American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 361-374 , August 2009

Antibodies to Heparin–Platelet Factor 4 Complex: Pathogenesis, Epidemiology, and Management of Heparin-Induced Thrombocytopenia in Hemodialysis

  • Andrew Davenport, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Andrew Davenport, MD, UCL Center for Nephrology, University College London Medical School, Royal Free Campus, Rowland Hill St, London NW3 2PF, UK

Received 6 January 2009 ,Accepted 24 March 2009.

References 

  1. Warkentin TE, Greinacher A. Heparin induced thrombocytopenia: Recognition, treatment, and prevention. Chest. 2004;126(suppl 3):S311–S337
  2. Natelson EA, Lynch EC, Alfrey CP, Gross JB. Heparin induced thrombocytopenia (An unexpected response to treatment of consumption coagulopathy). Ann Intern Med. 1969;71:1121–1125
  3. Chong BH, Berndt MC. Heparin induced thrombocytopenia. Blut. 1989;58:53–57
  4. Nguyên P, Droullé C, Potron G. Comparison between platelet factor 4/heparin complexes ELISA and platelet aggregation test in heparin-induced thrombocytopenia. Thromb Haemost. 1995;74:804–805
  5. Greinacher A. Heparin-induced thrombocytopenia: Frequency and pathogenesis. Pathophysiol Haemost Thromb. 2006;35:37–45
  6. Bream-Rouwenhorst HR, Hobbs RA. Heparin-dependent antibodies and thrombosis without heparin-induced thrombocytopenia. Pharmacotherapy. 2008;28:1401–1407
  7. Carlsson LE, Lubenow N, Blumentritt C, et al. Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin-induced thrombocytopenia. Pharmacogenetics. 2003;13:253–258
  8. Hong AP, Cook DJ, Sigouin CS, Warkentin TE. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Blood. 2003;101:3049–3051
  9. Davenport A. Heparin induced thrombocytopenia during renal replacement therapy. Hemodial Int. 2004;8:295–303
  10. Warkentin TE. History of heparin induced thrombocytopenia. In:  Warkentin TE,  Greinacher A editor. Heparin Induced Thrombocytopenia. (ed 3). New York, NY: Dekker; 2004;p. 1–23
  11. Amiral J, Bridey F, Wolf M, et al. Antibodies to macromolecular platelet factor 4 heparin induced thrombocytopenia: A study of 44 cases. Thromb Haemost. 1995;73:21–28
  12. Ahmad S. Heparin-induced thrombocytopenia: Impact of bovine versus porcine heparin in HIT pathogenesis. Front Biosci. 2007;12:3312–3320
  13. Greinacher A, Juhl D, Strobel U, et al. Heparin-induced thrombocytopenia: A prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost. 2007;5:1666–1673
  14. Palomo I, Pereira J, Alarcon M, et al. Prevalence of heparin induced antibodies in patients with chronic renal failure undergoing hemodialysis. J Clin Lab Anal. 2005;19:189–195
  15. Regnault V, de Maistre E, Carteaux JP, et al. Platelet activation induced by human antibodies to interleukin-8. Blood. 2003;101:1419–1421
  16. Hutchinson CA, Dasgupta I. National survey of heparin induced thrombocytopenia in the haemodialysis population of the UK population. Nephrol Dial Transplant. 2007;22:1680–1684
  17. Davenport A. Low molecular weight heparin as an alternative anticoagulant to unfractionated heparin for routine outpatient hemodialysis treatments. Nephrology. 2009;(in press)
  18. Matsuo T, Wanaka K. Management of uremic patients with heparin-induced thrombocytopenia requiring hemodialysis. Clin Appl Thromb Hemost. 2008;14:459–464
  19. Gregorini G, Bellandi D, Martini G, Volpi R. Heparin induced thrombocytopenia syndrome and thrombosis in patients undergoing periodic haemodialysis. G Ital Nefrol. 2002;19:672–692
  20. Lasocki S, Piednoir P, Ajzenberg N, Geffroy A, Benbara A, Montravers P. Anti-PF4/heparin antibodies associated with repeated hemofiltration-filter clotting: A retrospective study. Crit Care. 2008;12:R84
  21. Hartman V, Malbrain M, Daelemans R, Meersman P. Zachée P: Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: Safety of resuming heparin after disappearance of HIT antibodies. Nephron Clin Pract. 2006;104:c143–c148
  22. Davenport A. Sudden collapse during hemodialysis due to immune mediated heparin induced thrombocytopenia. Nephrol Dial Transplant. 2006;21:1721–1724
  23. Charif R, Davenport A. Heparin-induced thrombocytopenia: An uncommon but serious complication of heparin use in renal replacement therapy. Hemodial Int. 2006;10:235–240
  24. ElChoufani SE, Bolin P, Waien S, Christiano CR, Holbert D, Bode AP. Platelet adhesion testing may predict early hemodialysis arteriovenous graft and fistula failure in end stage renal failure patients. Clin Appl Thromb Haemost. 2008;14:399–409
  25. Nakamoto H, Shimada Y, Kanno T, Wanaka K, Matsuo T, Suzuki H. Role of platelet factor 4 heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis. Hemodial Int. 2005;9(suppl 1):S2–S7
  26. O'Shea SI, Lawson JH, Reddan D, Murphy M, Ortel TL. Hypercoagulable states and antihrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg. 2003;38:541–548
  27. O'Shea SI, Sands JL, Nudo SA, Ortel TL. Frequency of anti heparin platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis. Am J Hematol. 2002;69:72–73
  28. Asmis LM, Segal JB, Plantinga LC, et al. Heparin induced antibodies and cardiovascular risk in patients on dialysis. Thromb Haemost. 2008;100:498–504
  29. Mureebe L, Coats RD, Silliman WR, Shuster TA, Nicholls WK, Silver D. Heparin associated antiplatelet antibodies increase morbidity and mortality in haemodialysis patients. Surgery. 2004;136:848–853
  30. Pena de la Vega L, Miller RS, Benda MM, et al. Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: A population-based study. Mayo Clin Proc. 2005;8:995–1000
  31. Carrier M, Rodger MA, Ferguson D, et al. Increased mortality in haemodialysis patients having specific antibodies to the platelet factor 4 heparin complex. Kidney Int. 2008;73:213–219
  32. Davenport A. Anticoagulation options for patients with heparin-induced thrombocytopenia requiring renal support in the intensive care unit. Contrib Nephrol. 2007;156:259–266
  33. Warkentin TE, Greinacher A, Koster A, Lincoff AM American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (ed 8). Chest. 2008;133:40–380
  34. Warkentin TE, Greinacher A. Laboratory testing for heparin induced thrombocytopenia. In:  Warkentin TE,  Greinacher A editor. Heparin Induced Thrombocytopenia. (ed 3). New York, NY: Dekker; 2004;p. 313–334
  35. Suzuki S, Sakamoto S, Matsuo M, Shimano C, Kuroda T, Matsuo T. Thrombotic complications in three haemodialysis patients with heparin induced thrombocytopenia type 1. Clin Appl Thromb Hemost. 2004;10:81–84
  36. Neuhaus TJ, Goetschel P, Schmugge M, Leumann E. Heparin induced thrombocytopenia type II on haemodialysis: Switch to danaparoid. Pediatr Nephrol. 2000;14:713–716
  37. Aster RH. Heparin-induced immune thrombocytopenia—A clinical or laboratory diagnosis?. J Thromb Haemost. 2006;4:757–758
  38. Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med. 2009;133:309–314
  39. Davenport A. Heparin induced thrombocytopenia during renal replacement therapy in the intensive care unit. Crit Care. 2008;12:158
  40. Chan M, Malynn E, Shaz B, Uhl L. Utility of consecutive repeat HIT ELISA testing for heparin induced thrombocytopenia. Am J Hematol. 2008;83:212–217
  41. Davenport A. Intradialytic complications during hemodialysis. Hemodial Int. 2006;10:162–167
  42. Davenport A, Ahmad R. The effect of reuse of cuprophan dialysers on dialysis induced leukopenia and thrombocytopenia. Dial Transplant. 1988;17:132–134
  43. Davenport A. Pyrexia of unknown origin in a hemodialysis patient. Nephrol Dial Transplant Plus. 2008;1:109–111
  44. Kishimoto TK, Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008;358:2457–2467
  45. Davenport A. The coagulation system in the critically ill patient with acute renal failure and the effect of an extracorporeal circuit. Am J Kidney Dis. 1998;30(suppl 4):S20–S27
  46. Boon DM, Van Vliet HH, Zietse R, Kappers-Klunne MC. The presence of antibodies against a PF4-heparin complex in patients on hemodialysis. Thromb Haemost. 1996;76:480;(ltr)
  47. De Sancho M, Lema MG, Amiral J, Rand J. Frequency of antibodies directed against heparin-platelet factor 4 in patients exposed to heparin through chronic haemodialysis. Thromb Haemost. 1996;75:695–696
  48. Luzzatto G, Bertoli M, Cella G. Platelet count, antiheparin/platelet–factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis. Thromb Res. 1998;89:115–122
  49. Sitter T, Spannagl M, Banas B. Prevalence of heparin induced PF4-heparin antibodies in hemodialysis patients. Nephron. 1998;79:245–246
  50. Greinacher A, Zinn S, Wizemann S, Birk UW. Heparin induced antibodies as a risk for thromboembolism and hemorrhage in patients undergoing hemodialysis. Lancet. 1996;348:764;(ltr)
  51. Yamamoto S, Koide M, Matsuo M. Heparin-induced thrombocytopenia in hemodialysis patients. Am J Kidney Dis. 1996;25:82–85
  52. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. The quantitative interpretation of optical density measurements using PF4 dependent enzyme immunoassays. J Thromb Haemost. 2008;6:1304–1312
  53. Davenport A. Central venous catheters for haemodialysis: How to overcome the problems. Hemodial Int. 2000;4:78–82
  54. Warkentin E. Clinical picture of heparin induced thrombocytopenia. In:  Warkentin TE,  Greinacher A editor. Heparin Induced Thrombocytopenia. (ed 3). New York, NY: Dekker; 2004;p. 53–106
  55. Keeling D, Davidson S, Watson H Hemostasis and Thrombosis Task Force of the British Committee for Standards in Hematology. The management of heparin-induced thrombocytopenia. Br J Haematol. 2006;133:259–269
  56. Lubenow N, Eichler P, Lietz T, Greinacher A HIT Investigators Group. Lepirudin in patients with heparin induced thrombocytopenia—Results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2 and HAT-3. J Thromb Haemost. 2005;3:2428–2436
  57. Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT) (A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004). Thromb Haemost. 2006;95:967–981
  58. Roe SD, Cassidy MJ, Haynes AP, Byrne JL. Heparin induced thrombocytopenia and thrombosis in a haemodialysis dependent patient with systemic vasculitis. Nephrol Dial Transplant. 1998;13:3226–3229
  59. Kramel K, Furll B, Warkentin TE, et al. Heparin induced thrombocytopenia therapeutic concentrations of danaparoid, unlike fondaprinux and direct thrombin inhibitors inhibit formation of platelet factor 4–heparin complexes. J Thromb Haemost. 2008;6:2160–2167
  60. Haase M, Bellomo R, Rocktaeschel J, et al. Use of fondaprinux (ARIXTRA) in a dialysis patient with symptomatic heparin induced thrombocytopenia type II. Nephrol Dial Transplant. 2005;20:444–446
  61. Sombolos KI, Fragia TK, Gionanlis LC, et al. Use of fondaparinux as an anticoagulant during hemodialysis: A preliminary study. Int J Clin Pharmacol Ther. 2008;46:198–203
  62. Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost. 2008;99:779–781
  63. Bucha E, Kreml R, Nowak G. In vitro study of r-hirudin permeability through membranes of different haemodialysers. Nephrol Dial Transplant. 1999;14:2922–2926
  64. Benz K, Nauck MA, Bohler J, Fischer KG. Hemofiltration of recombinant hirudin by different hemodialyzer membranes, implications for clinical use. Clin J Am Soc Nephrol. 2007;2:470–476
  65. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost. 2008;99:819–829
  66. Eichler P, Friesen HJ, Lubennow N, Jaeger B, Greinacre A. Antihirudin antibodies in patients with heparin induced thrombocytopenia treated with lepirudin: Incidence, effects on aPTT, and clinical relevance. Blood. 2000;96:2373–2378
  67. Fischer KG, Liebe V, Hudek R, et al. Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin. Thromb Haemost. 2003;89:973–982
  68. Warkentin TE, Greinachre A, Koster A. Bivalirudin. Thromb Haemost. 2008;99:830–839
  69. Eichler P, Lubenow N, Strobel U, Greinacher A. Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood. 2004;103:613–616
  70. Murray PT, Reddy BV, Grossman EJ, et al. A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int. 2004;66:2446–2453
  71. Matsuo T, Kobayashi H, Matsuo M, et al. Frequency of anti-heparin-PF4 complex antibodies (HIT antibodies) in uremic patients on chronic intermittent hemodialysis. Pathophysiol Haemost Thromb. 2006;35:445–450
  72. Dager WE, White RH. Argatroban for heparin induced thrombocytopenia in hepatorenal failure and CVVHD. Ann Pharmacother. 2003;37:1232–1236
  73. Matsuo T, Kusano H, Wanaka K, Ishihara M, Oyama A. Heparin induced thrombocytopenia in a uremic patient requiring hemodialysis: An alternative treatment and re-exposure to heparin. Clin Appl Thromb Hemost. 2007;13:182–187
  74. Schenk P, Rosenkranz AR, Wolff G, Horl WH, Traindl O. Recombinant tissue plasminogen activator is a useful alternative to heparin in priming Quinton Permcath. Am J Kidney Dis. 2000;35:130–136
  75. O'Shea SI, Ortel TL, Ovalik EC. Alternative methods of anticoagulation for dialysis dependent patients with heparin induced thrombocytopenia. Semin Dial. 2003;16:61–67
  76. Davenport A. The management of heparin induced thrombocytopenia during renal replacement therapy. Hemodial Int. 2001;3:81–85
  77. Hall AV, Clark WF, Parbtani A. Heparin induced thrombocytopenia in renal failure. Clin Nephrol. 1992;38:86–89
  78. Matsuo T, Yamada T, Chikahira Y, Kadowaki S. Effect of aspirin on heparin induced thrombocytopenia (HIT) in a patient requiring haemodialysis. Blut. 1989;59:393–395
  79. Davenport A. Management of heparin-induced thrombocytopenia during continuous renal replacement therapy. Am J Kidney Dis. 1998;32:e1–e5
  80. Fiaccadori E, Maggiore U, Parenti E, et al. Sustained low-efficiency dialysis (SLED) with prostacyclin in critically ill patients with acute renal failure. Nephrol Dial Transplant. 2007;22:529–537
  81. Davenport A, Will EJ, Davison AM. The effect of prostacyclin on intracranial pressure in patients with acute hepatic and renal failure. Clin Nephrol. 1991;25:151–157
  82. Hofbauer R, Moser D, Frass M, et al. Effect of anticoagulation on blood membrane interactions during hemodialysis. Kidney Int. 1999;56:1578–1583
  83. Davenport A. Anticoagulation options for intermittent haemodialysis. Minerva Urol Nefrol. 2006;58:171–180
  84. Matsuo T, Matsuo M, Ouga-Maruyama S. Can nafamostat mesilate be used for temporary management of hemodialysis in a patient with heparin-induced thrombocytopenia (HIT)?. Thromb Haemost. 2001;86:1115–1116
  85. Davenport A. Anticoagulation in heparin induced thrombocytopenia thrombosis syndrome in patients on dialysis. Hosp Pharm Eur. 2007;33:48–49
  86. Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: A diagnosis and management update. Post Grad Med J. 2007;83:575–582
  87. Davenport A. HIT on dialysis—When is it safe to re-challenge?. Nephron Clin Pract. 2006;104:c149–c150
  88. Davenport A. Low molecular weight heparin for routine hemodialysis. Hemodial Int. 2008;12(suppl 2):S34–S37

 Originally published online as doi:10.1053/j.ajkd.2009.03.012 on June 1, 2009.

PII: S0272-6386(09)00608-8

doi: 10.1053/j.ajkd.2009.03.012

American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 361-374 , August 2009