International Journal of Hematology

, Volume 98, Issue 4, pp 472–477 | Cite as

Refractoriness to platelet transfusion in acute myeloid leukemia correlated with the optical density of anti-platelet factor 4/heparin antibodies

  • Mizuki Aimoto
  • Takahisa Yamane
  • Kazumasa Shiomoto
  • Chikahiko Sakamoto
  • Yasuhiro Nakashima
  • Hideo Koh
  • Takahiko Nakane
  • Yasunobu Takeoka
  • Asao Hirose
  • Mika Nakamae
  • Kiyoyuki Hagihara
  • Yoshiki Terada
  • Yoshitaka Nakao
  • Hirohisa Nakamae
  • Masayuki Hino
  • Shigeki Miyata
Case Report

Abstract

A small number of reports have described cases of heparin-induced thrombocytopenia complicating hematological disorders with impaired platelet production. We describe the case of a 66-year-old woman with acute myeloid leukemia who exhibited unexplained refractoriness to platelet transfusion, while receiving heparin flushes, and was found to have anti-platelet factor 4 (PF4)/heparin antibodies with high optical density (OD) values (>2 units) detected by an enzyme-linked immunosorbent assay. After cessation of heparin flushes, her refractoriness to platelet transfusion resolved. We retrospectively confirmed that the OD values for anti-PF4/heparin antibodies declined gradually; refractoriness to platelet transfusion resolved when the OD values fell below 1.0 units. Given the absence of any other evident explanation for this phenomenon, and the correlation between the OD values for anti-PF4/heparin antibodies and the efficacy of platelet transfusions, we conclude that the patient’s refractoriness to platelet transfusion was most likely caused by anti-PF4/heparin antibodies that had platelet-activating properties.

Keywords

Heparin-induced thrombocytopenia Refractoriness to platelet transfusion Anti-platelet factor 4/heparin antibodies 

References

  1. 1.
    Amiral J, Bridey F, Dreyfus M, Vissoc AM, Fressinaud E, Wolf M, et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost. 1992;68:95–6.PubMedGoogle Scholar
  2. 2.
    Hughes M, Hayward CP, Warkentin TE, Horsewood P, Chorneyko KA, Kelton JG. Morphological analysis of microparticle generation in heparin-induced thrombocytopenia. Blood. 2000;96:188–94.PubMedGoogle Scholar
  3. 3.
    Reilly MP, Taylor SM, Hartman NK, Arepally GM, Sachais BS, Cines DB, et al. Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA. Blood. 2001;98:2442–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Rauova L, Hirsch JD, Greene TK, Zhai L, Hayes VM, Kowalska MA, et al. Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood. 2010;116:5021–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med. 1987;316:581–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Warkentin TE. Drug-induced immune-mediated thrombocytopenia–from purpura to thrombosis. N Engl J Med. 2007;356:891–3.PubMedCrossRefGoogle Scholar
  7. 7.
    Kadidal VV, Mayo DJ, Horne MK. Heparin-induced thrombocytopenia (HIT) due to heparin flushes: a report of three cases. J Intern Med. 1999;246:325–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Muslimani AA, Ricaurte B, Daw HA. Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes. Am J Hematol. 2007;82:652–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Verso M, Mazzarino I, Agnelli G, Stefanelli M, Ceppi S, Paoletti F. Dermatan sulphate for heparin-induced thrombocytopenia and central venous catheter-related deep vein thrombosis in a child with acute lymphoblastic leukemia. Haematologica. 2004;89:ECR06.PubMedGoogle Scholar
  10. 10.
    Tezcan AZ, Tezcan H, Gastineau DA, Armitage JO, Haire WD. Heparin-induced thrombocytopenia after bone marrow transplantation: report of two cases. Bone Marrow Transplant. 1994;14:487–90.PubMedCrossRefGoogle Scholar
  11. 11.
    Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6:1304–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Greinacher A, Ittermann T, Bagemühl J, Althaus K, Fürll B, Selleng S, et al. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost. 2010;8:2025–31.PubMedCrossRefGoogle Scholar
  13. 13.
    Kawano H, Yamamoto H, Miyata S, Izumi M, Hirano T, Toratani N, et al. Prospective multicentre cohort study of heparin-induced thrombocytopenia in acute ischaemic stroke patients. Br J Haematol. 2011;154:378–86.PubMedCrossRefGoogle Scholar
  14. 14.
    Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e495S–530S.PubMedCrossRefGoogle Scholar
  15. 15.
    Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost. 1994;71:247–51.PubMedGoogle Scholar
  16. 16.
    Arepally GM, Mayer IM. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood. 2001;98:1252–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Pouplard C, Iochmann S, Renard B, Herault O, Colombat P, Amiral J, et al. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia. Blood. 2001;97:3300–2.PubMedCrossRefGoogle Scholar
  18. 18.
    Tun Nay Min, Bo Zaw Min, Ahluwalia Meena, Guevara Elizabeth, Villani Gina M. A rare case of intracerebral hemorrhage complicating heparin-induced thrombocytopenia with thrombosis: a clinical dilemma ameliorated by novel use of plasmapheresis. Int J Hematol. 2012;96:513–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101:502–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med. 1999;106:629–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Greinacher A, Alban S, Omer-Adam MA, Weitschies W, Warkentin TE. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb Res. 2008;122:211–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Rauova L, Poncz M, McKenzie SE, Reilly MP, Arepally G, Weisel JW, et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood. 2005;105:131–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Suvarna S, Espinasse B, Qi R, Lubica R, Poncz M, Cines DB, Wiesner MR, et al. Determinants of PF4/heparin immunogenicity. Blood. 2007;110:4253–60.PubMedCrossRefGoogle Scholar
  24. 24.
    British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol. 2003;122:10–23.CrossRefGoogle Scholar
  25. 25.
    Keeling D, Davidson S, Watson H. The management of heparin-induced thrombocytopenia. Br J Haematol. 2006;133:259–69.PubMedCrossRefGoogle Scholar
  26. 26.
    Babcock RB, Dumper CW, Scharfman WB. Heparin-induced immune thrombocytopenia. N Engl J Med. 1976;295:237–41.PubMedCrossRefGoogle Scholar
  27. 27.
    Cimo PL, Moake JL, Weinger RS, Ben-Menachem YB, Khalil KG. Heparin-induced thrombocytopenia: association with a platelet aggregating factor and arterial thromboses. Am J Hematol. 1979;6:125–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Hopkins CK, Goldfinger D. Platelet transfusions in heparin-induced thrombocytopenia: a report of four cases and review of the literature. Transfusion. 2008;48:2128–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Refaai MA, Chuang C, Menegus M, Blumberg N, Francis CW. Outcomes after platelet transfusion in patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2010;8:1419–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Blajchman MA, Slichter SJ, Heddle NM, Murphy MF. New strategies for the optimal use of platelet transfusions. Hematology Am Soc Hematol Educ Program. 2008;2008:198–204.Google Scholar
  31. 31.
    Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. New York: Informa Healthcare; 2007. p. 21–66.CrossRefGoogle Scholar
  32. 32.
    Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol. 1998;35(suppl 5):9–16.PubMedGoogle Scholar
  33. 33.
    Rauova L, Zhai L, Kowalska MA, Arepally GM, Cines DB, Poncz M. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006;107:2346–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Baroletti S, Hurwitz S, Conti NA, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med. 2012;125:44–9.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2013

Authors and Affiliations

  • Mizuki Aimoto
    • 1
  • Takahisa Yamane
    • 1
  • Kazumasa Shiomoto
    • 2
  • Chikahiko Sakamoto
    • 1
  • Yasuhiro Nakashima
    • 1
  • Hideo Koh
    • 1
  • Takahiko Nakane
    • 1
  • Yasunobu Takeoka
    • 1
  • Asao Hirose
    • 1
  • Mika Nakamae
    • 1
  • Kiyoyuki Hagihara
    • 1
  • Yoshiki Terada
    • 1
  • Yoshitaka Nakao
    • 1
  • Hirohisa Nakamae
    • 1
  • Masayuki Hino
    • 1
  • Shigeki Miyata
    • 3
  1. 1.Hematology, Graduate School of MedicineOsaka City UniversityOsakaJapan
  2. 2.Central Clinical LaboratoryOsaka City University Medical School HospitalOsakaJapan
  3. 3.Division of Transfusion MedicineNational Cerebral and Cardiovascular CentreSuitaJapan

Personalised recommendations