Platelet count recovery and seroreversion in immune HIT despite continuation of heparin: further observations and literature review
27 March 2017
Accepted after major revision: 16 June 2017
08 November 2017 (online)
One of the standard distinctions between type 1 (non-immune) and type 2 (immune-mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies (“seroreversion”). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued.
- 1 Greinacher A, Juhl D, Strobel U. et al. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007; 05: 1666-1673.
- 2 Chong BH, Berndt MC. Heparin-induced thrombocytopenia. Blut 1989; 58: 53-57.
- 3 Franchini M. Heparin-induced thrombocytopenia: an update. Thrombosis J 2005; 03: 14.
- 4 Warkentin TE. HITlights: a career perspective on heparin-induced thrombocytopenia. American journal of hematology 2012; 87 (Suppl. 01) S92-S99.
- 5 Greinacher A, Kohlmann T, Strobel U. et al. The temporal profile of the anti-PF4/heparin immune response. Blood 2009; 113: 4970-4976.
- 6 Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135: 502-506.
- 7 Denomme GA, Warkentin TE, Horsewood P. et al. Activation of platelets by sera containing IgG1 heparin-dependent antibodies: an explanation for the predominance of the Fc gammaRIIa „low responder“ (his131) gene in patients with heparin-induced thrombocytopenia. J Lab Clin Med 1997; 130: 278-284.
- 8 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-507.
- 9 Greinacher A. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373: 1883-1884.
- 10 Warkentin TE. Heparin-induced thrombocytopenia. Curr Opin Crit Care 2015; 21: 576-585.
- 11 Linkins LA, Dans AL, Moores LK. et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e495S-e530S.
- 12 Warkentin TE, Sheppard JA, Heels-Ansdell D. et al. Heparin-induced thrombocytopenia in medical surgical critical illness. Chest 2013; 144: 848-858.
- 13 Powers PJ, Kelton JG, Carter CJ. Studies on the frequency of heparin-associated thrombocytopenia. Thromb Res 1984; 33: 439-443.
- 14 Powers PJ, Cuthbert D, Hirsh J. Thrombocytopenia found uncommonly during heparin therapy. J Am Med Assoc 1979; 241: 2396-2397.
- 15 Nelson JC, Lerner RG, Goldstein R. et al. Heparin-induced thrombocytopenia. Arch Intern Med 1978; 138: 548-552.
- 16 King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100: 535-540.
- 17 Ansell J, Slepchuk Jr N, Kumar R. et al. Heparin induced thrombocytopenia: a prospective study. Thromb Haemost 1980; 43: 61-65.
- 18 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Progr Hemost Thromb 1991; 10: 1-34.
- 19 Kelton JG, Sheridan D, Brain H. et al. Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia. J Lab Clin Med 1984; 103: 606-612.
- 20 Olin J, Graor R. Heparin-associated thrombocytopenia. N Engl J Med 1981; 304: 609.
- 21 Malcolm ID, Wigmore TA, Steinbrecher UP. Heparin-associated thrombocytopenia: low frequency in 104 patients treated with heparin of intestinal mucosal origin. Canad Med Assoc J 1979; 120: 1086-1088.
- 22 Krueger SK, Andres E, Weinand E. Thrombolysis in heparin-induced thrombocytopenia with thrombosis. Ann Intern Med 1985; 103: 159.
- 23 Eika C, Godal HC, Laake K. et al. Low incidence of thrombocytopenia during treatment with hog mucosa and beef lung heparin. Scand J Haematol 1980; 25: 19-24.
- 24 Vatanparast R, Lantz S, Ward K. et al. Evaluation of a pretest scoring system (4Ts) for the diagnosis of heparin-induced thrombocytopenia in a university hospital setting. Postgrad Med 2012; 124: 36-42.
- 25 Lo GK, Juhl D, Warkentin TE. et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 04: 759-765.
- 26 Linkins LA, Warkentin TE. Heparin-induced thrombocytopenia: real-world issues. Semin Thromb Hemost 2011; 37: 653-663.
- 27 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344: 1286-1292.
- 28 Warkentin TE, Cook RJ, Marder VJ. et al. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost 2010; 08: 504-512.
- 29 Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost 2011; 09 (Suppl. 01) 105-117.
- 30 Warkentin TE, Sheppard JI, Moore JC. et al. The use of well-characterized sera for the assessment of new diagnostic enzyme-immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2010; 08: 216-218.
- 31 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.