Download PDF
Thromb Haemost 2008; 100(03): 498-504
DOI: 10.1160/TH08-03-0144
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Heparin-induced antibodies and cardiovascular risk in patients on dialysis

Lars M. Asmis
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
5   Department of Internal Medicine, Division of Hematology, University Hospital of Zurich, Zurich, Switzerland
,
Jodi B. Segal
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
,
Laura C. Plantinga
2   Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
3   Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
,
Nancy E. Fink
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
2   Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
3   Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
,
Jonathan S. Kerman
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
3   Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
,
Thomas S. Kickler
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
,
Josef Coresh
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
2   Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
3   Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA
,
Lawrence B. Gardner
1   Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
4   Division of Hematology, Department of Medicine, New York University School of Medicine, New York, New York, USA
› Author AffiliationsFinancial support: Supported in part by the General Clinical Research Center (NIH/NCRR grant M01-RR000052) at the Johns Hopkins University School of Medicine and an investigator initiated research grant by Glaxo Smith Kline Corporation. The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study was supported by RO1-HL-62985 (National Heart, Lung, and Blood Institute [NHLBI]) and RO1-DK-59616 (National Institute of Diabetes & Digestive & Kidney Diseases [NIDDK]). Dr Asmis was supported by the Swiss Foundation for Medical-Biological Grants (grant 1087) and an investigator-initiated research grant awarded by Glaxo Smith Kline Corporation to Johns Hopkins University School of Medicine. Dr Coresh is supported in part as an American HeartAssociation established investigator (01–4019–7N). The study was designed, conducted, analysed, and submitted for publication independently of the sponsors.
Further Information

Publication History

Received 07 March 2008

Accepted after major revision 20 June 2008

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

Summary

The clinical relevance of heparin-induced antibodies (HIA) in the absence of thrombocytopenia remains to be defined. The aims of this study were (i) to determine the prevalence of HIA in patients treated by dialysis, (ii) to determine the prevalence of thrombocytopenia and heparin-induced thrombocytopenia (HIT), and (iii) to test whether HIA are associated with adverse outcomes. Sera from 740 patients treated by hemodialysis (HD, n=596) and peritoneal dialysis (PD, n=144) were tested for HIA (IgG, IgA or IgM) by masked investigators at approximately six months after enrolment in the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study. We assessed, with time-to-event Cox proportional hazards models, whether the presence of HIA predicted any of four clinical outcomes: arterial cardiovascular events, venous thromboembolism, vascular access occlusion and mortality. HIA prevalence was 10.3% overall. HIA positivity did not predict development of thrombocytopenia or any of the four clinical outcomes over a mean follow-up of 3.6 years, with hazard ratios for arterial cardiovascular events of 0.98 (95% confidence interval 0.70–1.37), venous thromboembolism 1.39 (0.17–11.5), vascular access occlusion 0.82 (0.40–1.71), and mortality 1.18 (0.85–1.64). Chronic intermittent heparin exposure was associated with a high seroprevalence of HIA. In dialysis patients these antibodies were not an independent risk factor for cardiovascular events and mortality. Our data do not suggest that dialysis patients should be monitored for HIA antibodies in the absence of thrombocytopenia.

Keywords

Cardiovascular risk - dialysis - heparin-induced antibodies - survival analysis - thrombocytopenia
 

  • References

  • 1 Walenga JM, Jeske WP, Messmore HL. Mechanisms of venous and arterial thrombosis in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2000; 10: S13-S20.
    CrossrefPubMedGoogle Scholar
  • 2 Warkentin TE. An overview of the heparin-induced thrombocytopenia syndrome. Semin Thromb Hemost 2004; 30: 273-283.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med 2004; 164: 361-369.
    CrossrefPubMedGoogle Scholar
  • 4 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 311S-37S.
    CrossrefPubMedGoogle Scholar
  • 5 Warkentin TE, Sheppard JA, Horsewood P. et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96: 1703-1708.
    PubMedGoogle Scholar
  • 6 Williams RT, Damaraju LV, Mascelli MA. et al. Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction after acute coronary ischemic syndromes. Circulation 2003; 107: 2307-2312.
    CrossrefPubMedGoogle Scholar
  • 7 Gluckman TJ, Segal JB, Fredde NL. et al. Incidence of antiplatelet factor 4/heparin antibody induction in patients undergoing percutaneous coronary revascularization. Am J Cardiol 2005; 95: 744-747.
    CrossrefPubMedGoogle Scholar
  • 8 Sorrell VL. Diagnostic tools and management strategies for coronary artery disease in patients with endstage renal disease. Semin Nephrol 2001; 21: 13-24.
    CrossrefPubMedGoogle Scholar
  • 9 Ifudu O, Delaney VB, Barth RH. et al. Deep vein thrombosis in end-stage renal disease. ASAIO J 1994; 40: 103-105.
    CrossrefPubMedGoogle Scholar
  • 10 Casserly LF, Reddy SM, Dember LM. Venous thromboembolism in end-stage renal disease. Am J Kidney Dis 2000; 36: 405-411.
    CrossrefPubMedGoogle Scholar
  • 11 De Marchi S, Falleti E, Giacomello R. et al. Risk factors for vascular disease and arteriovenous fistula dysfunction in hemodialysis patients. J Am Soc Nephrol 1996; 07: 1169-1177.
    PubMedGoogle Scholar
  • 12 LeSar CJ, Merrick HW, Smith MR. Thrombotic complications resulting from hypercoagulable states in chronic hemodialysis vascular access. J Am Coll Surg 1999; 189: 73-81.
    CrossrefPubMedGoogle Scholar
  • 13 Sarnak MJ, Levey AS, Schoolwerth AC. et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension 2003; 42: 1050-1065.
    CrossrefPubMedGoogle Scholar
  • 14 Powe NR, Klag MJ, Sadler J. et al. CHOICE: Design and rationale. J Am Soc Nephrol 1995; 06: 557.
    PubMedGoogle Scholar
  • 15 Powe NR, Klag MJ, Sadler JH. et al. Choices for healthy outcomes in caring for end stage renal disease. Seminars in Dialysis 1996; 09: 9-11.
    PubMedGoogle Scholar
  • 16 Tracy RP, Lemaitre RN, Psaty BM. et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997; 17: 1121-1127.
    CrossrefPubMedGoogle Scholar
  • 17 Rocco MV, Yan G, Gassman J. et al. Comparison of causes of death using HEMO Study and HCFA endstage renal disease death notification classification systems. The National Institutes of Health-funded Hemodialysis. Health Care Financing Administration. Am J Kidney Dis 2002; 39: 146-153.
    CrossrefPubMedGoogle Scholar
  • 18 Astor BC, Eustace JA, Powe NR. et al. Timing of nephrologist referral and arteriovenous access use: the CHOICE Study. Am J Kidney Dis 2001; 38: 494-501.
    CrossrefPubMedGoogle Scholar
  • 19 Athienites NV, Miskulin DC, Fernandez G. et al. Comorbidity assessment in hemodialysis and peritoneal dialysis using the index of coexistent disease. Semin Dial 2000; 13: 320-326.
    PubMedGoogle Scholar
  • 20 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344: 1286-1292.
    CrossrefPubMedGoogle Scholar
  • 21 Localio AR, Berlin JA, Ten Have TR. et al. Adjustments for center in multicenter studies: an overview. Ann Intern Med 2001; 135: 112-123.
    CrossrefPubMedGoogle Scholar
  • 22 Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model. J Am Stat Assoc 1989; 84: 1074-1078.
    CrossrefPubMedGoogle Scholar
  • 23 de Sancho M, Lema MG, Amiral J. et al. Frequency of antibodies directed against heparinplatelet factor 4 in patients exposed to heparin through chronic hemodialysis. Thromb Haemost 1996; 75: 695-696.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Greinacher A, Wizemann Zinn S. et al. Heparin-induced antibodies as a risk factor for thromboembolism and haemorrhage in patients undergoing chronic haemodialysis. Lancet 1996; 348: 764.
    PubMedGoogle Scholar
  • 25 Boon DM, van Vliet HH, Zietse R. et al. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. Thromb Haemost 1996; 76: 480.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Yamamoto S, Koide M, Matsuo M. et al. Heparin-induced thrombocytopenia in hemodialysis patients. Am J Kidney Dis 1996; 28: 82-85.
    CrossrefPubMedGoogle Scholar
  • 27 Luzzatto G, Bertoli M, Cella G. et al. Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis. Thromb Res 1998; 89: 115-122.
    CrossrefPubMedGoogle Scholar
  • 28 Sitter T, Spannagl M, Banas B. et al. Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients. Nephron 1998; 79: 245-246.
    CrossrefPubMedGoogle Scholar
  • 29 O'Shea SI, Sands JJ, Nudo SA. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 30 Lee EY, Hwang KY, Yang JO. et al. Anti-heparinplatelet factor 4 antibody is a risk factor for vascular access obstruction in patients undergoing hemodialysis. J Korean Med Sci 2003; 18: 69-72.
    CrossrefPubMedGoogle Scholar
  • 31 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; 80: 995-1000.
    CrossrefPubMedGoogle Scholar
  • 32 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.
    CrossrefPubMedGoogle Scholar
  • 33 Liu JC, Lewis BE, Steen LH. et al. Patency of coronary artery bypass grafts in patients with heparin- induced thrombocytopenia. Am J Cardiol 2002; 89: 979-981.
    CrossrefPubMedGoogle Scholar
  • 34 Arepally G, Cines DB. Pathogenesis of heparin-induced thrombocytopenia and thrombosis. Autoimmun Rev 2002; 01: 125-132.
    CrossrefPubMedGoogle Scholar
  • 35 Carrier M, Rodger MA, Fergusson D. et al. Increased mortality in hemodialysis patients having specific antibodies to the platelet factor 4-heparin complex. Kidney Int 2008; 73: 213-219.
    CrossrefPubMedGoogle Scholar
  • 36 Warkentin TE, Sheppard JA. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev 2006; 20: 259-272.
    CrossrefPubMedGoogle Scholar
  • 37 Juhl D, Eichler P, Lubenow N. et al. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol 2006; 76: 420-426.
    CrossrefPubMedGoogle Scholar
  • 38 Hutchison CA, Dasgupta I. National survey of heparin-induced thrombocytopenia in the haemodialysis population of the UK population. Nephrol Dial Transplant 2007; 22: 1680-1684.
    CrossrefPubMedGoogle Scholar