ADAMTS13 variant does not cleave VWF multimer

Stable Identifier
R-HSA-9824402
Type
Reaction [transition]
Species
Homo sapiens
Compartment
extracellular region
ReviewStatus
5/5
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ADAMTS13 variant does not cleave VWF multimer
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In circulating blood, VWF senses a vessel injury to induce platelet adhesion to vascular injury sites (Reininger AJ 2008; Mojzisch A & Brehm MA 2021). VWF activity is dependent on its extent of multimerization, as larger VWF structures are more thrombogenic and display higher platelet tethering capacity at sites of a vascular injury. 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 (Furlan M et al., 1996; Tsai HM 1996; Crawley JTB et al., 2011). 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

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

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

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

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

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

Proc Natl Acad Sci U S A 2002
Participants
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Catalyst Activity

metalloendopeptidase activity of ADAMTS13 variant [extracellular region]

Physical Entity
ADAMTS13 variant [extracellular region] (Homo sapiens)
Activity
metalloendopeptidase activity (GO:0004222)
Normal reaction
ADAMTS13 cleaves VWF multimer (Homo sapiens)
Functional status

Loss of function of ADAMTS13 variant [extracellular region]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
blood platelet disease DOID:2218 platelet disorder, Thrombocytopathy
Cross References
Mondo
Authored
Shamovsky, V  (2023-01-07)
Reviewed
Gao, R  (2023-11-06)
Created
Shamovsky, V  (2023-01-19)
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