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Biochemistry

The von Willebrand factor cleaving protease belongs to a family of zinc-containing metalloproteases. ADAMTS-13 stands for a desintegrin and metalloprotease with thrombospondin-1-like domains 13. ADAMTS 13 regulates the size and thereby indirectly the biological activity of the von Willebrand factor. Defect in or deficiency of this enzyme leads to unusually large vWF-molecules (UL-vWF) and thereby to an increase in platelet aggregation.

Clinical significance

A high concentration of oversized von Willebrand factor molecules can lead to thrombotic microangiopathy. Some examples of such disorders are the thrombotic thrombocytopenic purpura (TTP, Moschcowitz syndrome), the haemolytic-uraemic syndrome and the HELLP-syndrome. These disease states stem from a disturbance in the blood flow in arterioles and capillaries. In modern TTP diagnoses an ADAMTS-13 functional disturbance is considered decisive.

The most common form of idiopathic TTP is an autoimmune disorder of unknown reasons, with autoantibodies directed against ADAMTS-13. Additionally, a hereditary form also exists (Upshaw-Schulman-syndrome), where a genetic defect on chromosome 9 hinders a correct ADAMTS-13 synthesis. Approximately 40 different mutations are known. Further trigging factors for TTP include pregnancy, bone marrow transplantation, pharmaceutical drugs or infectious diseases.

Indication

Differential diagnosis for causative determinations of thrombotic microangiopathies.

Literature

1. Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 14, 437-454, 2001.
2. Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14, 1072-1081, 2003.
3. Tang BL. ADAMTS. A novel family of extracellular matrix proteases. Int J Biochem Cell Biol 33, 33-44, 2001.
4. Fujimura Y, Matsumoto M, Yagi H et al. Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome. Int J Hematol 75 (1), 25-34, 2001.
5. Zheng X, Majerus EM, Sadler JE. ADAMTS-13 and TTP. Curr Opin Hematol 9 (5), 389-394, 2003.
6. Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost 1 (4), 625-631, 2003.
7. Remuzzi G. Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No. J Thromb Haemost 1 (4), 632-4, 2003.
8. Moake JL. von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin Hematol 41 (1), 4-14, 2004.
9. Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin. Hematol. 41 (1), 34-40, 2004.
10. Schneppenheim R, Budde U, Hassenpflug W, Obser T. Severe ADAMTS-13 deficiency in childhood. Semin Hematol 41 (1), 83-89, 2004.
11. Kremer Hovinga JA, Studt JD, Lämmle B. The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocy-topenic purpura (TTP). Pathophysiol Haemost Thromb 33 (5-6), 417-421, 2005.
12. Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 3 (8), 1710-1716, 2005.