Abnormal proteolytic degradation of von willebrand factor after desmopressin infusion in a new subtype of von willebrand disease (ID)

Abstract

We describe two members of a single family, father and son, with mild factor XII deficiency associated to von Willebrand disease (vWD) with aberrant structure in whom distinct multimeric abnormalities and an abnormal proteolytic processing of von Willebrand factor (vWF) after desmopressin (DDAVP) administration were present. They had a mild bleeding history, low levels of vWF-related activities, and a prolonged bleeding time. Low-resolution agarose gel electrophoresis showed a vWF with all size multimers in plasma and platelets. Higher-resolution agarose gels demonstrated that the main band was present, but the relative proportion of the satellite bands was markedly reduced. The smallest oligomer was not increased. After the infusion of DDAVP to the father, a transient increase in the relative proportion of the satellite bands was seen, as described in normal individuals. No difference in the structure of vWF was observed when blood was collected with proteinase inhibitors. The analysis of native subunits of vWF and their proteolytic derived fragments, after DDAVP administration, showed a temporary augmentation of the 176 kDa fragment, as seen in normal subjects, as well as an increase of the 189 kDa fragment. This finding had not been reported previously either in normal individuals or in patients with vWD.

Classification and Characterization of Hereditary Types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (Unclassifiable) von Willebrand Disease

“…Lopez-Fernandez et al (72) described autosomal dominant VWD type 1 in a father and son characterized by a mild to moderate bleeding tendency, prolonged BT, decreased RIPA, and low levels of FVIII:C, VWF:Ag and VWF:RCo (Table 9). A certain degree of disproportion of VWF:Ag and VWF:RCo was seen in resting states.…”

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.…”

DDAVP treatment in a child with von Willebrand disease type 2M

“…However, in rarely occurring defects and especially in type 2 de®ciencies many authors prefer replacement therapy with plasma products [1,3,5,11]. Although few reports have investigated the response of individual type 2M families to DDAVP in a test situation [2,6,8], to our knowledge nothing is known about the de®nite hemostatic eect in the clinical setting, such as oropharyngeal surgery. Since the preoperative DDAVP test administration had been proven to be eective and safe in our patient, this treatment might have prevented surgical hemorrhage, although the functional role of the structurally abnormal vWF multimers remains unclear.…”

“…This is caused by qualitatively abnormal vWF multimers containing subunits with structural defects [2,6,8]. The clinical picture comprises a mild to moderate bleeding tendency, probably due to varying degrees of an associated FVIII:C de®ciency [8,13].…”