Abstract
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disease that is defined as biallelic mutations of ADAMTS13 causing persistent absence of ADAMTS13 activity. The confirmed diagnosis requires a genetic study, and cTTP has never been previously reported in Taiwan. Our patient was a 29-year-old Taiwanese woman who presented with severe hyperbilirubinemia at birth. She had severe thrombocytopenia and hemolytic anemia at the age of 1, and another acute TTP event at the age of 7 triggered by an upper airway infection. Regular plasma replacement was started at age 12 based on a presumptive diagnosis of cTTP. Clinical diagnosis of cTTP, with undetectable ADAMTS13 activity and absence of ADAMTS13 inhibitor, was confirmed at age 27. A genetic study showed a previously reported mutation c.1921G to A, inherited from her father, and a maternally inherited, novel mutation at exon 12, c.1435+1dupG, which results in a splicing site change and frame shift. Reports of cTTP from East Asia, except Japan, are scarce. Some prevalent ADAMTS13 mutations are also race or region specific. With this report, we hope to raise awareness among physicians in Taiwan, promote early, proper diagnosis of cTTP, and reveal the true prevalence of cTTP in the Taiwanese population.
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References
Singer K, Bornstein FP, Wile SA. Thrombotic thrombocytopenic purpura; hemorrhagic diathesis with generalized platelet thromboses. Blood. 1947;2(6):542–54.
Kremer Hovinga JA, Heeb SR, Skowronska M, Schaller M. Pathophysiology of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. J Thromb Haemost. 2018;16(4):618–29. https://doi.org/10.1111/jth.13956.
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(44):41059–63. https://doi.org/10.1074/jbc.C100515200.
Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood. 2017;130(10):1181–8. https://doi.org/10.1182/blood-2017-04-636431.
Rennard S, Abe S. Decreased cold-insoluble globulin in congenital thrombocytopenia (Upshaw–Schulman syndrome). N Engl J Med. 1979;300(7):368. https://doi.org/10.1056/NEJM197902153000718.
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(1):101–8. https://doi.org/10.1007/BF02982558.
Wallace DC, Lovric A, Clubb JS, Carseldine DB. Thrombotic thrombocytopenic purpura in four siblings. Am J Med. 1975;58(5):724–34. https://doi.org/10.1016/0002-9343(75)90510-0.
Upshaw JD Jr. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med. 1978;298(24):1350–2. https://doi.org/10.1056/NEJM197806152982407.
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.
Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med. 1977;297(25):1386–9. https://doi.org/10.1056/NEJM197712222972507.
Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, Seder RH, Hong SL, Deykin D. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982;307(23):1432–5. https://doi.org/10.1056/NEJM198212023072306.
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(6855):488–94. https://doi.org/10.1038/35097008.
Kremer Hovinga JA, George JN. Hereditary thrombotic thrombocytopenic purpura. N Engl J Med. 2019;381(17):1653–62. https://doi.org/10.1056/NEJMra1813013.
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 Thromb Haemost. 2011;9(Suppl 1):283–301. https://doi.org/10.1111/j.1538-7836.2011.04341.x.
von Krogh AS, Quist-Paulsen P, Waage A, Langseth OO, Thorstensen K, Brudevold R, Tjonnfjord GE, Largiader CR, Lammle B, Kremer Hovinga JA. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost. 2016;14(1):73–82. https://doi.org/10.1111/jth.13186.
van Dorland HA, Taleghani MM, Sakai K, Friedman KD, George JN, Hrachovinova I, Knobl PN, von Krogh AS, Schneppenheim R, Aebi-Huber I, Butikofer L, Largiader CR, Cermakova Z, Kokame K, Miyata T, Yagi H, Terrell DR, Vesely SK, Matsumoto M, Lammle B, Fujimura Y, Kremer Hovinga JA, Hereditary TTPR. The international hereditary thrombotic thrombocytopenic purpura registry: key findings at enrollment until 2017. Haematologica. 2019;104(10):2107–15. https://doi.org/10.3324/haematol.2019.216796.
Alwan F, Vendramin C, Liesner R, Clark A, Lester W, Dutt T, Thomas W, Gooding R, Biss T, Watson HG, Cooper N, Rayment R, Cranfield T, van Veen JJ, Hill QA, Davis S, Motwani J, Bhatnagar N, Priddee N, David M, Crowley MP, Alamelu J, Lyall H, Westwood JP, Thomas M, Scully M. Characterization and treatment of congenital thrombotic thrombocytopenic purpura. Blood. 2019;133(15):1644–51. https://doi.org/10.1182/blood-2018-11-884700.
Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, Clark A, Creagh D, Rayment R, McDonald V, Roy A, Evans G, McGuckin S, Ni Ainle F, Maclean R, Lester W, Nash M, Scott R, Brien PO, Collaborators of the UKTTPR. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood. 2014;124(2):211–9. https://doi.org/10.1182/blood-2014-02-553131.
Liu F, Jin J, Dong NZ, Wang YG, Ruan CG. Identification of two novel mutations in ADAMTS13 gene in a patient with hereditary thrombotic thrombocytopenic purpura. Zhonghua Xue Ye Xue Za Zhi. 2005;26(9):521–4.
Jiang Y, Huang D, Kondo Y, Jiang M, Ma Z, Zhou L, Su J, Bai X, Ruan C, Wang Z, Xia L. Novel mutations in ADAMTS13 CUB domains cause abnormal pre-mRNA splicing and defective secretion of ADAMTS13. J Cell Mol Med. 2020;24(7):4356–61. https://doi.org/10.1111/jcmm.15025.
Lv H, Wang Z, Yang L, Wang S, Wang Q, Ren P, Li L. Neonate with congenital thrombotic thrombocytopenic purpura: a case report of a de novo compound heterozygote mutation in ADAMTS13 gene and review of literature. Clin Lab. 2020. https://doi.org/10.7754/Clin.Lab.2019.190715.
Hou L, Du Y. Two novel mutations in ADAMTS13 in a Chinese boy with congenital thrombocytopenic purpura: a case report. BMC Med Genet. 2020;21(1):57. https://doi.org/10.1186/s12881-020-00996-1.
Li C, Chen Z, Chen MY, Ma XL. A 2-day-old neonate with hyperbilirubinemia and thrombocytopenia. Zhongguo Dang Dai Er Ke Za Zhi. 2019;21(12):1218–22.
Fu LL, Ma J, Ma JY, Zhang R, Gu H, Chen ZP, Wu RH. Analysis of 5 children with congenital thrombotic thrombocytopenic purpura. Zhonghua Er Ke Za Zhi. 2019;57(1):50–4. https://doi.org/10.3760/cma.j.issn.0578-1310.2019.01.012.
Conboy E, Partain PI, Warad D, Kluge ML, Arndt C, Chen D, Rodriguez V. A severe case of congenital thrombotic thrombocytopenia purpura resulting from compound heterozygosity involving a novel ADAMTS13 pathogenic variant. J Pediatr Hematol Oncol. 2018;40(1):60–2. https://doi.org/10.1097/MPH.0000000000000895.
Prestidge TD, Rurali E, Wadsworth L, Wu JK, Moore JC, Bresin E. Congenital thrombotic thrombocytopenic purpura (cTTP) with two novel mutations. Pediatr Blood Cancer. 2012;59(7):1296–8. https://doi.org/10.1002/pbc.24159.
Lee SH, Park JH, Park SK, Lee EH, Choi JI, Visentin GP, Park TS, Oh SH, Kim SR. A novel homozygous missense ADAMTS13 mutation Y658C in a patient with recurrent thrombotic thrombocytopenic purpura. Ann Clin Lab Sci. 2011;41(3):273–6.
Fujimura Y, Lammle B, Tanabe S, Sakai K, Kimura T, Kokame K, Miyata T, Takahashi Y, Taniguchi S, Matsumoto M. Patent ductus arteriosus generates neonatal hemolytic jaundice with thrombocytopenia in Upshaw–Schulman syndrome. Blood Adv. 2019;3(21):3191–5. https://doi.org/10.1182/bloodadvances.2019000601.
Scully M, Knobl P, Kentouche K, Rice L, Windyga J, Schneppenheim R, Kremer Hovinga JA, Kajiwara M, Fujimura Y, Maggiore C, Doralt J, Hibbard C, Martell L, Ewenstein B. Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. Blood. 2017;130(19):2055–63. https://doi.org/10.1182/blood-2017-06-788026.
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MCS supervised this study and manuscript writing, SCC reviewed the chart, collected data, reviewed literature and wrote the manuscript, DTL and CYL helped manuscript wording and provided insight about patient’s condition, YCH and HNH helped the laboratory tests and data acquisition.
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Chou, SC., Lin, DT., Lin, CY. et al. First reported case of congenital thrombotic thrombocytopenic purpura in Taiwan with novel mutation of ADAMTS13 gene. Int J Hematol 113, 760–764 (2021). https://doi.org/10.1007/s12185-020-03068-5
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DOI: https://doi.org/10.1007/s12185-020-03068-5