Pathogenesis of Thrombotic Thrombocytopenic Purpura: ADAMTS13 Deficiency and Beyond

Eric Chun-Yet Lian

doi:10.1055/s-2005-925468

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2005; 31(6): 625-632
DOI: 10.1055/s-2005-925468

Pathogenesis of Thrombotic Thrombocytopenic Purpura: ADAMTS13 Deficiency and Beyond

Eric Chun-Yet Lian¹

¹Division of Hematology/Oncology, University of Miami, Miami, Florida

Abstract

ABSTRACT

Thrombotic thrombocytopenic purpura (TTP) is characterized by the systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. Recently, vWF protease (ADAMTS13) activity was found to be severely deficient in hereditary TTP as well as acquired idiopathic TTP. Homozygous or compound heterozygous mutations of ADAMTS13 gene were demonstrated in hereditary TTP. Autoantibodies against ADAMTS13 were present in majority of patients with idiopathic TTP and ticlopidine- and clopidogrel-associated TTP. The deficiency of ADAMTS13 leaves unchecked the hyperadhesive vWF unfolded under high shear stress in the microvessels, resulting in the formation of platelet thrombi, which in turn causes TTP. ADAMTS13 activity is usually normal in hemolytic uremic syndrome. Approximately 0 to 67% of idiopathic TTP patients reported may not be severely deficient of ADAMTS13. Therefore, acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13, and also induce platelet aggregation either dependent on or independent of vWF, and/or vascular injury, to account for variable clinical and laboratory presentations. Plasma samples from TTP patients have been shown to induce endothelial cell apoptosis and activation. Platelet aggregating factors independent of vWF purified from the plasma of a subset of TTP patients have been reported and shown to be inhibited by normal plasma and immunoglobulin G purified from normal plasma. Defective fibrinolysis and abnormal natural coagulation inhibitors may enhance the thrombi formation in the microcirculation.

KEYWORDS

Thrombotic thrombocytopenic purpura (TTP) - ADAMTS13 - autoantibodies - platelet aggregation - vascular injury

Full Text

References

REFERENCES

1 Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Y Pathol Soc. 1924; 24 21-24
2 Gore I. Disseminated arteriolar and capillary platelet thrombosis; a morphologic study of its histogenesis. Am J Pathol. 1950; 26(1) 155-175
3 Feldman J D, Mardiney M R, Unanue E R et al.. The vascular pathology of thrombotic thrombocytopenic purpura: An immunohistochemical and ultrastructural study. Lab Invest. 1966; 15 927-946
4 Asada Y, Sumiyoshi A, Hayashi T et al.. Immunohistochemistry of vascular lesions in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb Res. 1985; 38 469-479
5 Schulman I, Pierce M, Lukens A, Currimbhoy Z. Studies on thrombopoiesis. I. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency. Blood. 1960; 16 943-957
6 Upshaw J D. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med. 1978; 298 1350-1352
7 Moake J L, Rudy C K, Troll J H. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982; 307 1432-1435
8 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
9 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
10 Tsai H M, Lian E C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998; 339 1585-1594
11 Levy G G, Nichols W C, Lian E C et al.. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenia purpura. Nature. 2001; 413(6855) 488-494
12 Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood. 2001; 98 1662-1666
13 Gerritsen H E, Robles R, Lammle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood. 2001; 98 1654-1661
14 Zheng X, Chung D, Takayama T K et al.. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001; 276 41059-41063
15 Moake J L, Rudy C K, Troll J H et al.. von Willebrand factor abnormalities and endothelial cell perturbation in a patient with acute thrombotic thrombocytopenic purpura. Am J Med Sci. 1986; 291(1) 47-50
16 Mannucci P M, Lombardi R, Lattuada A et al.. Enhanced proteolysis of plasma von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Blood. 1989; 74(3) 978-988
17 Moake J L, McPherson P D. Abnormalities of von Willebrand factor multimers in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Am J Med. 1989; 87(3N) 9N-15N
18 Galbusera M, Benigni A, Paris S et al.. Unrecognized pattern of von Willebrand factor abnormalities in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 1999; 10(6) 1234-1241
19 Veyradier A, Obert B, Houllier A, Meyer D, Girma J P. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood. 2001; 98(6) 1765-1772
20 Wagner D D. Storage and secretion of von Willebrand factor. In: Ruggeri ZM, Zimmerman TS Coagulation and Bleeding Disorders: The Role of Factor VIII and von Willebrand Factor. New York and Basel; Marcel Dekker 1989: 161-180
21 Wagner D D. The Weibel-Palade body: the storage granule for von Willebrand factor and P-selectin. Thromb Haemost. 1993; 70 105-110
22 Ruggeri Z M, Dent J A, Saldivar E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood. 1999; 94 172-178
23 Berkowitz S D, Dent J, Roberts J et al.. Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. J Clin Invest. 1987; 79(2) 524-531
24 Dent J A, Berkowitz S D, Ware J, Kasper C K, Ruggeri Z M. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA. 1990; 87 6306-6310
25 Tsai H M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood. 1996; 87 4235-4244
26 Furlan M, Robles R, Lammie 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
27 Goto S, Ikeda Y, Saldivar E, Ruggeri Z M. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest. 1998; 101 479-486
28 Siedlecki C A, Lestini B J, Kottke-Marchant K et al.. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood. 1996; 88 2939-2950
29 Dong J F, Moake J L, Bernardo A et al.. ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem. 2003; 278(32) 29633-29639
30 Ajzenberg N, Denis C V, Veyradier A et al.. Complete defect in vWF-cleaving protease activity associated with increased shear-induced platelet aggregation in thrombotic microangiopathy. Thromb Haemost. 2002; 87(5) 808-811
31 Yagi H, Konno M, Kinoshita S et al.. Plasma of patients with Upshaw-Schulman syndrome, a congenital deficiency of von Willebrand factor-cleaving protease activity, enhances the aggregation of normal platelets under high shear stress. Br J Haematol. 2001; 115(4) 991-997
32 Lopez J A, Dong J F. Cleavage of von Willbrand factor by ADAMTS-13 on enodothelial cells. Semin Hematol. 2004; 41 15-23
33 Federici A B, Bader R, Pagani S et al.. Binding of von Willebrand factor to glycoproteins Ib and IIb/IIIa complex: affinity is related to multimeric size. Br J Haematol. 1989; 73(1) 93-99
34 Tsai H M. Von Willebrand factor. ADAMTS 13 and thrombotic thrombocytopenic purpura. J Mol Med. 2002; 80 639-647
35 Levy G G, Motto D G, Ginsburg D. ADAMTS13 turns 3. Blood. 2005; 106 11-17
36 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
37 Zhou W, Inada M, Lee T P et al.. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest. 2005; 85(6) 780-788
38 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
39 Assink K, Schiphorst R, Allford S et al.. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int. 2003; 63 1995-1999
40 Uchida T, Wada H, Mizutani M et al.. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood. 2004; 104 2081-2083
41 Veyradier A, Lavergne J M, Ribba A S 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
42 Pimanda J E, Maekawa A, Wind T et al.. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood. 2004; 103 627-629
43 Savasan S, Lee S K, Ginsburg D, Tsai H M. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal vWF cleaving protease activity. Blood. 2003; 101 4449-4451
44 Schneppenheim R, Budde U, Oyen F et al.. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood. 2003; 101 1845-1850
45 Licht C, Stapenhorst L, Simon T, Budde U, Schneppenheim R, Hoppe B. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Kidney Int. 2004; 66 955-958
46 Vesely S K, George J N, Lämmle 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
47 Peyvandi F, Ferrari S, Lavoretano S, Canciani M T, Mannucci P M. von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2004; 127(4) 433-439
48 Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol. 2004; 41(1) 68-74
49 Rieger M, Mannucci P M, Hovinga J A et al.. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005; 106(4) 1262-1267
50 Soejima K, Matsumoto M, Kokame K et al.. ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood. 2003; 102 3232-3237
51 Klaus C, Plaimauer B, Studt J-D et al.. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood. 2004; 103 4514-4519
52 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(9) 3241-3243
53 Albert L J, Inman R D. Mechanisms of Disease: Molecular Mimicry and Autoimmunity. N Engl J Med. 1999; 341 2068-2074
54 Davidson A, Diamond B. Advances in immunology: autoimmune diseases. N Engl J Med. 2001; 345 340-350
55 Tsai H M, Rice L, Sarode R, Chow T W, Moake J L. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000; 132(10) 794-799
56 Bennett C L, Connors J M, Carwile J M et al.. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000; 342(24) 1773-1777
57 Schults D R, Arnold P I, Ji W et al.. AntiCD36 autoantibodies in thrombotic thrombocytopenic purpura and other thrombotic disorders: identification of an 85 KD form of CD36 as a target antigen. Br J Haematol. 1998; 103 849-857
58 Wight J F, Wang H, Horstein A et al.. Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura. Br J Haematol. 1999; 107 546-555
59 Galbusera M, Benigni A, Paris S et al.. Unrecognized pattern of von Willebrand factor abnormalities in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 1999; 10(6) 1234-1241
60 Motto D, Zhang W, Zhu G et al.. Additional environmental and/or genetic factors are required to trigger TTP in ADAMTS13-deficient mice. Blood. 2004; 104 258
61 Hovinga J AK, Studt J-D, Alberio L, von Lammle B. Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol. 2004; 41 75-82
62 Zheng X L, Kaufman R M, Goodnough L T, Sadler J E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and non-idiopathic thrombotic thrombocytopenic purpura. Blood. 2004; 103 4043-4049
63 Bohm M, Betz C, Miesbach W et al.. The course of ADAMTS13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exachange and vicnrsitine. Br J Haematol. 2005; 129 644-652
64 Altschule M D. The Kidney: Medical and Surgical Disease. New York; Grume & Stratton 1953: 458
65 Mitra D, Jaffe E A, Weksler B et al.. Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood. 1997; 89 1224-1234
66 Dang C T, Magid M S, Weksler B et al.. Enhanced endothelial cell apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood. 1999; 93 1264-1270
67 Wu X W, Li Z Y, Lian E C. Plasma from a patient with thrombotic thrombocytopenic purpura induces endothelial cell apoptosis and platelet aggregation. Thromb Res. 1999; 93(2) 79-87
68 Jimennez J J, Ji W, Mauro L M et al.. Endothelial microparticles released in thrombotic thrombocytopenic purpura express von Willbrand factor and markers of endothelial activation. Br J Haematol. 2003; 123 896-902
69 Lian EC- Y, Harkness D R, Byrnes J J, Wallach H, Nunez R. The presence of a platelet aggregating factors in the plasma of patients with thrombotic thrombocytopenic purpura and its inhibition by normal plasma. Blood. 1979; 53 333-338
70 Suehiro A, Yoshimoto H, Higasa S, Kakishita E. Platelet aggregating activity of plasma in patients with thrombotic thrombocytopenic purpura evaluated by a particle counting method using light scattering. Int J Hematol. 1999; 70 40-46
71 Ahn Y S, Jy W, Kolodny L et al.. Activated platelet aggregates in thrombotic thrombocytopenic purpura: decrease with plasma infusions and normalization in remission. Br J Haematol. 1996; 95 408-415
72 Lian EC- Y, Mu P TK, Siddiqui F A, Chiu A Y, Chiu L L. Inhibition of aggregating activity in thrombotic thrombocytopenic purpura plasma by normal adult immunoglobulin G. J Clin Invest. 1984; 73 548-555
73 Siddiqui F A, Lian E CY. Platelet aggregation protein p37 from a thrombotic purpura. J Clin Invest. 1986; 76 1330-1337
74 Lian EC-Y. The role of increased platelet aggregation in TTP. Semin Thromb Hemost. 1980; 6 401-415
75 Chen S-H, Lian EC-Y, Zhang X, Zhan M X. Purification and some properties of platelet aggregating protein (PAP) from the plasma of a patient with thrombotic thrombocytopenic purpura. Natl Med J China. 1989; 69 382-384
76 Kwaan H C. The pathogenesis of thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 1979; 5(3) 84-98
77 Glas-Greenwalt P, Hall J M, Panke T W et al.. Fibrinolysis in health and disease: abnormal levels of plasminogen activator, plasminogen activator inhibitor, and protein C in thrombotic thrombocytopenic purpura. J Lab Clin Med. 1985; 108 415-422
78 Lian EC-Y, Nunez R L, Harkness D R. In vivo and in vitro effects of thrombin and plasmin on human Factor VIII (AHF). Am J Hematol. 1976; 1 481-491
79 Hamilton K K, Fretto L J, Grierson D S, McKee P A. Effects of plasmin on von Willebrand factor multimers. Degradation in vitro and stimulation of release in vivo. J Clin Invest. 1985; 76(1) 261-270
80 Kunicki T J, Montgomery R R, Schullek J. Cleavage of human von Willebrand factor by platelet calcium-activated protease. Blood. 1985; 65(2) 352-356
81 Jelenska M, Kopec M, Sopata I et al.. Fibrinogen does not protect von Willebrand factor against proteolysis by human cathepsin G. Thromb Res. 1991; 61(4) 433-440

Eric
C.-Y. LianM.D.

Division of Hematology/Oncology, University of Miami, 1475 NW 12th Avenue, Miami, FL 33136

Email: elian@med.miami.edu