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Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis

Theodore E. Warkentin, MD; and John G. Kelton, MD
[+] Article, Author, and Disclosure Information

From McMaster University and the Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada.

Acknowledgments: The authors thank Wendy M. Nicholson (Burlington, Ontario), Harold Richter (Boca Raton, Florida), Donald H. Berdeaux (Great Falls, Montana), and M.E. Tweeddale (Toronto, Ontario) for referring four of the patients described in this report.

Grant Support: By the Heart and Stroke Foundation of Ontario (B-3763 and T-4502 [Dr. Warkentin] and T-4404 [Dr. Kelton]).

Requests for Single Reprints: Theodore E. Warkentin, MD, Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Current Author Addresses: Dr. Warkentin: Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. Kelton: Department of Medicine, Room 3W10, McMaster University Medical Centre, Hamilton Health Sciences, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Author Contributions: Conception and design: T.E. Warkentin, J.G. Kelton.

Analysis and interpretation of the data: T.E. Warkentin, J.G. Kelton.

Drafting of the article: T.E. Warkentin, J.G. Kelton.

Critical revision of the article for important intellectual content: T.E. Warkentin, J.G. Kelton.

Final approval of the article: T.E. Warkentin, J.G. Kelton.

Provision of study materials or patients: T.E. Warkentin.

Statistical expertise: T.E. Warkentin.

Obtaining of funding: T.E. Warkentin.

Administrative, technical, or logistic support: T.E. Warkentin.

Collection and assembly of data: T.E. Warkentin.

Ann Intern Med. 2001;135(7):502-506. doi:10.7326/0003-4819-135-7-200110020-00009
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Background: Heparin-induced thrombocytopenia is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize complexes of platelet factor 4 and heparin.

Objective: To describe a syndrome termed delayed-onset heparin-induced thrombocytopenia, in which thrombocytopenia and thrombotic events begin 5 or more days after withdrawal of heparin.

Design: Case series.

Setting: Secondary and tertiary care hospitals.

Patients: 12 patients who presented with serologically confirmed, delayed-onset heparin-induced thrombocytopenia, including 6 outpatients presenting after hospital discharge.

Measurements: The platelet serotonin-release assay was used to measure IgG-induced heparin-dependent and heparin-independent platelet activation; an enzyme immunoassay that detects IgG against platelet factor 4–heparin complexes was also used.

Results: Patients with delayed-onset heparin-induced thrombocytopenia presented with thrombocytopenia and associated thrombosis a mean of 9.2 days (range, 5 to 19 days) after stopping heparin therapy. Nine patients received additional heparin, with further decrease in platelet counts. Compared with controls, patients with delayed-onset heparin-induced thrombocytopenia had higher titers of IgG antibodies to platelet factor 4–heparin and greater IgG-induced heparin-dependent and heparin-independent platelet activation.

Conclusions: Delayed-onset heparin-induced thrombocytopenia should be suspected when patients present with thrombocytopenia and thrombosis up to 3 weeks after exposure to heparin. This syndrome could be caused by high titers of platelet-activating IgG induced by heparin.


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Heparin-dependent and heparin-independent platelet activation produced by serum specimens from 12 patients with delayed-onset heparin-induced thrombocytopenia ( ) and 24 control patients with typical heparin-induced thrombocytopenia ( ). Serum dilutions (final) ranged from 1/5 (standard assay) to 1/160. Addition of Fc receptor–blocking monoclonal antibodies consistently reduced the amount of serotonin release to less than 5% (not shown), confirming that the platelet activation was caused by IgG antibodies interacting with the platelet Fc receptors. Normal control specimens consistently produced less than 5% serotonin release under all reaction conditions (not shown). Platelet factor 4–heparin IgG antibodies detected by enzyme immunoassay. Serum dilutions (final) ranged from 1/50 (standard assay) to 1/2000. Normal control specimens yielded negative results (not shown). Error bars indicate the standard error of the mean. *0.01 < < 0.05; † < 0.01; ‡ = 0.063; § > 0.2; ‖ = 0.193.
Figure.Serum specimens from 12 patients with delayed-onset heparin-induced thrombocytopenia.Top.gray barswhite barsBottom.PPPPP
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Summary for Patients

Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis

The summary below is from the full report titled “Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis.” It is in the 2 October 2001 issue of Annals of Internal Medicine (volume 135, pages 502-506). The authors are TE Warkentin and JG Kelton.


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