ADAMTS13

== ADAMTS13 ==

ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 13) is an enzyme that plays a crucial role in the regulation of blood clotting. It is a member of the ADAMTS family of proteins, which are characterized by their disintegrin and metalloproteinase domains, as well as thrombospondin type 1 motifs. ADAMTS13 is primarily known for its role in cleaving von Willebrand factor (vWF), a large multimeric protein that is essential for platelet adhesion and aggregation at sites of vascular injury.

Structure

ADAMTS13 is a zinc-containing metalloprotease that is synthesized as a preproenzyme. It consists of several distinct domains:

• A signal peptide that directs the nascent protein to the secretory pathway.
• A propeptide that is cleaved to activate the enzyme.
• A metalloprotease domain that contains the active site.
• A disintegrin-like domain.
• A thrombospondin type 1 repeat (TSP1) domain.
• A cysteine-rich domain.
• A spacer domain.
• Additional TSP1 repeats.
• Two CUB domains at the C-terminus.

Function

The primary function of ADAMTS13 is to cleave von Willebrand factor (vWF) at the Tyr1605-Met1606 bond in the A2 domain. This cleavage reduces the size of vWF multimers, which is essential for regulating their prothrombotic activity. Large vWF multimers are highly active in promoting platelet adhesion and aggregation, and their excessive accumulation can lead to pathological clot formation.

Clinical Significance

Deficiency or dysfunction of ADAMTS13 is associated with thrombotic thrombocytopenic purpura (TTP), a rare but life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neurological symptoms, and fever. TTP can be hereditary, due to mutations in the ADAMTS13 gene, or acquired, often due to the development of inhibitory autoantibodies against ADAMTS13.

Hereditary TTP

Hereditary TTP, also known as Upshaw-Schulman syndrome, is caused by mutations in the ADAMTS13 gene that lead to reduced enzyme activity. Patients with hereditary TTP typically present with episodes of microangiopathic hemolytic anemia and thrombocytopenia, often triggered by infections or other stressors.

Acquired TTP

Acquired TTP is more common and is usually caused by the development of autoantibodies that inhibit ADAMTS13 activity. This form of TTP can occur idiopathically or in association with other conditions such as autoimmune diseases, infections, or certain medications.

Diagnosis and Treatment

The diagnosis of TTP involves clinical assessment and laboratory tests, including measurement of ADAMTS13 activity and the presence of ADAMTS13 inhibitors. A severe deficiency of ADAMTS13 activity (<10% of normal) is highly suggestive of TTP.

Treatment of TTP typically involves plasma exchange therapy, which removes inhibitory antibodies and replenishes functional ADAMTS13. Immunosuppressive therapies, such as corticosteroids and rituximab, may also be used to reduce antibody production.

Research and Future Directions

Ongoing research is focused on better understanding the regulation of ADAMTS13 activity, the mechanisms underlying the development of inhibitory antibodies, and the development of novel therapeutic approaches for TTP. Gene therapy and recombinant ADAMTS13 are potential future treatments that are currently under investigation.

References

• Zheng, X. L., & Sadler, J. E. (2008). Pathogenesis of thrombotic microangiopathies. Annual Review of Pathology: Mechanisms of Disease, 3, 249-277.
• Furlan, M., Robles, R., & Lämmle, B. (1998). Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood, 91(10), 2839-2846.
• Tsai, H. M. (2003). Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Journal of the American Society of Nephrology, 14(4), 1072-1081.