Caplacizumab resistance in immune thrombotic thrombocytopenic purpura is associated with a von Willebrand factor A1 domain missense variant.

Caplacizumab has been shown to reduce time to platelet normalization, reduce thrombotic thrombocytopenic purpura (TTP) exacerbations, and prevent refractory acute disease. We report the first case of caplacizumab "resistance" in a patient with immune TTP with a failure of suppression of in vivo von Willebrand factor (VWF) activity by the drug and persistence of VWF-mediated platelet capture in a flow-based in vitro assay. Genetic analysis revealed a missense variant, P1266L, in exon 28 of the VWF gene that affects the A1-domain binding site of glycoprotein Ib, but it is associated with normal platelet counts and the missense variant V1279I. Failure of caplacizumab therapy resulting in TTP exacerbation or relapse has to date been related to premature stopping of therapy associated with severe ADAMTS-13 (adisintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. This case presents a previously unreported phenomenon involving a VWF variant that affects the A1 domain at the caplacizumab-binding site, impairing its effect.