High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC)

Abstract

In Type I von Willebrand disease, the whole series of von Willebrand factor (vWF) multimers is present in plasma, but all are decreased in quantity. No structural abnormality of individual multimers has been demonstrated so far in these patients. We now describe five individuals, from two unrelated families, who had this form of the disease and in whom the complex banding pattern of each vWF multimer was markedly abnormal. Inheritance was autosomal dominant and the clinical expression was mild. A bleeding history was elicited in three of the patients and included recurrent epistaxis, menometrorrhagia, and bleeding following tooth extraction. Replacement therapy had never been required. Although vWF levels in plasma were within the normal range in all of them, the ristocetin cofactor activity was decreased in four, and the bleeding time was prolonged in three. Analysis of vWF multimeric structure by agarose gel electrophoresis, including a newly developed high-resolution technique, demonstrated that the main band of each multimer was present, but a second, well-defined band always seen in normal individuals was missing in the patients. Two additional bands had altered mobility and were less well defined than in normal subjects, and a fifth, less intense band was also undetectable in the patients. Treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) was assessed in two patients. It caused the circulating levels of vWF to increase and correct the bleeding time, but did not alter the structural abnormality. This study describes, therefore, a new variant form of Type I von Willebrand disease with aberrant structure of individual repeating multimers and an associated functional abnormality of vWF. In keeping with previously accepted terminology, the designation of Type IC von Willebrand disease has been adopted for this new variant.

Laboratory Diagnosis of Congenital von Willebrand Disease

“…We therefore propose to acknowledge the former subtypes of vWD 2A, namely IIA, IIC, IID, and IIE/IIF, as subtypes of their own (Table 2). 6,8,9,11,12,50,80,89,[108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124] To avoid too much confusion because of such an extension, the classification should employ terms with which most users are familiar; in other words, the current classification should be used as a basis and extended by terms from the older classification, if applicable. This can be done easily by naming the particular subtypes with Arabic numbers in extension of the current classification.…”

Response to desmopressin in type IID von Willebrand's disease

“…This suggests that the flanking bands may be involved in the polymerization process. However, the discovery of type IC vWD with absent subsidiary bands but a full range of multimeric forms up to the largest found in normal plasma casts doubt on this hypothesis (Ciavarella et al 1985).…”

“…On the higher resolution 3% gel ( Figure 2) it can be appreciated that the aberrant intermediate band is itself resolved into a triplet. By contrast, type IC (Ciavarella et al 1985) multimers have no flanking bands at all between the main bands.…”

Appendix II: A revised classification of Von Willebrand disease*

“…Despite the multimer distribution, the presence of a structural or functional defect indicates that the multimers contain qualitatively abnormal VWF subunits. This category includes the present VWD types Β [42], Vicenza [43], IC [44], and ID [45].…”