(From left) Frank Edwin, MB, ChB, Mark Mawutor Tettey, MB, ChB, and Martin Nartey Tamatey, MB, ChB
Central Message.
The name heparin-induced thrombocytopenia (HIT) suggests obligatory thrombocytopenia, yet HIT may still occur without thrombocytopenia, a diagnostic trap for the unwary clinician.
See Article page 36.
Heparin-induced thrombocytopenia (HIT) is primarily a prothrombotic disorder, the end result of heparin-platelet factor 4 antibody complexes causing platelet activation with the release of procoagulant platelet microparticles, increased thrombin generation, platelet consumption, and thrombocytopenia.1,2 Paradoxically, thrombosis is a far more prevalent manifestation of HIT than bleeding.
Heparin-induced thrombocytopenia suggests the obligatory association of absolute or relative thrombocytopenia, yet, as shown by Catalano and coworkers,3 HIT may still be present without thrombocytopenia. In 5 of 6 patients readmitted for thromboembolism after cardiopulmonary bypass, readmission platelet counts were not significantly different from the preoperative values. Because thrombocytopenia was not obvious on readmission, HIT was not suspected and these patients were inappropriately reexposed to heparin. After all, how do you convince anyone that a patient has HIT without the T? In the case of these patients, the term HIT appears to be a misnomer. Notably, thrombocytopenia occurs in ∼95% of HIT patients sometime during the course of illness,4 and other workers have reported cases in which heparin-induced thrombosis was confirmed in the absence of thrombocytopenia.5, 6, 7, 8, 9, 10
HIT typically occurs within 5-10 days of heparin exposure,11 a period that coincides with reactionary thrombocytosis in the postoperative period. This means that in a postoperative patient experiencing HIT, activation and depletion of preformed platelets leading to a prothrombotic state and a tendency toward thrombocytopenia could occur in synchrony with reactive postoperative thrombocytosis that masks the thrombocytopenia on laboratory testing. This allows dissociation between the onsets of thrombosis and thrombocytopenia so that thrombotic complications may be present without the hallmark thrombocytopenia for which HIT is (mis-) named. Warkentin and Kelton6 reported that 12 patients with HIT that they investigated, thrombocytopenia began an average of 9.2 days (range, 5-19 days) after the last use of unfractionated heparin; 6 of these patients manifested thrombotic complications beginning at an average of 8.3 days (range, 5-14 days) after heparin was withdrawn.
Without the awareness that heparin-induced thrombosis may occur without thrombocytopenia, patients with “HIT minus T” are at risk for heparin reexposure, which can result in a 33% mortality rate.12 In the 12 patients reported by Warkentin and Kelton,6 9 (including 3 without thrombocytopenia) were retreated with heparin, resulting in further decreases in platelet counts in all 9 patients and cardiac arrest in 1 patient.
The present study is retrospective and limited by a small sample size, but it emphasizes 2 very important points. The first point is that cardiac surgery patients may be discharged to home just at the time when HIT starts, and the platelet count may fail to reveal this. The second point is that the patient may be readmitted with thromboembolism, and the platelet count may fail to reveal this as well. The learning point is appreciating that the beguiling factor in the setting of postoperative thromboembolism after cardiac surgery is the absence of thrombocytopenia. Undue reliance on the platelet count as the hallmark of HIT risks getting hit with “HIT minus T.”
Footnotes
Disclosures: The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
References
- 1.Warkentin T.E., Hayward C.P., Boshkov L.K., Santos A.V., Sheppard J.A., Bode A.P., et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994;84:3691–3699. [PubMed] [Google Scholar]
- 2.Warkentin T.E., Elavathil L.J., Hayward C.P., Johnston M.A., Russett J.I., Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804–812. doi: 10.7326/0003-4819-127-9-199711010-00005. [DOI] [PubMed] [Google Scholar]
- 3.Catalano M.A., Prasad V., Spring A.M., Cassiere H., Chang T.Y., Hartman A., et al. Heparin-induced thrombocytopenia in patients readmitted after open cardiac surgical procedures: a case series. J Thorac Cardiovasc Surg Open. 2020;4:36–42. doi: 10.1016/j.xjon.2020.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Greinacher A., Farner B., Kroll H., Kohlmann T., Warkentin T.E., Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost. 2005;94:132–135. doi: 10.1160/TH04-12-0825. [DOI] [PubMed] [Google Scholar]
- 5.Phelan B.K. Heparin-associated thrombosis without thrombocytopenia. Ann Intern Med. 1983;99:637–638. doi: 10.7326/0003-4819-99-5-637. [DOI] [PubMed] [Google Scholar]
- 6.Warkentin T.E., Kelton J.G. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001;135:502–506. doi: 10.7326/0003-4819-135-7-200110020-00009. [DOI] [PubMed] [Google Scholar]
- 7.Busche M.N., Peters T., Knobloch K., Vogt P.M., Rennekampff H.O. Heparin-induced thrombocytopenia in a nonthrombocytopenic patient with toxic epidermal necrolysis causing fatal outcome: is HIT still a HIT? J Burn Care Res. 2009;30:747–751. doi: 10.1097/BCR.0b013e3181ac05bf. [DOI] [PubMed] [Google Scholar]
- 8.Klement D., Rammos S., Kries Rv, Kirschke W., Kniemeyer H.W., Greinacher A. Heparin as a cause of thrombus progression. Heparin-associated thrombocytopenia is an important differential diagnosis in pediatric patients even with normal platelet counts. Eur J Pediatr. 1996;155:11–14. doi: 10.1007/BF02115618. [DOI] [PubMed] [Google Scholar]
- 9.Hach-Wunderle V., Kainer K., Salzman G., Müller-Berghaus G., Pötzsch B. Heparin-associated thrombosis despite normal platelet counts in vascular surgery. Am J Surg. 1997;173:117–119. doi: 10.1016/S0002-9610(96)00407-2. [DOI] [PubMed] [Google Scholar]
- 10.Warkentin T.E. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol. 1998;35(4 suppl 5):9–16. discussion 35-6. [PubMed] [Google Scholar]
- 11.Warkentin T.E., Kelton J.G. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344:1286–1292. doi: 10.1056/NEJM200104263441704. [DOI] [PubMed] [Google Scholar]
- 12.Follis F., Schmidt C.A. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis. Ann Thorac Surg. 2000;70:2173–2181. doi: 10.1016/s0003-4975(00)01329-1. [DOI] [PubMed] [Google Scholar]