Rens De Groot: The 1st Reported Case of Caplacizumab Resistance
Rens De Groot, Principal Research Fellow at University College London, shared on LinkedIn about a recent article he and his colleagues co-authored, adding:
”The first reported case of caplacizumab resistance
Caplacizumab is an anti-VWF nanobody directed against the VWF A1 domain which forms part of standard of care of acute Thrombotic Thrombocytopenic Purpura (TTP) management. Caplacizumab reduces time to platelet normalisation and TTP exacerbations.
In our latest paper in the Journal of Thrombosis and Haemostasis (JTH) we reveal a critical exception to the rule.
The TTP specialists at University College London Hospital (UCLH) identified the first-ever case of caplacizumab ‘resistance’ in a patient with TTP.
Despite strict adherence to the medication, the patient experienced a clinical exacerbation because the drug failed to suppress von Willebrand factor (VWF) activity
The culprit? A specific missense variant, P1266L, located in the VWF A1 domain.
The Mechanism:
This variant affects the exact site where caplacizumab is supposed to bind.
The Impact:
In vitro assays confirmed that the mutation impairs the nanobody’s ability to inhibit platelet capture.
Key Distinction:
Unlike other failures—which are usually caused by stopping therapy too early—this was a direct result of genetic resistance.
Clinical takeaway:
This variant is rare, but if a TTP patient experiences an exacerbation while on daily caplacizumab, clinicians should consider checking VWF activity levels.
If these aren’t fully suppressed, genetic resistance may be the hidden driver. Sequencing of VWF exon 28 can confirm the mutation.
VWF P1266L is more common in certain populations:
Finland: 1 in 112 people are estimated to be carriers.
Ashkenazi Jewish: 1 in 151 people.
Latin/South America: 1 in 484 people.
Rest of Europe (non-Finnish): 1 in 1,116 people.
Congratulations to Mari Thomas, Marie Scully, and the TTP team at UCLH for unravelling this clinical mystery.
Read the full ‘Journal Pre-proof’.”
Title: Caplacizumab resistance in immune thrombotic thrombocytopenic purpura (iTTP) associated with VWF A1 domain missense variant
Authors: Mari Thomas, Imogen Buckle, Adela Constantinescu-Bercu, Rens De Groot, Sabina McCann, Marie Scully
Read the Full Article on JTH
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