ADAMTS13 is the Metalloprotease That Cleaves Ultra-Large von Willebrand Factor Multimers
ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) is the metalloprotease responsible for cleaving ultra-large/large high molecular weight von Willebrand factor (VWF) multimers after their secretion from endothelial cells. 1
Mechanism of Action
ADAMTS13 plays a crucial role in hemostasis by:
- Cleaving the proteolytically sensitive bond between Tyr842 and Met843 located in the A2 domain of VWF when it unfolds under high shear stress conditions 1
- Converting hyper-reactive and thrombogenic ultra-large VWF multimers into smaller, less adhesive plasma forms 2
- Preventing spontaneous thrombus formation in the microvasculature 3
Binding and Interaction with VWF
ADAMTS13 interacts with VWF through several domains:
- The spacer domain is essential for ADAMTS13 binding to VWF 4
- ADAMTS13 binds primarily to the A3 domain of VWF, which serves as the main docking site for the metalloprotease 2
- Once bound, ADAMTS13 cleaves within the A2 domain of VWF 2
- The binding occurs with high affinity (Kd of approximately 14 nM) and a stoichiometry of one ADAMTS13 per two VWF monomers 4
Clinical Significance
Deficiency or dysfunction of ADAMTS13 has significant clinical implications:
- In approximately 90% of cases of thrombotic thrombocytopenic purpura (TTP), ADAMTS13 is either absent or inhibited by autoantibodies 2, 3
- Without functional ADAMTS13, ultra-large VWF multimers accumulate in the circulation, leading to spontaneous platelet aggregation and microvascular thrombosis 3
- ADAMTS13 deficiency can also contribute to bleeding complications in patients on extracorporeal membrane oxygenation (ECMO) due to acquired von Willebrand syndrome (AVWS) 1, 5
Diagnostic Considerations
ADAMTS13 can be detected and measured through various methods:
- Flow cytometry using specific antibodies 6
- Immunoblotting techniques 6
- Activity assays such as FRETS-VWF73 6
Therapeutic Implications
Understanding ADAMTS13's role has important therapeutic implications:
- Recombinant ADAMTS13 has potential as an antithrombotic agent 3
- In ECMO patients with acquired von Willebrand syndrome, monitoring for bleeding complications related to ADAMTS13-mediated VWF proteolysis is important, particularly during the first 24-48 hours after ECMO removal 5
In summary, ADAMTS13 is the critical metalloprotease that regulates VWF multimer size in circulation, and its deficiency or inhibition by autoantibodies is responsible for approximately 90% of cases of thrombotic thrombocytopenic purpura.