Heterogeneous abnormalities in the multimeric structure, antigenic properties, and plasma-platelet content of factor VIII/von Willebrand factor in subtypes of classic (type I) and variant (type IIA) von Willebrand's disease.

FVIII/VWF in plasma and platelets was studied by various methods in 16 patients with von Willebrand's disease. These methods included measurements of both VIIIR:Ag and VIIIR:RCo levels, radio-crossed immunoelectrophoresis, analysis of the dose-response curves with both fluid-phase and two-site immunoradiometric assays, and SDS-agarose-acrylamide gel electrophoresis. Studies of normal plasma and platelets by the last-named method disclosed the presence of nine to 10 clearly resolvable bands with molecular weights of approximately 1 to 10 X 10(6) and unresolved higher-molecular-weight material, consistent with the previously described multimeric structure of FVIII/VWF. The multimeric structure and antigenic reactivity of FVIII/VWF were normal in 11 patients with type I von Willebrand's disease. However, measurements of the VIIIR:Ag content in plasma and platelets disclosed the presence of three subgroups. In one (type I-1), the VIIIR:Ag content of both plasma and platelets was decreased; in type I-2, VIIIR:Ag was decreased in plasma but normal in platelets, whereas the reverse was found in two patients with type I-3. In five patients with type IIA von Willebrand's disease we observed various abnormalities in the multimeric structure and antigenic reactivity of FVIII/VWF. The distinguishing features in two patients, designated type IIA-1 and IIA-2, were a decreased amount of high-molecular-weight FVIII/VWF and an impaired antigenic reactivity in both plasma and platelets; the defects in type IIA-2 were qualitatively different and more strikingly abnormal than those in type IIA-1. In three other patients, designated type IIIA-3, a less severe deficit of high-molecular-weight FVIII/VWF in plasma was observed and, in addition, the multimeric structure of FVIII/VWF in platelets was normal. The findings in this study demonstrate that a variety of defects in the synthesis, release, antigenic reactivity, and multimerization of FVIII/VWF are probably responsible for the heterogeneous findings in patients with von Willebrand's disease.