Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.

Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P <.00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% ( approximately 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P <.02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment.

[1]  J. Pimanda,et al.  Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. , 2004, Blood.

[2]  E. Ito,et al.  Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. , 2003, Blood.

[3]  B. Lämmle,et al.  von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. , 2004, Seminars in hematology.

[4]  F. Dorner,et al.  Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. , 2003, Blood.

[5]  J. Sadler,et al.  Cleavage of von Willebrand Factor Requires the Spacer Domain of the Metalloprotease ADAMTS13* , 2003, Journal of Biological Chemistry.

[6]  S. Vesely,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. , 2003, Blood.

[7]  B. Lämmle,et al.  Von Willebrand factor-cleaving protease (ADAMTS-13) activity in thrombotic microangiopathies: diagnostic experience 2001/2002 of a single research laboratory. , 2003, Swiss medical weekly.

[8]  L. P. Van den Heuvel,et al.  Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. , 2003, Kidney international.

[9]  A. Dispenzieri,et al.  Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. , 2003, Mayo Clinic proceedings.

[10]  B. Lämmle,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 , 2003, British journal of haematology.

[11]  D. Mueller-Wiefel,et al.  von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. , 2003, Blood.

[12]  L. Goodnough,et al.  Remission of Chronic Thrombotic Thrombocytopenic Purpura after Treatment with Cyclophosphamide and Rituximab , 2003, Annals of Internal Medicine.

[13]  K. Laczika,et al.  Immunoadsorption for the treatment of a patient with severe thrombotic thrombocytopenic purpura resistant to plasma exchange: kinetics of an inhibitor of ADAMTS13 , 2003, Journal of thrombosis and haemostasis : JTH.

[14]  A. Xenocostas,et al.  Transplantation-associated thrombotic microangiopathy: twenty-two years later , 2002, Bone Marrow Transplantation.

[15]  J. Sadler.  A new name in thrombosis, ADAMTS13 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. Miyata,et al.  Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  E. Gabazza,et al.  Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF‐cleaving protease activity , 2002, Transfusion.

[18]  D. Marks,et al.  Thrombotic Thrombocytopenic Purpura Following Stem Cell Transplantation , 2002, Leukemia & lymphoma.

[19]  K. Fujikawa,et al.  Structure of von Willebrand Factor-cleaving Protease (ADAMTS13), a Metalloprotease Involved in Thrombotic Thrombocytopenic Purpura* , 2001, The Journal of Biological Chemistry.

[20]  L. Brass.  VWF meets the ADAMTS family , 2001, Nature Medicine.

[21]  T. Foroud,et al.  Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura , 2001, Nature.

[22]  T. Hamamoto,et al.  A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? , 2001, Journal of biochemistry.

[23]  B. Lämmle,et al.  Partial amino acid sequence of purified von Willebrand factor-cleaving protease. , 2001, Blood.

[24]  A. Houllier,et al.  Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. , 2001, Blood.

[25]  K. Fujikawa,et al.  Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. , 2001, Blood.

[26]  J. George,et al.  Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome , 2001, Current opinion in hematology.

[27]  B. Lämmle,et al.  Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. , 2001, Best practice & research. Clinical haematology.

[28]  J. Cornish,et al.  The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation , 2001, British journal of haematology.

[29]  H. Tsai.  High titers of inhibitors of von Willebrand factor‐cleaving metalloproteinase in a fatal case of acute thrombotic thrombocytopenic purpura , 2000, American journal of hematology.

[30]  P. Holland,et al.  Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. , 1999, The American journal of medicine.

[31]  B. Lämmle,et al.  Assay of von Willebrand Factor (vWF)-cleaving Protease Based on Decreased Collagen Binding Affinity of Degraded vWF , 1999, Thrombosis and Haemostasis.

[32]  C. Porta,et al.  Thrombotic thrombocytopenic purpura and autoimmunity: a tale of shadows and suspects. , 1999, Haematologica.

[33]  H. Tsai,et al.  Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. , 1998, The New England journal of medicine.

[34]  B. Lämmle,et al.  von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. , 1998, The New England journal of medicine.

[35]  B. Lämmle,et al.  16 Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura , 1998 .

[36]  B. Lämmle,et al.  Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. , 1998, Blood.

[37]  B. Lämmle,et al.  Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura. , 1998, Bailliere's clinical haematology.

[38]  B. Lämmle,et al.  Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. , 1997, Blood.

[39]  H. Tsai.  Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. , 1996, Blood.

[40]  B. Lämmle,et al.  Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. , 1996, Blood.

[41]  F. Morrison,et al.  Thrombotic thrombocytopenic purpura: Evolution across 15 years , 1996, Journal of clinical apheresis.

[42]  R. Holman,et al.  Increasing mortality from thrombotic thrombocytopenic purpura in the United States—analysis of national mortality data, 1968–1991 , 1995, American journal of hematology.

[43]  C. Fisher,et al.  Morbidity and Mortality in Adults With “Idiopathic” Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome , 1994 .

[44]  E. D. Campbell,et al.  Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. , 1994, Archives of internal medicine.

[45]  J. Kelton,et al.  Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. , 1991, The New England journal of medicine.

[46]  W. Bell,et al.  Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. , 1991, The New England journal of medicine.

[47]  S. Karpatkin,et al.  Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus type 1 (HIV-1) infection. , 1988, Annals of internal medicine.

[48]  D. Deykin,et al.  Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. , 1982, The New England journal of medicine.

[49]  W. Thornton,et al.  Thrombotic thrombocytopenic purpura associated with pregnancy. , 1976, American journal of obstetrics and gynecology.

[50]  J. Ultmann,et al.  THROMBOTIC THROMBOCYTOPENIC PURPURA: REPORT OF 16 CASES AND REVIEW OF THE LITERATURE , 1966 .

[51]  E. Moschcowitz.  Hyaline thrombosis of the terminal arterioles and capillaries : a hitherto undescribed disease , 1924 .