Molecular Biology of ADAMTS13 and Diagnostic Utility of ADAMTS13 Proteolytic Activity and Inhibitor Assays

 

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ABSTRACT

ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disintegrin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1bα, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.

REFERENCES

• 1 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
  CrossrefPubMedGoogle Scholar
• 2 Gerritsen H E, Robles R, Lämmle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease.  Blood. 2001;  98 1654-1661
  CrossrefPubMedGoogle Scholar
• 3 Soejima K, Mimura N, Hirashima M et al.. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease?.  J Biochem (Tokyo). 2001;  130 475-480
  CrossrefPubMedGoogle Scholar
• 4 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
  CrossrefPubMedGoogle Scholar
• 5 Levy G G, Nichols W C, Lian E C et al.. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.  Nature. 2001;  413 488-494
  CrossrefPubMedGoogle Scholar
• 6 Cal S, Obaya A J, Llamazares M et al.. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains.  Gene. 2002;  283 49-62
  CrossrefPubMedGoogle Scholar
• 7 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
  CrossrefPubMedGoogle Scholar
• 8 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
  CrossrefPubMedGoogle Scholar
• 9 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 11 Moake J L. Thrombotic microangiopathies.  N Engl J Med. 2002;  347 589-600
  CrossrefPubMedGoogle Scholar
• 12 Furlan M. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome.  Adv Nephrol Necker Hosp. 2000;  30 71-81
  PubMedGoogle Scholar
• 13 Zheng X, Majerus E M, Sadler J E. ADAMTS13 and TTP.  Curr Opin Hematol. 2002;  9 389-394
  CrossrefPubMedGoogle Scholar
• 14 Veyradier A, Obert B, Houllier A et al.. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases.  Blood. 2001;  98 1765-1772
  CrossrefPubMedGoogle Scholar
• 15 Veyradier A, Obert B, Haddad E et al.. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome.  J Pediatr. 2003;  142 310-317
  CrossrefPubMedGoogle Scholar
• 16 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
  CrossrefPubMedGoogle Scholar
• 17 Zheng X L, Richard K 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
  CrossrefPubMedGoogle Scholar
• 18 Hosler G A, Cusumano A M, Hutchins G M. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases.  Arch Pathol Lab Med. 2003;  127 834-839
  PubMedGoogle Scholar
• 19 Shepard K V, Bukowski R M. The treatment of thrombotic thrombocytopenic purpura with exchange transfusions, plasma infusions, and plasma exchange.  Semin Hematol. 1987;  24 178-193
  PubMedGoogle Scholar
• 20 Rock G A, Shumak K H, Buskard N A et al.. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.  N Engl J Med. 1991;  325 393-397
  CrossrefPubMedGoogle Scholar
• 21 Bell W R, Braine H G, Ness P M, Kickler T S. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.  N Engl J Med. 1991;  325 398-403
  CrossrefPubMedGoogle Scholar
• 22 Plaimauer B, Scheiflinger F. Expression and characterization of recombinant human ADAMTS-13.  Semin Hematol. 2004;  41 24-33
  CrossrefPubMedGoogle Scholar
• 23 Kremer Hovinga J A, Studt J D, Lämmle B. The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP).  Pathophysiol Haemost Thromb. 2003;  33 417-421
  CrossrefPubMedGoogle Scholar
• 24 Tsai H M. Molecular mechanisms in thrombotic thrombocytopenic purpura.  Semin Thromb Hemost. 2004;  30 549-557
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Moake J L. von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura.  Semin Hematol. 2004;  41 4-14
  PubMedGoogle Scholar
• 26 Sadler J E, Moake J L, Miyata T, George J N. Recent advances in thrombotic thrombocytopenic purpura.  Hematology (Am Soc Hematol Educ Program). 2004;  1 407-423
  PubMedGoogle Scholar
• 27 George J N, Sadler J E, Lämmle B. Platelets: thrombotic thrombocytopenic purpura.  Hematology (Am Soc Hematol Educ Program). 2002;  1 315-334
  PubMedGoogle Scholar
• 28 Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura.  Semin Hematol. 2004;  41 34-40
  CrossrefPubMedGoogle Scholar
• 29 Veyradier A, Girma J P. Assays of ADAMTS-13 activity.  Semin Hematol. 2004;  41 41-47
  CrossrefPubMedGoogle Scholar
• 30 Furlan M. Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura.  Expert Rev Cardiovasc Ther. 2003;  1 243-255
  CrossrefPubMedGoogle Scholar
• 31 Bork P, Beckmann G. The CUB domain. A widespread module in developmentally regulated proteins.  J Mol Biol. 1993;  231 539-545
  CrossrefPubMedGoogle Scholar
• 32 Bruno K, Volkel D, Plaimauer B et al.. Cloning, expression and functional characterization of the full-length murine ADAMTS13.  J Thromb Haemost. 2005;  3 1064-1073
  CrossrefPubMedGoogle Scholar
• 33 Banno F, Kaminaka K, Soejima K et al.. Identification of strain-specific variants of mouse Adamts13 gene encoding von Willebrand factor-cleaving protease.  J Biol Chem. 2004;  279 30896-30903
  CrossrefPubMedGoogle Scholar
• 34 Uemura M, Tatsumi K, Matsumoto M et al.. Localization of ADAMTS13 to the stellate cells of human liver.  Blood. 2005;  106 922-924
  CrossrefPubMedGoogle Scholar
• 35 Zhou W, Inada M, Lee T P et al.. ADAMTS13 is expressed in hepatic stellate cells.  Lab Invest. 2005;  85 780-788
  CrossrefPubMedGoogle Scholar
• 36 Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis.  FASEB J. 1991;  5 271-277
  PubMedGoogle Scholar
• 37 Benyon R C, Arthur M J. Extracellular matrix degradation and the role of hepatic stellate cells.  Semin Liver Dis. 2001;  21 373-384
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 Okazaki I, Watanabe T, Hozawa S et al.. Molecular mechanism of the reversibility of hepatic fibrosis: with special reference to the role of matrix metalloproteinases.  J Gastroenterol Hepatol. 2000;  15(suppl) D26-D32
  PubMedGoogle Scholar
• 39 Majerus E M, Zheng X, Tuley E A, Sadler J E. Cleavage of the ADAMTS13 propeptide is not required for protease activity.  J Biol Chem. 2003;  278 46643-46648
  CrossrefPubMedGoogle Scholar
• 40 Zheng X, Nishio K, Majerus E M, Sadler J E. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13.  J Biol Chem. 2003;  278 30136-30141
  CrossrefPubMedGoogle Scholar
• 41 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
  CrossrefPubMedGoogle Scholar
• 42 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
  CrossrefPubMedGoogle Scholar
• 43 Kuno K, Matsushima K. ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region.  J Biol Chem. 1998;  273 13912-13917
  CrossrefPubMedGoogle Scholar
• 44 Kuno K, Terashima Y, Matsushima K. ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix.  J Biol Chem. 1999;  274 18821-18826
  CrossrefPubMedGoogle Scholar
• 45 Loechel F, Gilpin B J, Engvall E et al.. Human ADAM 12 (meltrin alpha) is an active metalloprotease.  J Biol Chem. 1998;  273 16993-16997
  CrossrefPubMedGoogle Scholar
• 46 Milla M E, Leesnitzer M A, Moss M L et al.. Specific sequence elements are required for the expression of functional tumor necrosis factor-alpha-converting enzyme (TACE).  J Biol Chem. 1999;  274 30563-30570
  CrossrefPubMedGoogle Scholar
• 47 Cao J, Hymowitz M, Conner C et al.. The propeptide domain of membrane type 1-matrix metalloproteinase acts as an intramolecular chaperone when expressed in trans with the mature sequence in COS-1 cells.  J Biol Chem. 2000;  275 29648-29653
  CrossrefPubMedGoogle Scholar
• 48 Nishio K, Anderson P J, Zheng X L, Sadler J E. Binding of platelet glycoprotein Ib alpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13.  Proc Natl Acad Sci USA. 2004;  101 10578-10583
  CrossrefPubMedGoogle Scholar
• 49 Ai J, Smith P, Wang S et al.. The proximal carboxyl terminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor.  J Biol Chem. 2005;  280 29428-29434
  CrossrefPubMedGoogle Scholar
• 50 Kokame K, Matsumoto M, Fujimura Y, Miyata T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13.  Blood. 2003;  103 607-612
  PubMedGoogle Scholar
• 51 Tsai H M. Shear stress and von Willebrand factor in health and disease.  Semin Thromb Hemost. 2003;  29 479-488
  Article in Thieme ConnectPubMedGoogle Scholar
• 52 De Cristofaro R, Peyvandi F, Palla R et al.. Role of chloride ions in the modulation of the interaction between von Willebrand factor and ADAMTS-3.  J Biol Chem. 2005;  280 23295-23302
  CrossrefPubMedGoogle Scholar
• 53 Bernardo A, Ball C, Nolasco L et al.. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.  Blood. 2004;  104 100-106
  CrossrefPubMedGoogle Scholar
• 54 Jenkins P V, Pasi K J, Perkins S J. Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand's disease.  Blood. 1998;  91 2032-2044
  PubMedGoogle Scholar
• 55 Studt J D, Hovinga J A, Antoine G et al.. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin.  Blood. 2005;  105 542-544
  CrossrefPubMedGoogle Scholar
• 56 Crawley J T, Lam J K, Rance J B et al.. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin.  Blood. 2005;  105 1085-1093
  PubMedGoogle Scholar
• 57 Antoine G, Zimmermann K, Plaimauer B et al.. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13.  Br J Haematol. 2003;  120 821-824
  CrossrefPubMedGoogle Scholar
• 58 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
  CrossrefPubMedGoogle Scholar
• 59 Matsumoto M, Kokame K, Soejima K et al.. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.  Blood. 2003;  103 1305-1310
  CrossrefPubMedGoogle Scholar
• 60 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
  CrossrefPubMedGoogle Scholar
• 61 Soejima K, Nakagaki T. Interplay between ADAMTS13 and von Willebrand factor in inherited and acquired thrombotic microangiopathies.  Semin Hematol. 2005;  42 56-62
  CrossrefPubMedGoogle Scholar
• 62 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. 2001;  14 437-454
  CrossrefPubMedGoogle Scholar
• 63 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
  CrossrefPubMedGoogle Scholar
• 64 Bongers T N, De Maat M P, Dippel D W et al.. Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians.  J Thromb Haemost. 2005;  3 805 , (comment)
  CrossrefPubMedGoogle Scholar
• 65 Ruan C, Dai L, Su J, Wang Z. The frequency of P475S polymorphism in von Willebrand factor-cleaving protease in the Chinese population and its relevance to arterial thrombotic disorders.  Thromb Haemost. 2004;  91 1257-1258
  PubMedGoogle Scholar
• 66 Majerus E M, Anderson P J, Sadler J E. Binding of ADAMTS13 to von Willebrand factor.  J Biol Chem. 2005;  280 21773-21778
  CrossrefPubMedGoogle Scholar
• 67 Yoo G, Blomback M, Schenck-Gustafsson K, He S. Decreased levels of von Willebrand factor-cleaving protease in coronary heart disease and thrombotic thrombocytopenic purpura: study of a simplified method for assaying the enzyme activity based on ristocetin-induced platelet aggregation.  Br J Haematol. 2003;  121 123-129
  CrossrefPubMedGoogle Scholar
• 68 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
  CrossrefPubMedGoogle Scholar
• 69 Kinoshita S, Yoshioka A, Park Y D et al.. Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura.  Int J Hematol. 2001;  74 101-108
  PubMedGoogle Scholar
• 70 Schneppenheim R, Budde U, Oyen F et al.. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.  Blood. 2003;  101 1845-1850
  CrossrefPubMedGoogle Scholar
• 71 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
  CrossrefPubMedGoogle Scholar
• 72 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
  CrossrefPubMedGoogle Scholar
• 73 Furlan M, Robles R, Solenthaler M, Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura.  Blood. 1998;  91 2839-2846
  PubMedGoogle Scholar
• 74 Mannucci P M, Canciani M T, Forza I et al.. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.  Blood. 2001;  98 2730-2735
  CrossrefPubMedGoogle Scholar
• 75 Loof A H, van Vliet H H, Kappers-Klunne M C. 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
  CrossrefPubMedGoogle Scholar
• 76 Bianchi V, Robles R, Alberio L et al.. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura.  Blood. 2002;  100 710-713
  CrossrefPubMedGoogle Scholar
• 77 Remuzzi G. Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No.  J Thromb Haemost. 2003;  1 632-634
  CrossrefPubMedGoogle Scholar
• 78 Tsai H M. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes.  J Thromb Haemost. 2003;  1 625-631
  CrossrefPubMedGoogle Scholar
• 79 Mannucci P M. Consistency of ADAMTS-13 activity assays: a moderately optimistic view.  J Thromb Haemost. 2003;  1 1880-1881
  CrossrefPubMedGoogle Scholar
• 80 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
  PubMedGoogle Scholar
• 81 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 82 Fujimura Y, Matsumoto M, Yagi H et al.. Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome.  Int J Hematol. 2002;  75 25-34
  CrossrefPubMedGoogle Scholar
• 83 Tsai H M, Sussman I I, Ginsburg D et al.. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1.  Blood. 1997;  89 1954-1962
  PubMedGoogle Scholar
• 84 Whitelock J L, Nolasco L, Bernardo A et al.. ADAMTS-13 activity in plasma is rapidly measured by a new ELISA method that uses recombinant VWF-A2 domain as substrate.  J Thromb Haemost. 2004;  2 485-491
  CrossrefPubMedGoogle Scholar
• 85 Kokame K, Nobe Y, Kokubo Y et al.. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay.  Br J Haematol. 2005;  129 93-100
  CrossrefPubMedGoogle Scholar
• 86 Furlan M, Lammle B. Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura.  Baillieres Clin Haematol. 1998;  11 509-514
  CrossrefPubMedGoogle Scholar
• 87 Zheng X, Pallera A M, Goodnough L T et al.. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab.  Ann Intern Med. 2003;  138 105-108
  CrossrefPubMedGoogle Scholar
• 88 Gerritsen H E, Turecek P L, Schwarz H P et al.. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP).  Thromb Haemost. 1999;  82 1386-1389
  PubMedGoogle Scholar
• 89 Rick M E, Moll S, Taylor M A et al.. Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura.  Thromb Haemost. 2002;  88 598-604
  PubMedGoogle Scholar
• 90 Owen J. Inappropriate use of positive predictive value in describing the rapid collagen binding assay for von Willebrand factor cleaving protease.  Thromb Haemost. 2003;  89 768-769
  PubMedGoogle Scholar
• 91 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
  CrossrefPubMedGoogle Scholar
• 92 Bohm M, Vigh T, Scharrer I. Evaluation and clinical application of a new method for measuring activity of von Willebrand factor-cleaving metalloprotease (ADAMTS13).  Ann Hematol. 2002;  81 430-435
  CrossrefPubMedGoogle Scholar
• 93 Shenkman B, Inbal A, Tamarin I et al.. Diagnosis of thrombotic thrombocytopenic purpura based on modulation by patient plasma of normal platelet adhesion under flow condition.  Br J Haematol. 2003;  120 597-604
  CrossrefPubMedGoogle Scholar
• 94 Dong J F, Moake J L, Nolasco L et al.. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.  Blood. 2002;  100 4033-4039
  CrossrefPubMedGoogle Scholar
• 95 Zhou W, Tsai H M. An enzyme immunoassay of ADAMTS13 distinguishes patients with thrombotic thrombocytopenic purpura from normal individuals and carriers of ADAMTS13 mutations.  Thromb Haemost. 2004;  91 806-811
  PubMedGoogle Scholar
• 96 Klaus C, Plaimauer B, Studt J D et al.. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.  Blood. 2004;  103 4514-4519
  CrossrefPubMedGoogle Scholar
• 97 Rieger M, Mannucce P, Kremer Hovinga J A et al.. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases.  Blood. 2005;  106 1262-1267
  CrossrefPubMedGoogle Scholar
• 98 Fakhouri F, Vernant J P, 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
  CrossrefPubMedGoogle Scholar
• 99 Fakhouri F, Teixeira L, Delarue R et al.. Responsiveness of thrombotic thrombocytopenic purpura to rituximab and cyclophosphamide.  Ann Intern Med. 2004;  140 314-315
  PubMedGoogle Scholar
• 100 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
  CrossrefPubMedGoogle Scholar
• 101 Licht C, Stapenhorst L, Simon T et al.. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS).  Kidney Int. 2004;  66 955-958
  CrossrefPubMedGoogle Scholar

X. Long ZhengM.D. Ph.D. 

Assistant Professor, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania

34th St. and Civic Center Blvd, Abramson Research Center 816G, Philadelphia, PA 19104

Email: zheng@email.chop.edu