Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B–associated thrombocytopenia

Abstract

Key Points• Adsorption of VWF type 2B mutants to platelets induces thrombocytopenia in VWD type 2B mice.• VWF/platelet complexes are phagocytosed by macrophages in liver and spleen.Von Willebrand disease (VWD) type 2B is characterized by mutations causing enhanced binding of von Willebrand factor (VWF) to platelets. Bleeding tendency is associated with heterogeneous clinical manifestations, including moderate to severe thrombocytopenia. The underlying mechanism of the thrombocytopenia has remained unclear. Here, a mouse model of VWD type 2B was used to investigate pathways contributing to thrombocytopenia. Immunohistochemical analysis of blood smears revealed that mutant VWF was exclusively detected on platelets of thrombocytopenic VWD type 2B mice, suggesting that thrombocytopenic VWD type 2B mice were elevated two-to threefold upon chemical macrophage depletion. Colocalization of platelets with CD68-positive Kupffer cells and CD168-positive marginal macrophages in liver and spleen, respectively, confirmed the involvement of macrophages in the removal of VWF/platelet complexes. Significantly more platelets were found in liver and spleen of VWD type 2B mice compared with control mice. Finally, platelet survival was significantly shorter in VWD type 2B mice compared with control mice, providing a rationale for lower platelet counts in VWD type 2B mice. In conclusion, our data indicate that VWF type 2B binds to platelets and that this is a signal for clearance by macrophages, which could contribute to the thrombocytopenia in patients with VWD type 2B. (Blood. 2013;122(16):2893-2902

von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

“…28 It has been suggested that the mutant VWF is cleared faster in these patients because of the spontaneous binding of VWF to platelets. 29 Our results also showed that the mutant type 2N VWF is cleared faster than normal VWF.…”

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

“…have given rise to a prothrombotic condition, it is now accepted that several causes underlie the thrombocytopenia, such as an increased platelet clearance of vWF/platelet complexes (10). However, the presence of giant platelets also point to vWF-type 2B mutants playing a role in the fine regulation of the processes that result in platelet production.…”

“…In VWD-type 2B, gainof-function mutations in the GPIbα-binding A1 domain of vWF increase the affinity for this platelet receptor, provoking spontaneous interactions between vWF and platelets and loss of high-molecular-weight vWF multimers (9). The underlying causes of thrombocytopenia in VWD-type 2B are multiple, such as the incorporation of platelets bound to plasma vWF into circulating aggregates that display an increased platelet clearance (10,11). While platelet apoptosis does not seem to be involved (12), defective platelet production appears central to the mechanism of thrombocytopenia in VWD-type 2B.…”

2B or not 2B: when VWF is not a good platelet friend

“…3 Here Lechtenberg and colleagues neatly surmount these problems and determine the structure of a reengineered form of pseutarin C, a preassembled soluble snake venom prothrombinase. 1 The actual structure determined is between the 2 P textilis components in their preactivated state: factor V in complex with a truncated form of factor X. In an elegant series of experiments, the authors validate the relevance of their system, showing that the relevant forms of pseutarin C that they investigate are capable of cleaving and activating human prothrombin.…”

“…The study by Casari and colleagues is aimed at filling these gaps. 1 They developed a murine model for VWD2B that reproduces the phenotype observed in human patients with the disorder. As an important background to the study, the same group previously reported that macrophages in liver and spleen bind and endocytose VWF and that chemical blockade of these cells leads to a twofold prolongation of VWF half-life in circulation.…”