Regular Article
The prevalence of antibodies to the platelet factor 4 -heparin complex and association with access thrombosis in patients on chronic hemodialysis

https://doi.org/10.1016/j.thromres.2006.09.014Get rights and content

Abstract

Introduction

Heparin-induced thrombocytopenia is a serious complication that can lead to thrombocytopenia, venous and arterial thrombosis. Patients with this disorder develop antibodies to the platelet factor 4-heparin (PF4-H) complex. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing PF4-H antibodies.

We sought to determine the prevalence of PF4-H antibodies in a large cohort of patients on chronic hemodialysis and to evaluate the relationship between PF4-H antibodies and hemodialysis vascular access thrombosis in a case-control study.

Material and methods

Pre-dialysis blood samples were drawn on 419 patients; 107 cases with access thrombosis and 312 controls that never had access thrombosis. All samples were screened for PF4-H antibodies using an ELISA assay (GTI PF4 Enhanced, GTI Diagnostics). All positive and indeterminate samples were then tested using an IgG-specific PF4-H ELISA assay and a platelet serotonin-release assay.

Results

Antibodies to PF4-H were positive in 54 (12.9%) patients using the screening ELISA assay. Nine (2.1%) patients had IgG-specific PF4-H antibodies. None of the patient's had a positive platelet serotonin-release assay. No relationship between hemodialysis access thrombosis and PF4-H antibodies was noted using the screening ELISA assay (unadjusted odds ratio 0.63; 95% CI 0.30–1.30; P = 0.21), the IgG-specific ELISA assay (unadjusted odds ratio 0.83; 95% CI 0.17–4.06; P = 0.82) or indeterminate platelet serotonin-release assay results (unadjusted odds ratio 0.97;95% CI 0.10–9.44;P = 0.98).

Conclusions

Hemodialysis with repeated exposure to unfractionated heparin was associated with a moderately elevated prevalence of PF4-H antibodies. However, our results do not support a relationship between PF4-H antibodies and hemodialysis vascular access thrombosis.

Introduction

Heparin-induced thrombocytopenia (HIT) is a serious complication of systemic heparin therapy. Exposure to heparin can trigger an immune response resulting in the production of antibodies formed against a platelet factor 4-heparin complex. [1], [2]. IgG platelet factor 4-heparin (PF4-H) antibodies have been associated with the development of venous or arterial thrombosis. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing PF4-H antibodies.

The maintenance of adequate vascular access is crucial to patient survival on hemodialysis. Complications related to vascular access account for 20 to 25% of all hospitalizations in dialysis patients [3], [4] and cost over one billion dollars annually in the United States [3]. Thrombosis is the leading cause of arteriovenous fistula and graft failure [4].

PF4-H antibodies have been suggested as a possible cause of dialysis access thrombosis [5]. Studies to date have generated conflicting results. Whereas some suggest the presence of an association between vascular access thrombosis and PF4-H antibodies [6], [7], [8], [9], others do not [10], [11]. These studies were case reports or case series describing the occurrence or specific management of heparin-induced thrombocytopenia in dialysis patients. We there sought to determine the prevalence and association of PF4-H antibodies with vascular access thrombosis in a large case-control study of hemodialysis patients.

Section snippets

Study design and participants

A case-control study evaluating thrombophilia and dialysis access thrombosis was recently completed at the Ottawa Hospital [12]. Sera from the 419 patients who participated in this study were used to measure PF4-H antibodies. The study was approved by the Ottawa Hospital Research Ethics Board.

Adult patients on maintenance hemodialysis from three in-center and five satellite units associated with the Ottawa Hospital, a Canadian academic health science center, were approached for study

Results

Eight hundred and forty-eight patients were screened for enrollment. Patients were excluded for the following reasons: fistula or graft never created or never functioned (n = 345); access created but not yet used (n = 21). Of the 482 eligible patients, 63 refused or were unable to consent leaving 419 participants in the study. There were 107 cases with access thrombosis and 312 controls that never had access thrombosis [12].

The baseline characteristics of the cases and controls are depicted in

Discussion

To our knowledge, this is the largest and most comprehensive examination of the association between PF4-H antibodies and dialysis access thrombosis. In the present analysis, hemodialysis with repeated exposure to systemic UFH was associated with a moderately elevated prevalence of PF4-H antibodies. Although the results of previous research suggest a link between the presence of PF4-H antibodies and an increase in hypercoagulability leading to thrombotic complications [6], [7], [8], [9], [10],

Acknowledgements

This study was funded by the Physician' Services Incorporated Foundation (Grant #R05–28). Dr. Rodger is a recipient of the Maureen Andrew New Investigator Award from the Heart and Stroke Foundation of Canada. We thank the staff and patients from the dialysis units that participated in the study. Special thanks to Dr. Paul Greenman for his helpful comments on an earlier version of this manuscript.

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