Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

Summary

Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed.

In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.

Zusammenfassung

Die hereditäre thrombotisch-thrombozytopenische Purpura, auch bekannt als UpshawSchulman-Syndrom (USS), ist eine seltene, rezessiv vererbte Erkrankung. Ihr zugrunde liegt ein schwerer angeborener Mangel der von-Willebrand-Faktor-spaltenden Protease, ADAMTS13, verursacht durch Mutationen im ADAMTS13-Gen. Die klinische Präsentation kann sehr variabel sein und immer öfter werden auch Patienten mit einem Krankheitsbeginn im Erwachsenenalter identifiziert.

Die regelmäßige Gabe von Plasma kann Krankheitsschübe verhindern. Der Entscheid, eine regelmäßige Plasmaprophylaxe zu beginnen, ist oft nicht einfach, weil Leitlinien und Langzeitverläufe weitgehend fehlen. Das 2006 lancierte hereditäre TTP-Register (www.ttpregistry.net, CinicalTRials.gov NCT01257269), das USS-Patienten und ihren Familienangehörigen offen steht, hat zum Ziel, Wissen und Informationen über diese seltene Krankheit zu sammeln, um so in Zukunft zu besserer Diagnostik und Betreuung der betroffen Patienten beizutragen.

Keywords

Hereditary thrombotic thrombocytopenic purpura - Upshaw-Schulman syndrome - ADAMTS13

Schlüsselwörter

Hereditäre thrombotisch-thrombozytopenische Purpura - Upshaw-Schulman-Syndrom - ADAMTS13

• References

• 1 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
• 2 Furlan M, Robles R, Solenthaler M. et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997; 89: 3097-3103.
• 3 Furlan M, Robles R, Galbusera M. et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998; 339: 1578-1584.
• 4 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-1594.
• 5 Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol 2008; 03: 249-277.
• 6 Schaller M, Studt JD, Voorberg J, Kremer JAHovinga. Acquired thrombotic thrombocytopenic purpura. Hämostaseologie 2013; 33: 121-130.
• 7 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
• 8 Schulman I, Pierce M, Lukens A, Currimbhoy Z. Studies on thrombopoiesis. Blood 1960; 16: 943-957.
• 9 Upshaw JD. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med 1978; 298: 1350-1352.
• 10 Furlan M, Robles R, Morselli B. et al. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 1999; 81: 8-13.
• 11 Barbot J, Costa E, Guerra M, Barreirinho MS. et al. Ten years of prophylactic treatment with freshfrozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease. Br J Haematol 2001; 113: 649-651.
• 12 Meyer SC, Jeddi R, Meddeb B. et al. A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13. Ann Hematol 2008; 87: 663-666.
• 13 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
• 14 Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87: 4223-4234.
• 15 Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87: 4235-4244.
• 16 Plaimauer B, Zimmermann K, Volkel D. et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 2002; 100: 3626-3632.
• 17 Miyata T, Kokame K, Matsumoto M, Fujimura Y. ADAMTS13 activity and genetic mutations in Japan. Hämostaseologie 2013; 33: 131-137.
• 18 Schneppenheim R, Kremer JAHovinga, Becker T. et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost 2006; 96: 3-6.
• 19 Assink K, Schiphorst R, Allford S. et al. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int 2003; 63: 1995-9.
• 20 Manea M, Kristoffersson A, Schneppenheim R. et al. Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol 2007; 138: 651-662.
• 21 Cermakova Z, Hrdlikova R, Sulakova T. et al. Thrombotic thrombocytopenic purpura. Prague Med Rep 2009; 110: 239-244.
• 22 Tao Z, Anthony K, Peng Y. et al. Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. J Thromb Haemost 2006; 04: 1931-1935.
• 23 Camilleri RS, Cohen H, Mackie IJ. et al. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J Thromb Haemost 2008; 06: 331-338.
• 24 Moatti-Cohen M, Garrec C, Wolf M. et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012; 119: 5888-5897.
• 25 Fujimura Y, Matsumoto M, Isonishi A. et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011; 09 (Suppl. 01) 283-301.
• 26 Lotta LA, Wu HM, Mackie IJ. et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 2012; 120: 440-448.
• 27 Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Best Pract Res Clin Haematol 2001; 14: 437-454.
• 28 Fujimura Y, Matsumoto M, Kokame K. et al. Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome. Br J Haematol 2009; 144: 742-754.
• 29 Meyer SC, Jin S, Cao W. et al. Characterization of five homozygous ADAMTS13 mutations in hereditary thrombotic thrombocytopenic purpura – Towards a phenotype-genotype correlation?. ASH Annual Meeting Abstracts 2008; 112: 274.
• 30 Schneppenheim R, Budde U, Oyen F. et al. Von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003; 101: 1845-1850.
• 31 Veyradier A, Lavergne JM, Ribba AS. et al. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J Thromb Haemost 2004; 02: 424-429.
• 32 Lotta LA, Garagiola I, Palla R. et al. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat 2010; 31: 11-19.
• 33 Camilleri RS, Scully M, Thomas M. et al. A phenotype-genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom. J Thromb Haemost 2012; 10: 1792-1801.
• 34 Deal T, Kremer JAHovinga, Marques MB, Adamski J. Novel ADAMTS13 mutations in an obstetric patient with Upshaw-Schulman syndrome. J Clin Apher 2012. doi: 10.1002/jca.21251.
• 35 Kentouche K, Voigt A, Schleussner E. et al. Pregnancy in Upshaw-Schulman syndrome. Hämostaseologie 2013; 33: 144-148.
• 36 Noris M, Bucchioni S, Galbusera M. et al. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol 2005; 16: 1177-1183.
• 37 Du VX, van Os G, Kremer JAHovinga. et al. Indications for a protective function of beta2-glycoprotein I in thrombotic thrombocytopenic purpura. Br J Haematol 2012; 159: 94-103.
• 38 Kokame K, Matsumoto M, Soejima K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 2002; 99: 11902-11907.
• 39 Matsumoto M, Kokame K, Soejima K. et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 2004; 103: 1305-1310.
• 40 George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010; 116: 4060-4069.
• 41 Knöbl P. Treatment of thrombotic microangiopathy with a focus on new treatment options. Hämostaseologie 2013; 33: 149-159.
• 42 Kremer JAHovinga, Meyer SC. Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol 2008; 15: 445-450.
• 43 Antoine G, Zimmermann K, Plaimauer B. et al. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factorcleaving protease activity by recombinant human ADAMTS13. Br J Haematol 2003; 120: 821-824.
• 44 Kremer JAHovinga, Lämmle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2012; 610-616.