Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von willebrand factor

Abstract

The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described “pseud” von Willebrand's disease and “platelet-type” von Willebrand's disease.

von Willebrand disease (VWD): evidence‐based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)1

“…In type 1 VWD, persons who have accelerated clearance of plasma VWF may have a transient response to desmopressin [43,225]. Whether desmopressin should be used at all in persons with type 2B VWD is controversial [226,234,254,255,380–383]. In type 2N VWD, the baseline FVIII level may be a good predictor of the magnitude and duration of the FVIII response to desmopressin [79,224,228,384].…”

Identification of new type 2B von Willebrand disease mutations: Arg543Gln, Arg545Pro and Arg578Leu

“…Most of these variants, previously named IIB, VWD patients specifically lack the largest multimers of VWF in plasma but not in platelets ( Ruggeri & Zimmerman, 1980). As, in addition, VWF secreted by type 2B VWD umbilical vein endothelial cells have been shown to contain the full range of VWF multimers ( De Groot et al , 1989 ), the characteristic multimeric pattern of plasma VWF and the frequent associated thrombocytopenia ( Ruggeri et al , 1980 ) may be related to the spontaneous binding of plasma HMW multimers to platelets and their subsequent clearance from the circulation ( Ruggeri et al , 1982 ).…”

Identification and characterization of a novel mutation in von Willebrand factor causing type 2B von Willebrand's disease

“…Type 2B VWD is a rare variant of VWD in which patient VWF demonstrates unregulated binding to the platelet GPIb–IX–V complex. The defect is thought to be due to the rapid clearance of the endogenous VWF molecule by abnormal binding of VWF to the platelet GPIb–IX–V complex, followed by platelet aggregation and clearance (Ruggeri et al , 1982). There have been more than 20 different mutations described which are responsible for the type 2B VWD phenotype.…”