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Two newborn-onset patients of Upshaw–Schulman syndrome with distinct subsequent clinical courses

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Abstract

Upshaw–Schulman syndrome (USS) is caused by a congenital deficit in ADAMTS13 activity owing to genetic mutations. USS is characterized by severe neonatal jaundice with a negative Coombs test and repeated childhood episodes of thrombocytopenia reversible by fresh frozen plasma (FFP) infusions. We present two patients with USS, both of whom underwent exchange blood transfusions as newborns, although the disease subsequently developed along different clinical courses. USS-CC5 initially received a diagnosis of neonatal jaundice due to fetomaternal ABO incompatibility with an indirect positive Coombs test, which masked the diagnosis of USS. Before prophylactic FFP infusions were initiated, USS-CC5 had chronic thrombocytopenia. In contrast, thrombocytopenia developed in USS-HH4 only in response to infections and spontaneously normalized without FFP infusions. Analyses of the ADAMTS13 genes in USS-CC5 and USS-HH4 revealed compound heterozygotes of p.R398C/p.Q723K and p.Q449X/p.Q1374Sfs, respectively. Analysis of von Willebrand factor (VWF) multimers in plasma samples taken from both patients in remission showed single symmetrical multimer bands, which differ from the triplet structure of bands observed in normal samples. These data suggested that plasma VWF multimers in the patients had not been proteolytically modified. Our results indicate the presence of a previously unknown regulatory mechanism for VWF-dependent high-shear stress-induced platelet aggregation.

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References

  1. 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;16:943–57.

    PubMed  CAS  Google Scholar 

  2. Upshaw JD Jr. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med. 1978;298:1350–2.

    Article  PubMed  Google Scholar 

  3. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94.

    Article  PubMed  CAS  Google Scholar 

  4. Fujimura Y, Matsumoto M, Isonishi A, Yagi H, Kokame K, Soejima K, Murata M, Miyata T. Natural history of Upshaw–Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Throm Haemostat. 2011;9(Suppl 1):283–301.

    Article  CAS  Google Scholar 

  5. Lotta LA, Garagiola I, Palla R, Cairo A, Peyvandi F. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat. 2010;31:11–9.

    Article  PubMed  CAS  Google Scholar 

  6. Kokame K, Kokubo Y, Miyata T. Polymorphisms and mutations of ADAMTS13 in the Japanese population and estimation of the number of patients with Upshaw–Schulman syndrome. J Throm Haemostat. 2011;9:1654–6.

    Article  CAS  Google Scholar 

  7. Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K. Von Willebrand factor-cleaving protease and Upshaw–Schulman syndrome. Int J Hematol. 2002;75:25–34.

    Article  PubMed  CAS  Google Scholar 

  8. 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;14:437–54.

    Article  PubMed  CAS  Google Scholar 

  9. Bartlett A, Dormandy KM, Hawkey CM, Stableforth P, Voller A. Factor-VIII-related antigen: measurement by enzyme immunoassay. Br Med J. 1976;1:994–6.

    Article  PubMed  CAS  Google Scholar 

  10. Matsumoto M, Kawaguchi S, Ishizashi H, Yagi H, Iida J, Sakaki T, Fujimura Y. Platelets treated with ticlopidine are less reactive to unusually large von Willebrand factor multimers than are those treated with aspirin under high shear stress. Pathophysiol Haemost Thromb. 2005;34:35–40.

    Article  PubMed  CAS  Google Scholar 

  11. Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest. 1980;65:1318–25.

    Article  PubMed  CAS  Google Scholar 

  12. Budde U, Schneppenheim R, Plendl H, Dent J, Ruggeri ZM, Zimmerman TS. Luminographic detection of von Willebrand factor multimers in agarose gels and on nitrocellulose membranes. Thromb Haemost. 1990;63:312–5.

    PubMed  CAS  Google Scholar 

  13. Kato S, Matsumoto M, Matsuyama T, Isonishi A, Hiura H, Fujimura Y. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion. 2006;46:1444–52.

    Article  PubMed  CAS  Google Scholar 

  14. Yagi H, Matsumoto M, Fujimura Y. Brain nerve symptoms due to thrombotic microangiopathy. Nihon Naika Gakkai Zasshi. 2007;96:353–62.

    Article  PubMed  CAS  Google Scholar 

  15. Ishizashi H, Yagi H, Matsumoto M, Soejima K, Nakagaki T, Fujimura Y. Quantitative Western blot analysis of plasma ADAMTS13 antigen in patients with Upshaw–Schulman syndrome. Thromb Res. 2007;120:381–6.

    Article  PubMed  CAS  Google Scholar 

  16. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, Tamai H, Konno M, Kamide K, Kawano Y, Miyata T, Fujimura Y. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA. 2002;99:11902–7.

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto M, Kokame K, Soejima K, Miura M, Hayashi S, Fujii Y, Iwai A, Ito E, Tsuji Y, Takeda-Shitaka M, Iwadate M, Umeyama H, Yagi H, Ishizashi H, Banno F, Nakagaki T, Miyata T, Fujimura Y. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw–Schulman syndrome. Blood. 2004;103:1305–10.

    Article  PubMed  CAS  Google Scholar 

  18. Pinsky DJ, Naka Y, Liao H, Oz MC, Wagner DD, Mayadas TN, Johnson RC, Hynes RO, Heath M, Lawson CA, Stern DM. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest. 1996;97:493–500.

    Article  PubMed  CAS  Google Scholar 

  19. Wilkie ME, Stevens CR, Cunningham J, Blake D. Hypoxia-induced von Willebrand factor release is blocked by verapamil. Miner Electrolyte Metab. 1992;18:141–4.

    PubMed  CAS  Google Scholar 

  20. Kinoshita S, Yoshioka A, Park YD, Ishizashi H, Konno M, Funato M, Matsui T, Titani K, Yagi H, Matsumoto M, Fujimura Y. Upshaw–Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int J Hematol. 2001;74:101–8.

    Article  PubMed  CAS  Google Scholar 

  21. Camilleri RS, Cohen H, Mackie IJ, Scully M, Starke RD, Crawley JT, Lane DA, Machin SJ. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J Throm Haemostat. 2008;6:331–8.

    CAS  Google Scholar 

  22. Taguchi F, Yagi H, Matsumoto M, Sadamura S, Isonishi A, Soejima K, Fujimura Y. The homozygous p.C1024R––ADAMTS13 gene mutation links to a late-onset phenotype of Upshaw–Schulman syndrome in Japan. Thromb Haemost. 2012;107:1003–5.

    Article  PubMed  CAS  Google Scholar 

  23. Kokame K, Sakata T, Kokubo Y, Miyata T. von Willebrand factor-to-ADAMTS13 ratio increases with age in a Japanese population. J Throm Haemostat. 2011;9:1426–8.

    Article  CAS  Google Scholar 

  24. Makita K, Shimoyama T, Sakurai Y, Yagi H, Matsumoto M, Narita N, Sakamoto Y, Saito S, Ikeda Y, Suzuki M, Titani K, Fujimura Y. Placental ecto-ATP diphosphohydrolase: its structural feature distinct from CD39, localization and inhibition on shear-induced platelet aggregation. Int J Hematol. 1998;68:297–310.

    Article  PubMed  CAS  Google Scholar 

  25. Matsumoto M, Sakurai Y, Kokubo T, Yagi H, Makita K, Matsui T, Titani K, Fujimura Y, Narita N. The cDNA cloning of human placental ecto-ATP diphosphohydrolases I and II. FEBS Lett. 1999;453:335–40.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, from the Ministry of Health, Labor, and Welfare of Japan, and from Takeda Science Foundation of Japan.

Conflict of interest

Y. Fujimura is a member of clinical advisory boards for Baxter BioScience.

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Authors and Affiliations

  1. Department of Pediatrics, Nihonkai General Hospital, Sakata, Yamagata, Japan

    Saori Tanabe, Toshiyuki Kimura & Shinsuke Ohtaki

  2. Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara, Japan

    Hideo Yagi, Ayami Isonishi, Seiji Kato, Yoko Yoshida, Masaki Hayakawa, Masanori Matsumoto & Yoshihiro Fujimura

  3. Division of Neonatal Intensive Care, Nara Medical University Hospital, Kashihara, Nara, Japan

    Yukihiro Takahashi

Authors
  1. Saori Tanabe
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  2. Hideo Yagi
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  3. Toshiyuki Kimura
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  4. Ayami Isonishi
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  5. Seiji Kato
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  7. Masaki Hayakawa
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  8. Masanori Matsumoto
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  9. Shinsuke Ohtaki
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  10. Yukihiro Takahashi
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  11. Yoshihiro Fujimura
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Correspondence to Yoshihiro Fujimura.

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Tanabe, S., Yagi, H., Kimura, T. et al. Two newborn-onset patients of Upshaw–Schulman syndrome with distinct subsequent clinical courses. Int J Hematol 96, 789–797 (2012). https://doi.org/10.1007/s12185-012-1221-8

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  • DOI: https://doi.org/10.1007/s12185-012-1221-8

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