SEARCH:   Advanced

Blood, 15 January 2004, Vol. 103, No. 2, pp. 627-629. Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-04-1346. This Article Abstract Full Text (PDF) All Versions of this Article: 2003-04-1346v1 103/2/627    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pimanda, J. E. Articles by Hogg, P. J. Search for Related Content PubMed PubMed Citation Articles by Pimanda, J. E. Articles by Hogg, P. J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Brief report Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13 John E. Pimanda, Akiko Maekawa, Troels Wind, Julian Paxton, Colin N. Chesterman, and Philip J. Hogg From the Centre for Vascular Research, University of New South Wales, Sydney, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, Australia; and Division of Paediatrics, Mildura Base Hospital, Mildura, Australia.    Abstract Top Abstract Introduction Study design Results and discussion References   Severe deficiency of the von Willebrand Factor (VWF)–cleaving proteinase, ADAMTS13, is associated with the development of thrombotic thrombocytopenic purpura (TTP). Several mutations spread across the ADAMTS13 gene have been identified in association with a deficiency of VWF-cleaving proteinase activity in patients with congenital TTP. The spread of these dysfunctional mutations and the domain structure of ADAMTS13 are suggestive of a complex interaction between the enzyme and its substrate. We have studied a patient with congenital TTP who is a compound heterozygote for the Thr196Ile mutation in the metalloproteinase domain and a frameshift mutation (4143-4144insA) in the second CUB domain that results in loss of the last 49 amino acids of the protein. The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wild-type enzyme but its secretion from transfected COS-7 cells was about 14% of the wild type.    Introduction Top Abstract Introduction Study design Results and discussion References   Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by a schistocytic hemolytic anemia and consumptive thrombocytopenia with varying degrees of neurologic and renal impairment. The presence of ultralarge von Willebrand factor (VWF) multimers in the plasmas of patients with chronic relapsing TTP during remission that disappear during an attack led to the implication of these multimers in the pathogenesis of the platelet-rich, fibrin-poor thrombi that occlude arterioles and are the hallmark of this disorder.1 The VWF-cleaving metalloproteinase, ADAMTS13, hydrolyzes the ultralarge VWF multimers as they emerge from endothelial cells and undergo conformational strain due to shear stress in arterioles and capillaries.2 A severe deficiency of VWF-cleaving proteinase activity is associated with the pathogenesis of congenital TTP (the Schulman-Upshaw syndrome).3,4 A number of mutations, spread throughout the ADAMTS13 gene, have been reported in association with congenital TTP.3,5-9 The CUB domains at the C-terminus of ADAMTS13 are of uncertain physiologic relevance. The findings that the CUB domains are not required for VWF-cleaving proteinase activity measured under static conditions10,11 and that certain strains of mice have a variant form of murineADAMTS13 that lacks the CUB domains (together with the seventh and eighth thrombospondin type 1 (TSP-1) repeats) support the premise that these domains are dispensable in vivo.12 However, a report that peptides from the CUB domains inhibit VWF-cleaving proteinase activity under flow, but not static, conditions suggests a functional role for these domains.13 We studied a patient with congenital TTP who is a compound heterozygote for the Thr196Ile mutation in the metalloproteinase domain and the insertion of a nucleotide (A) at 4143-4144. This insertion results in a frameshift in the second CUB domain and loss of the last 49 amino acids of the protein. The CUB mutation had little effect on the specific activity of the enzyme but its secretion from COS-7 cells was impaired.    Study design Top Abstract Introduction Study design Results and discussion References   Case history We investigated an 8-year-old white girl with congenital TTP. Diagnosis was made when she was 18 months of age; she receives a plasma infusion every 2 to 3 months when her platelet count falls below 30 x 109/L. Assay of plasma VWF-cleaving proteinase activity An assay based on the collagen-binding activity of digested VWF14 was used to measure the VWF-cleaving proteinase activity in the plasma of the patient (during remission) and her family. ADAMTS13 sequence analysis DNA was extracted from peripheral blood leukocytes and all the exons and intron-exon boundaries of the ADAMTS13 gene were amplified by polymerase chain reaction (PCR) and sequenced.5 The study was conducted with parental consent and institutional ethics approval. Transient expression of the ADAMTS13 mutant The 4143insA mutant of the ADAMTS13 cDNA15 was created using PCR-based mutagenesis. The wild-type and mutant constructs were subcloned into the mammalian expression vector pCXN and transiently expressed in COS-7 cells.10 Serum-free medium was applied to equivalent numbers of confluent cells at 24 hours and the conditioned medium collected at 48 hours was clarified by centrifugation and concentrated 50-fold. Equivalent numbers of cells were lysed with 0.5% Triton X-100, 5 mM EDTA (ethylenediaminetetraacetic acid), and 1 mM AEBSF ([4-(2-aminoethyl)benzenesulfonylfluoride HCl]). The samples were resolved on 8% to 16% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions and visualized by Western blot using the anti-ADAMTS13 monoclonal antibody, 242/H2.16 Assay of ADAMTS13 activity VWF-cleaving proteinase activity was determined as previously described.16,17 Dilutions of purified recombinant ADAMTS13 of known concentration were used for assay calibration. Proteolysis of VWF was measured by resolving reactions on 1% agarose gel electrophoresis or 8% SDS-PAGE under reducing conditions and blotting the VWF and fragments with iodinated or peroxidase-conjugated anti-VWF polyclonal antibodies (Dako, Carpinteria, CA), respectively.18    Results and discussion Top Abstract Introduction Study design Results and discussion References   Three mutations (587C>T, 1342G>C, and 4143-4144insA) were identified in this patient (Figure 1). The nucleotides are numbered from the A of the initiation Met codon. The 587C>T (Thr196Ile) missense mutation has been previously identified in patients with familial TTP and the recombinant mutant protein is reported to have less than 25% VWF-cleaving proteinase activity of the wild type.3,19 The 1342G>C (Gln448Glu) missense mutation on the other hand is not associated with reduced VWF-cleaving proteinase activity and is a single nucleotide polymorphism (SNP) with a reported heterozygosity of 31.2% to 42.5%.5,6 The insertion of a nucleotide (A) at 4143-4144 results in a frameshift in the second CUB domain after Ser1381 followed by a predicted 5–amino acid extension (Arg-Glu-Gln-Pro-Gly) and premature termination of the protein with the loss of 49 amino acids. View larger version (9K): [in this window] [in a new window]   Figure 1.. VWF-cleaving proteinase activity and ADAMTS13 mutations in a patient with congenital TTP. (A) The pedigree with the ADAMTS13 activity levels of the father (I-1), the mother (I-2), the patient (II-1), and the patient's brother (II-2). The values are expressed as a percentage of VWF-cleaving proteinase activity in normal pooled human plasma. (B) The 1427–amino acid precursor protein of ADAMTS13 contains a signal peptide (SP), a propeptide (Pro), a metalloprotease domain (MP), a disintegrin-like domain (Dis), a type-1 TSP module (T), a cysteine-rich (Cys) and spacer domain, 7 additional type-1 TSP modules, and 2 CUB (complement components C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein) domains. The mutation at Thr196Ile on exon 6 is positioned within the metalloprotease domain and the mutation after Ser1381 truncates the second CUB domain of the protein.   The CUB domain mutation impaired secretion of the enzyme from transfected COS-7 cells but had little effect on VWF-cleaving proteinase activity. The secretion (Figure 2A) and the specific activity (Figure 2B) of the mutant were about 14% and about 85%, respectively, of the wild-type enzyme. Whether this in vitro activity translates into full functional activity in vivo is unknown. The reported VWF-cleaving proteinase activities in patients with hereditary TTP and ADAMTS13 mutations are all less than 10%. The plasma VWF-cleaving proteinase activity in our patient was below the detection threshold of 10% and has been noted to be less than 2% to 5% in other compound heterozygotes with this mutation.7 Asymptomatic heterozygotes, including the mother of our patient, have VWF-cleaving proteinase levels ranging from 21% to 55%.7 It is possible that the plasma level of this mutant is further compromised after secretion due to increased clearance. Complete absence of enzyme activity is thought to be lethal in utero.3 A recent report that 2 brothers with congenital TTP are homozygous for this mutation8 supports the notion that the mutant retains at least some of its biologic activity in vivo. View larger version (66K): [in this window] [in a new window]   Figure 2.. Expression and activity of the ADAMTS13 mutant. (A) COS-7 cells were transfected with plasmids encoding wild-type or mutant ADAMTS13. The ADAMTS13 in the conditioned media (top panel) and cell lysates (bottom panel) were analyzed by Western blotting. Controls were cells transfected with empty vector (lane 1), wild-type cDNA (lane 3), or mutant cDNA (lane 5) inserted in the reverse orientation. The band density of the secreted mutant (lane 4) was about 14% of the wild-type protein (lane 2). (B) ADAMTS13 activity in the conditioned medium of the transfected COS-7 cells was assayed using purified VWF. Reactions were resolved on 1% agarose and visualized by autoradiography (top panel) and 8% SDS-PAGE under reducing conditions and visualized by Western blotting (bottom panel). Purified rADAMTS13 (lanes 12-15 top panel; 7-9 bottom panel) was used to calibrate the assay. Wild-type conditioned medium (lanes 1-5 top panel; 3 and 4 bottom panel) had about 0.36 µg/mL VWF-cleaving proteinase activity, whereas mutant conditioned medium (lanes 7-11 top panel; 5 and 6 bottom panel) had about 0.04 µg/mL activity. Conditioned medium of cells transfected with wild-type ADAMTS13 cDNA in the reverse orientation had no activity (lane 2 bottom panel). Based on a secretion efficiency of 14% (panel A), the VWF-cleaving proteinase activity of the mutant was about 85% of the wild-type protein. (C) A 3-dimensional representation of the structure of acidic seminal fluid protein illustrating the CUB domain architecture. The strands are shown as ribbons (blue) and the connecting loops as C traces (gray). The expected position of the free cysteine in the first CUB domain of ADAMTS13 is indicated with an arrow. The side chains of disulfides (SS1 and SS2) are shown in yellow. Note that SS2 can exist in the reduced dithiol form in the acidic seminal fluid protein and is absent from the second CUB domain in ADAMTS13. The 2 central strands that are predicted to be deleted in the first or second CUB domain of ADAMTS13 as a result of the 3769-3770insT or 4143-4144insA mutation, respectively, are shown in red. C indicates C-terminus.   In addition to the 4143-4144insA mutation in the second CUB domain, another frameshift mutation 3769-3770insT that leads to truncation at Leu1257 in the first CUB domain and a predicted extension of 34 amino acids has been described in association with congenital TTP.3 The structural consequences of the truncations in the CUB domains were evaluated by searching the Superfamily 1.61 database (http://supfam.org) of all known 3-dimensional protein structures20 using either residues 1131-1298 or residues 1287-1427 as templates. These stretches correspond to the first and the second CUB domains and their flanking regions, respectively. This analysis suggested that residues 1192-1286 and 1299-1407 have structural similarity to the CUB domains of the spermadhesins, porcine major seminal plasma glycoprotein Psp-I and bovine acidic seminal fluid protein, respectively. The CUB domain is a sandwich of two 5-stranded sheets with one or 2 disulfides.21 The mutations 3769-3770insT and 4143-4144insA are predicted to remove the central strands from both sheets in the affected CUB domain thereby destroying its architecture. The first CUB domain of ADAMTS13 contains 5 cysteines of which one (Cys1275) is predicted to be unpaired and surface exposed in the loop connecting the 2 central strands in this domain (Figure 2C). Furthermore, the second disulfide in the acidic seminal fluid protein CUB domain can exist in the cleaved dithiol form.21 The first ADAMTS13 CUB domain, therefore, may contain one to 3 free thiols. This is noteworthy, considering that the Cys974 thiol of TSP-1 can reduce VWF multimer size by facilitating reduction of inter-subunit disulfide bonds.22 It is possible, therefore, that the first CUB domain has a similar activity. CUB domains in general are involved in protein-protein and protein-carbohydrate interactions,23-25 but the specific ligands for the CUB domains of ADAMTS13 are not known. The sequences of the CUB domains of ADAMTS13 did not align sufficiently with those of other human proteins to predict the identity of these ligands.    Acknowledgements   The authors thank Dr J. Evan Sadler for the ADAMTS13 cDNA, Dr Freidrich Scheiflinger for the 242/H2 antibody, Dr Robert Andrews for the purified VWF, Mr Tim Ganderton for technical assistance, and Mr Peter Taylor for helpful comments.    Footnotes   Submitted April 30, 2003; accepted September 11, 2003. Prepublished online as Blood First Edition Paper, September 25, 2003; DOI 10.1182/blood-2003-04-1346. Supported by the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, the New South Wales Health Department, and the Danish Natural Science Research Council. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Philip J. Hogg, Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia; e-mail: p.hogg{at}unsw.edu.au.    References Top Abstract Introduction Study design Results and discussion References   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.[Medline] [Order article via Infotrieve] Moake JL. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Arch Pathol Lab Med. 2002;126: 1430-1433.[Medline] [Order article via Infotrieve] 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.[CrossRef][Medline] [Order article via Infotrieve] Furlan M, Robles R, Solenthaler M, Lammle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood. 1998;91: 2839-2846.[Abstract/Free Full Text] 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 U S A. 2002;99: 11902-11907.[Abstract/Free Full Text] 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.[CrossRef][Medline] [Order article via Infotrieve] Schneppenheim R, Budde U, Oyen F, et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood. 2003;101: 1845-1850.[Abstract/Free Full Text] 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.[CrossRef][Medline] [Order article via Infotrieve] Savasan S, Lee SK, Ginsburg D, Tsai HM. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood. 2003;101: 4449-4451.[Abstract/Free Full Text] Zheng X, Nishio K, Majerus EM, Sadler JE. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J Biol Chem. 2003;278: 30136-30141.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] Banno F, Kaminaka K, Soejima K, Kokame K, Miyata T. Identification of strain-specific variants of mouse adamts13 gene encoding von Willebrand factor-cleaving protease [abstract]. J Thromb Haemost. 2003;1: 120a. Bernardo A, Nolasco L, Ball Y, et al. Peptides from the C-terminal regions of ADAMTS-13 specifically block cleavage of ultra-large von Willebrand factor multimers on the endothelial surface under flow [abstract]. J Thromb Haemost. 2003;1: 405a. Gerritsen HE, Turecek PL, Schwarz HP, Lammle B, Furlan M. 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.[Medline] [Order article via Infotrieve] Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276: 41059-41063.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] Furlan M, Robles R, Lammle 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.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] Motto M, Levy GG, McGee B, Tsai HM, Ginsburg D. ADAMTS13 mutations identified in familial TTP patients result in loss of VWF-cleaving protease activity [abstract]. Blood. 2002;100: 15a. Gough J, Karplus K, Hughey R, Chothia C. Assignment of homology to genome sequences using a library of hidden Markov models that represent all proteins of known structure. J Mol Biol. 2001;313: 903-919.[CrossRef][Medline] [Order article via Infotrieve] Romero A, Romao MJ, Varela PF, et al. The crystal structures of two spermadhesins reveal the CUB domain fold. Nat Struct Biol. 1997;4: 783-788.[CrossRef][Medline] [Order article via Infotrieve] Pimanda JE, Annis DS, Raftery M, Mosher DF, Chesterman CN, Hogg PJ. The von Willebrand factor-reducing activity of thrombospondin-1 is located in the calcium-binding/C-terminal sequence and requires a free thiol at position 974. Blood. 2002;100: 2832-2838.[Abstract/Free Full Text] Bernocco S, Steiglitz BM, Svergun DI, et al. Low resolution structure determination shows procollagen C-proteinase enhancer to be an elongated multidomain glycoprotein. J Biol Chem. 2003; 278: 7199-7205.[Abstract/Free Full Text] Thielens NM, Cseh S, Thiel S, et al. Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and -2, MBL-associated protein 19, and MBL. J Immunol. 2001;166: 5068-5077.[Abstract/Free Full Text] Arlaud GJ, Gaboriaud C, Thielens NM, et al. Structural biology of C1: dissection of a complex molecular machinery. Immunol Rev. 2001;180: 136-145.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. Zhou and H.-M. Tsai N-Glycans of ADAMTS13 modulate its secretion and von Willebrand factor cleaving activity Blood, January 22, 2009; 113(4): 929 - 935. [Abstract] [Full Text] [PDF] I. Garagiola, C. Valsecchi, S. Lavoretano, H. Oren, M. Bohm, and F. Peyvandi Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion Haematologica, November 1, 2008; 93(11): 1678 - 1685. [Abstract] [Full Text] [PDF] J. Song, K. A Lee, T. S. Park, R. Park, and J. R. Choi Linear Relationship between ADAMTS13 Activity and Platelet Dynamics Even Before Severe Thrombocytopenia Ann. Clin. Lab. Sci., January 1, 2008; 38(4): 368 - 375. [Abstract] [Full Text] [PDF] P. Zhang, W. Pan, A. H. Rux, B. S. Sachais, and X. L. Zheng The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow Blood, September 15, 2007; 110(6): 1887 - 1894. [Abstract] [Full Text] [PDF] D. Shang, X. W. Zheng, M. Niiya, and X. L. Zheng Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts Blood, October 1, 2006; 108(7): 2207 - 2215. [Abstract] [Full Text] [PDF] F. Banno, K. Kokame, T. Okuda, S. Honda, S. Miyata, H. Kato, Y. Tomiyama, and T. Miyata Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura Blood, April 15, 2006; 107(8): 3161 - 3166. [Abstract] [Full Text] [PDF] B. Plaimauer, J. Fuhrmann, G. Mohr, W. Wernhart, K. Bruno, S. Ferrari, C. Konetschny, G. Antoine, M. Rieger, and F. Scheiflinger Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation Blood, January 1, 2006; 107(1): 118 - 125. [Abstract] [Full Text] [PDF] Z. Tao, Y. Peng, L. Nolasco, S. Cal, C. Lopez-Otin, R. Li, J. L. Moake, J. A. Lopez, and J.-f. Dong Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions Blood, December 15, 2005; 106(13): 4139 - 4145. [Abstract] [Full Text] [PDF] W. Zhou, L. Dong, D. Ginsburg, E. E. Bouhassira, and H.-M. Tsai Enzymatically Active ADAMTS13 Variants Are Not Inhibited by Anti-ADAMTS13 Autoantibodies: A NOVEL THERAPEUTIC STRATEGY? J. Biol. Chem., December 2, 2005; 280(48): 39934 - 39941. [Abstract] [Full Text] [PDF] J. Ai, P. Smith, S. Wang, P. Zhang, and X. L. Zheng The Proximal Carboxyl-terminal Domains of ADAMTS13 Determine Substrate Specificity and Are All Required for Cleavage of von Willebrand Factor J. Biol. Chem., August 19, 2005; 280(33): 29428 - 29434. [Abstract] [Full Text] [PDF] G. G. Levy, D. G. Motto, and D. Ginsburg ADAMTS13 turns 3 Blood, July 1, 2005; 106(1): 11 - 17. [Abstract] [Full Text] [PDF] M. Noris, S. Bucchioni, M. Galbusera, R. Donadelli, E. Bresin, F. Castelletti, J. Caprioli, S. Brioschi, F. Scheiflinger, G. Remuzzi, et al. Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1177 - 1183. [Abstract] [Full Text] [PDF] F. Banno, K. Kaminaka, K. Soejima, K. Kokame, and T. Miyata Identification of Strain-specific Variants of Mouse Adamts13 Gene Encoding von Willebrand Factor-cleaving Protease J. Biol. Chem., July 16, 2004; 279(29): 30896 - 30903. [Abstract] [Full Text] [PDF] X. L. Zheng, R. M. Kaufman, L. T. Goodnough, and J. E. Sadler Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura Blood, June 1, 2004; 103(11): 4043 - 4049. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2003-04-1346v1 103/2/627    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pimanda, J. E. Articles by Hogg, P. J. Search for Related Content PubMed PubMed Citation Articles by Pimanda, J. E. Articles by Hogg, P. J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020