TTP and ADAMTS13: When Is Testing Appropriate?

Hematology. American Society of Hematology. Education Program - Tập 2007 Số 1 - Trang 121-126 - 2007
Pier Mannuccio Mannucci1, Flora Peyvandi2
1The University of Milan , Via Pace 9, 20122 Milano, Italy.
2Fondazione IRCCS Cá Granda-Ospedale Maggiore Policlinico

Tóm tắt

Abstract The last 10 years witnessed the publication of many studies on the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure. The most important finding was the identification of a novel metalloprotease, named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motives), that is involved in the regulation of the size of von Willebrand factor (VWF), a major modulator of platelet adhesion and aggregation in the microcirculation. Inherited or acquired deficiencies of ADAMTS13 impair VWF cleavage, leading in turn to the disseminated formation of platelet-rich thrombi in the micro-circulation and to symptoms of end-organ ischemia. By measuring ADAMTS13 in plasma, it has been clearly shown that patients with inherited TTP have severe ADAMTS13 deficiency. However, patients with acquired TTP present with clinical and laboratory heterogeneity, and there are unequivocal cases of acquired TTP with measurable plasma levels of ADAMTS13. This heterogeneity poses a challenge for understanding the pathogenesis of TTP and selecting appropriate therapies.

Từ khóa


Tài liệu tham khảo

Terrell DR, Williams LA, Vesely SK, et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost. 2005;3:1432–1436.

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.

Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest. 1986;78:1456–1461.

Remuzzi G, Galbusera M, Noris M, et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood. 2002;100:778–785.

Peyvandi F, Ferrari S, Lavoretano S, Canciani MT, Mannucci PM. von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2004;127:433–439.

Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood. 2001;98:1765–1772.

Furlan M, Robles R, Lamlle 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.

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.

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.

Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578–1584.

Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–1594.

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.

Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276:41059–41063.

Scheiflinger F, Knobl P, Trattner B, et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood. 2003;102:3241–3243.

Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005;106:1262–1267.

Moore JC, Hayward CP, Warkentin TE, Kelton JG. Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders. Blood. 2001;98:1842–1846.

Mori Y, Wada H, Gabazza EC, et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity. Transfusion. 2002;42:572–580.

Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102:60–68.

Coppo P, Bengoufa D, Veyradier A, et al. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. Medicine (Baltimore). 2004;83:233–244.

Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004;103:4043–4049.

Loof AH, van Vliet HH, Kappers-Klunne MC. Low activity of von Willebrand factor-cleaving protease is not restricted to patients suffering from thrombotic thrombocytopenic purpura. Br J Haematol. 2001;112:1087–1088

Mannucci PM, Canciani MT, Forza I, et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood. 2001;98:2730–2735.

Bianchi V, Robles R, Alberio L, Furlan M, Lammle B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100:710–713.

Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost. 2003;1:625–631.

Remuzzi G. Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No. J Thromb Haemost. 2003;1:632–634.

Studt JD, Bohm M, Budde U, et al. Measurement of von Willebrand factor-cleaving protease (ADAMTS-13) activity in plasma: a multicenter comparison of different assay methods. J Thromb Haemost. 2003;1:1882–1887.

Tripodi A, Chantarangkul V, Bohm M, et al. Measurement of von Willebrand factor cleaving protease (ADAMTS-13): results of an international collaborative study involving 11 methods testing the same set of coded plasmas. J Thromb Haemost. 2004;2:1601–1609.

Schneppenheim R, Budde U, Oyen F, et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood. 2003;101:1845–1850.

Peyvandi F, Lavoretano S, Palla R, et al. Mechanisms of the interaction between two ADAMTS13 gene mutations leading to severe deficiency of enzymatic activity. Hum Mutat. 2006;27:330–336.

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;2:424–429.

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.

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;4:1931–1935

Barbot J, Costa E, Guerra M, et al. Ten years of prophylactic treatment with fresh-frozen 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.

Furlan M, Lammle 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. 2001;14:437–454.

Raife T, Atkinson B, Montgomery R, Vesely S, Friedman K. Severe deficiency of VWF-cleaving protease (ADAMTS13) activity defines a distinct population of thrombotic microangiopathy patients. Transfusion. 2004;44:146–150.

Bohm M, Betz C, Miesbach W, et al. The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol. 2005;129:644–652

Coppo P, Wolf M, Veyradier A, et al. Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura. Br J Haematol. 2006;132:66–74.

Tsai H-M, Li A, Rock G. Inhibitors of von Willebrand Factor cleaving protease in thrombotic thrombocytopenic purpura. Clin Lab. 2001;47:387–392.

Wyllie BF, Garg AX, Macnab J, Rock GA, Clark WF. Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome: a new index predicting response to plasma exchange. Br J Haematol. 2006;132:204–209.

Patton JF, Manning KR, Case D, Owen J. Serum lactate dehydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura. Am J Hematol. 1994;47:94–99

Ferrari S, Scheiflinger F, Rieger, M et al. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood. 2007;109:2815–2822.

Peyvandi F, Lavoretano S, Palla R, et al. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica. 2007. In press.

Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood. 2005;106:1932–1937.

Scully M, Cohen H, Cavenagh J, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol. 2007;136:451–461.

Thông tin
Thông tin xuất bản

Hematology. American Society of Hematology. Education Program

Tập 2007 Số 1

121-126

Thông tin tác giả