Defective VWF cleavage by ADAMTS13 variant

Stable Identifier
R-HSA-9845621
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Defective VWF cleavage by ADAMTS13 variant
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Under normal physiological conditions, a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS13) downregulates VWF procoagulant activity by cleaving the peptide bond between Tyr1605 and Met1606 within the A2 domain of VWF in a shear-dependent manner. Deficiencies in ADAMTS13 activity results in defective cleavage of ultra large VWF multimer in the plasma and are associated with excessive thrombi formation in the microvasculature in patients with thrombotic thrombocytopenic purpura (TTP) (Zheng XL 2015; Sukumar S et al. 2021). TTP is caused either by inherited mutations in the ADAMTS13 gene or by acquired inhibitory autoantibodies directed against the ADAMTS13 protein. This Reactome event describes defective cleavage of VWF by TTP-causing loss-of-function ADAMTS13 variants, A250V, P475S, Q449*, which showed normal or slightly reduced secretion (Kokame K et al., 2002; Uchida T et al., 2004; Markham-Lee Z et al., 2022).
Literature References
PubMed ID Title Journal Year
15126318 Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura

Shibano, T, Ishihara, H, Mizutani, M, Uchida, T, Matsubara, Y, Wada, H, Murata, M, Research Project on Genetics of Thrombosis, -, Ikeda, Y, Matsumoto, M, Suzuki, M, Fujimura, Y, Iwashita, M, Soejima, K

Blood 2004
36281781 Inherited ADAMTS13 mutations associated with Thrombotic Thrombocytopenic Purpura: a short review and update

Emsley, J, Markham-Lee, Z, Morgan, NV

Platelets 2023
12181489 Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

Funato, M, Kamide, K, Tamai, H, Ishizashi, H, Konno, M, Yagi, H, Miyata, T, Matsumoto, M, Kawano, Y, Kokame, K, Fujimura, Y, Soejima, K

Proc Natl Acad Sci U S A 2002
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
blood platelet disease DOID:2218 platelet disorder, Thrombocytopathy
Authored
Shamovsky, V  (2023-01-07)
Reviewed
Gao, R  (2023-11-06)
Created
Shamovsky, V  (2023-10-06)
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