregation of washed, normal platelets and the concentration of normal plasma present in the test system. We assayed the activity of VIIIVWF as well as antihemophilic factor procoagulant activity (VIIIAHF) and factor VIII antigen (VIIIAGN) in 15 patients with von Willebrand's disease and 20 normal subjects. A highly significant correlation (r ∼ 0.80) between VIIIVWF and both VIIIAHF was found in normal subjects and in patients with von Willebrand's disease. This finding, in addition to the observation that agarose gel chromatography fractions that have VIIIAHF procoagulant activity also have VIIIVWF activity, strongly suggests that the von Willebrand factor is associated with the factor VIII molecule. VIIIVWF in normal plasma was not inhibited by human anti-VIII, and VIIIVWF levels were normal in hemophilic plasma. Thus, the VIIIVWF site on the factor VIII molecule appears to be different from that determining VIIIAHF. Finally, the activity of VIIIVWF appeared to correlate better with the bleeding time than either VIIIAHF or VIIIAGN. This suggests that VIIIVWF assayed in this study may be the “anti-bleeding factor” that is deficient in von Willebrand's disease. These findings are consistent with a decreased synthesis of the factor VIII molecule in von Willebrand's disease and suggest the possibility of additional abnormalities of the site on the molecule that determines the activity of VIIIVWF.

Authors

Harvey J. Weiss, Leon W. Hoyer, Frederick R. Rickles, André Varma, John Rogers