Skip to main content
Top
Published in: Experimental Hematology & Oncology 1/2018

Open Access 01-12-2018 | Research

Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin

Authors: Satish Maharaj, Simone Chang, Karan Seegobin, James Morales, Agnes Aysola, Fauzia Rana, Marwan Shaikh

Published in: Experimental Hematology & Oncology | Issue 1/2018

Login to get access

Abstract

Background

Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population.

Methods

We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up.

Results

Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400–1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance.

Conclusions

The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.
Literature
1.
go back to reference Weismann RE, Tobin RW. Arterial embolism occurring during systemic heparin therapy. AMA Arch Surg. 1958;76(2):219–25 (discussion 225–7).CrossRefPubMed Weismann RE, Tobin RW. Arterial embolism occurring during systemic heparin therapy. AMA Arch Surg. 1958;76(2):219–25 (discussion 225–7).CrossRefPubMed
2.
go back to reference Krauel K, Pötschke C, Weber C, et al. Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood. 2011;117(4):1370–8.CrossRefPubMed Krauel K, Pötschke C, Weber C, et al. Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood. 2011;117(4):1370–8.CrossRefPubMed
3.
go back to reference Haile LA, Rao R, Polumuri SK, et al. PF4-HIT antibody (KKO) complexes activate broad innate immune and inflammatory responses. Thromb Res. 2017;159:39–47.CrossRefPubMed Haile LA, Rao R, Polumuri SK, et al. PF4-HIT antibody (KKO) complexes activate broad innate immune and inflammatory responses. Thromb Res. 2017;159:39–47.CrossRefPubMed
4.
go back to reference Hayes V, Johnston I, Arepally GM, et al. Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest. 2017;127(3):1090–8.CrossRefPubMedPubMedCentral Hayes V, Johnston I, Arepally GM, et al. Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest. 2017;127(3):1090–8.CrossRefPubMedPubMedCentral
5.
go back to reference Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin TE. The temporal profile of the anti-PF4/heparin immune response. Blood. 2009;113(20):4970–6.CrossRefPubMed Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin TE. The temporal profile of the anti-PF4/heparin immune response. Blood. 2009;113(20):4970–6.CrossRefPubMed
6.
go back to reference Hursting MJ, Pai PJ, McCracken JE, Hwang F, Suvarna S, Lokhnygina Y, Bandarenko N, Arepally GM. Platelet factor 4/heparin antibodies in blood bank donors. Am J Clin Pathol. 2010;134(5):774–80.CrossRefPubMedPubMedCentral Hursting MJ, Pai PJ, McCracken JE, Hwang F, Suvarna S, Lokhnygina Y, Bandarenko N, Arepally GM. Platelet factor 4/heparin antibodies in blood bank donors. Am J Clin Pathol. 2010;134(5):774–80.CrossRefPubMedPubMedCentral
7.
go back to reference Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703.PubMed Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703.PubMed
8.
go back to reference Mattioli AV, Bonetti L, Zennaro M, Ambrosio G, Mattioli G. Heparin/PF4 antibodies formation after heparin treatment: temporal aspects and long-term follow-up. Am Heart J. 2009;157(3):589–95.CrossRefPubMed Mattioli AV, Bonetti L, Zennaro M, Ambrosio G, Mattioli G. Heparin/PF4 antibodies formation after heparin treatment: temporal aspects and long-term follow-up. Am Heart J. 2009;157(3):589–95.CrossRefPubMed
9.
go back to reference Williams RT, Damaraju LV, Mascelli MA, et al. Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction afteracute coronary ischemic syndromes. Circulation. 2003;107:2307–12.CrossRefPubMed Williams RT, Damaraju LV, Mascelli MA, et al. Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction afteracute coronary ischemic syndromes. Circulation. 2003;107:2307–12.CrossRefPubMed
11.
go back to reference Hutchison CA, Dasgupta I. National survey of heparin-induced thrombocytopenia in the haemodialysis population of the UK population. Nephrol Dial Transplant. 2007;22(6):1680–4.CrossRefPubMed Hutchison CA, Dasgupta I. National survey of heparin-induced thrombocytopenia in the haemodialysis population of the UK population. Nephrol Dial Transplant. 2007;22(6):1680–4.CrossRefPubMed
12.
go back to reference Saran R, Li Y, Robinson B, et al. US renal data system 2015 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2016;67(3 suppl 1):S1–434. Saran R, Li Y, Robinson B, et al. US renal data system 2015 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2016;67(3 suppl 1):S1–434.
13.
go back to reference Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937–41.CrossRefPubMed Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937–41.CrossRefPubMed
14.
go back to reference Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344(17):1286–92.CrossRef Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344(17):1286–92.CrossRef
16.
go back to reference Suvarna S, Rauova L, McCracken EK, Goss CM, Sachais BS, McKenzie SE, Reilly MP, Gunn MD, Cines DB, Poncz M, Arepally G. PF4/heparin complexes are T cell-dependent antigens. Blood. 2005;106(3):929–31.CrossRefPubMedPubMedCentral Suvarna S, Rauova L, McCracken EK, Goss CM, Sachais BS, McKenzie SE, Reilly MP, Gunn MD, Cines DB, Poncz M, Arepally G. PF4/heparin complexes are T cell-dependent antigens. Blood. 2005;106(3):929–31.CrossRefPubMedPubMedCentral
19.
go back to reference Khandelwal S, Lee GM, Hester CG, et al. The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21). Blood. 2016;128(14):1789–99.CrossRefPubMedPubMedCentral Khandelwal S, Lee GM, Hester CG, et al. The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21). Blood. 2016;128(14):1789–99.CrossRefPubMedPubMedCentral
20.
go back to reference Khandelwal S, Arepally GM. Immune pathogenesis of heparin-induced thrombocytopenia. Thromb Haemost. 2016;116(5):792–8.CrossRefPubMed Khandelwal S, Arepally GM. Immune pathogenesis of heparin-induced thrombocytopenia. Thromb Haemost. 2016;116(5):792–8.CrossRefPubMed
21.
go back to reference Zheng Y, Wang AW, Yu M, Padmanabhan A, Tourdot BE, Newman DK, White GC, Aster RH, Wen R, Wang D. B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood. 2014;123(6):931–4.CrossRefPubMedPubMedCentral Zheng Y, Wang AW, Yu M, Padmanabhan A, Tourdot BE, Newman DK, White GC, Aster RH, Wen R, Wang D. B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood. 2014;123(6):931–4.CrossRefPubMedPubMedCentral
22.
go back to reference Boon DM, van Vliet HH, Zietse R, Kappers-Klunne MC. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. Thromb Haemost. 1996;76(3):480.CrossRefPubMed Boon DM, van Vliet HH, Zietse R, Kappers-Klunne MC. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. Thromb Haemost. 1996;76(3):480.CrossRefPubMed
23.
go back to reference 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 hemodialysis. Thromb Haemost. 1996;75(4):695–6.PubMed 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 hemodialysis. Thromb Haemost. 1996;75(4):695–6.PubMed
24.
go back to reference Luzzatto G, Bertoli M, Cella G, Fabris F, Zaia B, Girolami A. Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis. Thromb Res. 1998;89(3):115–22.CrossRefPubMed Luzzatto G, Bertoli M, Cella G, Fabris F, Zaia B, Girolami A. Platelet count, anti-heparin/platelet factor 4 antibodies and tissue factor pathway inhibitor plasma antigen level in chronic dialysis. Thromb Res. 1998;89(3):115–22.CrossRefPubMed
25.
go back to reference Sitter T, Spannagl M, Banas B, Schiffl H. Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients. Nephron. 1998;79(2):245–6.CrossRefPubMed Sitter T, Spannagl M, Banas B, Schiffl H. Prevalence of heparin-induced PF4-heparin antibodies in hemodialysis patients. Nephron. 1998;79(2):245–6.CrossRefPubMed
26.
go back to reference O’Shea SI, Sands JJ, 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(1):72–3.CrossRefPubMed O’Shea SI, Sands JJ, 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(1):72–3.CrossRefPubMed
27.
go back to reference Yu A, Jacobson S, Bygden A, Egberg N. The presence of heparin platelet factor 4 antibodies as a marker of hypercoagulability during haemodialysis. Clin Chem Lab Med. 2002;40:21.CrossRefPubMed Yu A, Jacobson S, Bygden A, Egberg N. The presence of heparin platelet factor 4 antibodies as a marker of hypercoagulability during haemodialysis. Clin Chem Lab Med. 2002;40:21.CrossRefPubMed
28.
go back to reference 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(8):995–1000.CrossRefPubMed 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(8):995–1000.CrossRefPubMed
29.
go back to reference Palomo I, Pereira J, Alarcón M, et al. Prevalence of heparin-induced antibodies in patients with chronic renal failure undergoing hemodialysis. J Clin Lab Anal. 2005;19(5):189–95.CrossRefPubMed Palomo I, Pereira J, Alarcón M, et al. Prevalence of heparin-induced antibodies in patients with chronic renal failure undergoing hemodialysis. J Clin Lab Anal. 2005;19(5):189–95.CrossRefPubMed
30.
go back to reference 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):S2–7.CrossRefPubMed 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):S2–7.CrossRefPubMed
31.
go back to reference 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(6):445–50.CrossRefPubMed 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(6):445–50.CrossRefPubMed
32.
go back to reference Carrier M, Knoll GA, Kovacs MJ, Moore JC, Fergusson D, Rodger MA. The prevalence of antibodies to the platelet factor 4 -heparin complex and association with access thrombosis in patients on chronic hemodialysis. Thromb Res. 2007;120(2):215–20.CrossRefPubMed Carrier M, Knoll GA, Kovacs MJ, Moore JC, Fergusson D, Rodger MA. The prevalence of antibodies to the platelet factor 4 -heparin complex and association with access thrombosis in patients on chronic hemodialysis. Thromb Res. 2007;120(2):215–20.CrossRefPubMed
33.
go back to reference Asmis LM, Segal JB, Plantinga LC, et al. Heparin-induced antibodies and cardiovascular risk in patients on dialysis. Thromb Haemost. 2008;100(3):498–504.PubMed Asmis LM, Segal JB, Plantinga LC, et al. Heparin-induced antibodies and cardiovascular risk in patients on dialysis. Thromb Haemost. 2008;100(3):498–504.PubMed
34.
go back to reference Benjamin J, Moldavsky S, Lee J, Rubin R. Prevalence of heparin-induced antibody in African-American hemodialysis patients—comparison to non-dialysis patients. Clin Nephrol. 2009;71(3):263–6.CrossRefPubMed Benjamin J, Moldavsky S, Lee J, Rubin R. Prevalence of heparin-induced antibody in African-American hemodialysis patients—comparison to non-dialysis patients. Clin Nephrol. 2009;71(3):263–6.CrossRefPubMed
35.
go back to reference Zhao D, Sun X, Yao L, et al. The clinical significance and risk factors of anti-platelet factor 4/heparin antibody on maintenance hemodialysis patients: a two-year prospective follow-up. PLoS ONE. 2013;8(4):e62239.CrossRefPubMedPubMedCentral Zhao D, Sun X, Yao L, et al. The clinical significance and risk factors of anti-platelet factor 4/heparin antibody on maintenance hemodialysis patients: a two-year prospective follow-up. PLoS ONE. 2013;8(4):e62239.CrossRefPubMedPubMedCentral
36.
go back to reference Shavit L, Bar-Lev M, Lifschitz M, Fink D, Rudensky B, Slotki I. Prevalence and clinical significance of heparin induced antibodies in chronic hemodialysis patients and cardiac surgery patients. Int J Artif Organs. 2011;34(12):1172–8.CrossRefPubMed Shavit L, Bar-Lev M, Lifschitz M, Fink D, Rudensky B, Slotki I. Prevalence and clinical significance of heparin induced antibodies in chronic hemodialysis patients and cardiac surgery patients. Int J Artif Organs. 2011;34(12):1172–8.CrossRefPubMed
37.
go back to reference Mya HT, Tay HM, Gan SW, et al. Screening frequency, incidence and pattern of heparin-induced thrombocytopenia syndrome at a large tertiary institution. Int J Hematol. 2016;104(1):92–8.CrossRefPubMed Mya HT, Tay HM, Gan SW, et al. Screening frequency, incidence and pattern of heparin-induced thrombocytopenia syndrome at a large tertiary institution. Int J Hematol. 2016;104(1):92–8.CrossRefPubMed
38.
go back to reference Syed S, Reilly RF. Heparin-induced thrombocytopenia: a renal perspective. Nat Rev Nephrol. 2009;5(9):501–11.CrossRefPubMed Syed S, Reilly RF. Heparin-induced thrombocytopenia: a renal perspective. Nat Rev Nephrol. 2009;5(9):501–11.CrossRefPubMed
40.
go back to reference Greinacher A, Holtfreter B, Krauel K, et al. Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease. Blood. 2011;118(5):1395–401.CrossRefPubMed Greinacher A, Holtfreter B, Krauel K, et al. Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease. Blood. 2011;118(5):1395–401.CrossRefPubMed
41.
go back to reference Brito F, Almeida S, Figueredo CM, Bregman R, Suassuna JH, Fischer RG. Extent and severity of chronic periodontitis in chronic kidney disease patients. J Periodontal Res. 2012;47(4):426–30.CrossRefPubMed Brito F, Almeida S, Figueredo CM, Bregman R, Suassuna JH, Fischer RG. Extent and severity of chronic periodontitis in chronic kidney disease patients. J Periodontal Res. 2012;47(4):426–30.CrossRefPubMed
43.
go back to reference Lee EY, Hwang KY, Yang JO, Hong SY. Anti heparin platelet factor 4 antibody is a risk factor for vascular access obstruction in patients undergoing haemodialysis. J Korean Med Sci. 2003;18:69.CrossRefPubMedPubMedCentral Lee EY, Hwang KY, Yang JO, Hong SY. Anti heparin platelet factor 4 antibody is a risk factor for vascular access obstruction in patients undergoing haemodialysis. J Korean Med Sci. 2003;18:69.CrossRefPubMedPubMedCentral
44.
go back to reference Nazi I, Arnold DM, Warkentin TE, Smith JW, Staibano P, Kelton JG. Distinguishing between anti-platelet factor 4/heparin antibodies that can and cannot cause heparin-induced thrombocytopenia. J Thromb Haemost. 2015;13(10):1900–7.CrossRefPubMed Nazi I, Arnold DM, Warkentin TE, Smith JW, Staibano P, Kelton JG. Distinguishing between anti-platelet factor 4/heparin antibodies that can and cannot cause heparin-induced thrombocytopenia. J Thromb Haemost. 2015;13(10):1900–7.CrossRefPubMed
Metadata
Title
Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin
Authors
Satish Maharaj
Simone Chang
Karan Seegobin
James Morales
Agnes Aysola
Fauzia Rana
Marwan Shaikh
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2018
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/s40164-018-0115-8

Other articles of this Issue 1/2018

Experimental Hematology & Oncology 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine