Acquired von Willebrand syndrome in patients with monoclonal gammopathy of undetermined significance investigated using a mechanistic approach

Abstract

Background: Acquired von Willebrand syndrome (AVWS) has been reported to occur in association with monoclonal gammopathy, usually of undetermined significance (MGUS). It may present as a type 1 or type 2 von Willebrand factor (VWF) defect depending on the patient's representation of large VWF multimers.

Materials and methods: The mathematical model by Galvanin et al., already employed for studying inherited von Willebrand disease (VWD), was used to explore the pathogenic mechanisms behind MGUS-associated AVWS.

Results: The patients studied showed significantly reduced VWF levels and function; an increased VWF propeptide to VWF antigen ratio; and all VWF multimers present but in reduced quantities, with the low-molecular-weight VWF forms being significantly more represented than those of higher molecular weight. Our mathematical model revealed a significantly increased VWF elimination rate constant, with values similar to those of type Vicenza VWD. An even more increased VWF proteolysis rate constant was observed, with values one order of magnitude higher than in type 2A VWD but, in contrast, no loss of large multimers. The model predicted the same elimination rate for high- and low-molecular-weight VWF multimers, but proteolysis of the high-molecular-weight forms also contributes to the pool of low-molecular-weight oligomers, which explains why they were relatively over-represented.

Discussion: In MGUS-associated AVWS the increase of both clearance and proteolysis contributes to the circulating levels and multimer pattern of VWF, with a phenotype that appears to be a combination of type Vicenza and type 2A VWD. Hence, the mechanisms behind the onset of AVWS seem to differ from those of inherited VWD.

Figure 1

von Willebrand factor multimer pattern observed in three patients (1–3) with monoclonal gammopathy of undetermined significance Electrophoresis was performed under non-reducing conditions, using 1.6% agarose gel. The oligomers were detected with a ¹²⁵I anti-VWF antibody. High multimers are at the top, low ones at the bottom. NP: normal plasma; VWF: von Willebrand factor.

Figure 2

von Willebrand factor multimer pattern observed in patient 1 before (0), and at various times after DDAVP infusion For multimer representation, see legend to Figure 1. At 15 min, the increase in multimers is associated with the presence of ultra-large oligomers. Starting from 120 min, ultra-large and large multimers start to decline. At 360 min, the multimer pattern is much the same as before DDAVP infusion. DDAVP: 1-desamino-8-D-arginine vasopressin; NP: normal plasma.

Figure 3

von Willebrand factor multimer pattern seen in patient 1 after the infusion of 2,000 U Haemate P (panel A) and 2,000 U Wilfactin (panel B) Note that large VWF multimers never appear in the circulation, even right after infusing the concentrate, and the other VWF oligomers seem to be quickly removed from the bloodstream. VWF: von Willebrand factor; NP: normal plasma.

Figure 4

Pharmacokinetic values: k_e (A), k₁ (B) and k₀ (C) estimated with the mathematical model in patient 1 with acquired von Willebrand syndrome, healthy controls, and patients with type Vicenza and type 2A-II von Willebrand disease (D) Relative amounts of multimeric units over time after DDAVP challenge as quantified with ImageJ software from the photographic plate (stacked bars), and as predicted by the mathematical model in terms of UL+HMW vs LMW multimers (solid and dashed lines). Before the infusion, the proportion of the AVWS patient’s LMW multimers was significantly larger than that of the MMW and HMW multimers, unlike the picture seen in normal plasma. DDAVP infusion drastically reversed the relationship between LMW and HMW von Willebrand factor multimers. AVWS: acquired von Willebrand syndrome; DDAVP: 1-desamino-8-D-arginine vasopressin; UL: ultralarge, HMW: high-molecular-weight, MMW: intermediate-molecular-weight, LMW: low-molecular-weight.

Figure 5

Time course of multimeric units after DDAVP infusion as quantified by the model for patients with acquired von Willebrand syndrome (A), type Vicenza von Willebrand disease (B), type 2A-II von Willebrand disease (C) and healthy controls (D) UL: ultralarge; HMW: high molecular weight; MMW: intermediate molecular weight; LMW: low molecular weight.