- Email: [email protected]
Hemodialysis-Associated Acute Systemic Reactions and Heparin-Induced Thrombocytopenia
Thrombosis Research 129 (2012) 405–406
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Hemodialysis-Associated Acute Systemic Reactions and Heparin-Induced Thrombocytopenia
Hemodialysis results in the exposure of patient blood to anticoagulation—usually with heparin—and to contact with the dialyzer artificial surfaces. Either can result in the patient developing one or more untoward symptoms or signs termed “acute systemic reactions” (or “anaphylactoid”) reactions, due to at least two distinct mechanisms [1]. One mechanism is immune heparin-induced thrombocytopenia (HIT); here, in vivo platelet activation occurs due to the consequences of heparin-dependent platelet-activating antibodies that recognize complexes of platelet factor 4 (PF4) bound to heparin. Through poorly-defined mechanisms, abrupt HIT antibody-induced platelet activation upon heparin bolus administration can result in a variety of clinical adverse effects [2], including fever, chills [3,4], flushing, tachycardia, blood pressure changes, dyspnea [4,5], unusual neurologic sequelae (transient global amnesia) [6], and sometimes even pulmonary or cardiac arrest [1,7,8]. Such HIT-associated acute systemic reactions differ from the usual prothrombotic effects of HIT, such as venous and arterial thrombosis (although some patients may suffer from both HIT-associated thrombosis and HIT-associated acute systemic reactions [4–6]). However, other patients with hemodialysis-associated acute systemic reactions do not have HIT but rather develop symptoms and signs due to exposure of their blood to the dialyzer membranes. Dialysis systems expose patients to immunogenic materials besides heparin (e.g., latex, formaldehyde) [9]. In addition, the large negatively-charged artificial surfaces of the dialyzer can activate the contact system, especially in patients with other risk factors (such as treatment with angiotensin-converting enzyme inhibitors). Indeed, hemodialysis patients represented one of the main patient groups affected by the epidemic of heparin-induced anaphylaxis due to contamination of heparin by oversulfated chondroitin sulfate (OSCS) [1]. Although OSCS directly contributed to contact system activation, the disproportionate occurrence of OSCS-associated anaphylaxis in the hemodialysis population likely reflected the additional contribution of dialyzer-mediated potentiation of contact system activation [1]. In this issue of Thrombosis Research, Matsuo and colleagues have performed the first systematic study of the role of HIT antibodies as an explanation for acute systemic reactions in the setting of hemodialysis [10]. They evaluated 27 patients who developed hemodialysis-associated acute systemic reaction; to meet study eligibility, the patients also needed to have a minimum 30% fall in platelet count associated with hemodialysis performed either with unfractionated or low-molecular-weight heparin anticoagulation, and the reaction(s) needed to occur within 3 months of commencing new treatment with hemodialysis (this last criterion reflecting the known propensity of HIT antibodies to develop 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.11.004
within two weeks of an immunizing heparin exposure and—once generated—to remain subsequently detectable at clinically-important concentrations for only approximately 2 or 3 months [11]). All of the study patients underwent systematic clinical evaluation of their hemodialysisassociated symptoms and signs. They also underwent systematic evaluation for presence of heparin-dependent antibodies, using two different types of immunoassays to detect anti-PF4/heparin antibodies, as well as two different kinds of platelet activation assays to detect “functional” (i.e., platelet-activating) antibodies. A fundamental tenet of HIT research over the past decade is that only the minority of anti-PF4/heparin antibodies with platelet-activating antibodies have the potential to cause clinically-evident HIT [12]. Platelet-activating antibodies were detected in approximately half (13/27 [48%]) of the patients. However, of these 13 patients, only 8 (62%) were judged by the investigators to have developed HITassociated acute systemic reactions (the others were judged to be hemodialysis-associated). Nevertheless, even if one assumes that all the study patients with detectable platelet-activating antibodies had acute systemic reactions that were at least partly related to HIT mechanisms, that still means approximately half the patients with hemodialysis-associated acute systemic reactions developed these due to non-HIT-related mechanisms. This study of Matsuo and colleagues also provides additional support for a quantitative relationship between the magnitude of a positive PF4-dependent immunoassay result and the probability of platelet-activating antibodies being detectable [13,14]. These investigators found that median (IQR) anti-PF4/heparin IgG levels were much higher when platelet-activating antibodies were present compared with when they were non-detectable: 846.7 (513.6, 2115.7) versus 48.7 (10.7, 105.9) μg/mL; p = 0.0001. Higher OD levels do not merely predict for presence of platelet-activating antibodies, but also for greater risk of clinically-significant complications such as HITassociated thrombosis [15–17] and, it now appears, HIT-associated acute systemic reactions. One point of interest is that Matsuo and coworkers noted blood pressure changes in their patients with acute systemic reactions to manifest usually as hypotension, rather than as hypertension. This differs from patients with HIT-associated acute systemic reactions that I have observed in my own practice, where patients (unless they developed cardiopulmonary arrest) usually evinced hypertension [18]. However, the report by Matsuo and colleagues only studied hemodialysis patients, and it is possible that this patient population is at greater risk for bradykinin-mediated hypotension (due to exposure to the dialyzer), compared with post-heparin bolus acute systemic reactions that occur in non-hemodialysis patient settings (such as the one I practice in). Indeed, other case reports of acute systemic
406
Editorial
reactions in the setting of hemodialysis have also emphasized the occurrence of hypotension [19,20]. This study of HIT-associated acute systemic reactions also helps to implicate IgG class antibodies in the pathogenesis of this type of “anaphylactoid” reaction. Many clinicians incorrectly assume that anaphylaxis/anaphylactoid reactions invariably involve IgE antibodies. However, IgE antibodies have never been implicated in HIT, and one study that specifically sought the presence of IgE antibodies in a patient with a HIT-associated anaphylactic reaction failed to find IgE anti-PF4/ heparin antibodies (rather, IgG class antibodies were detected) [5]. Lepirudin-associated hypersensitivity reactions are another example of a well-documented IgG-mediated adverse event [21]. Indeed, as pointed out by Levy and Adkinson, both IgG and IgE class antibodies can cause anaphylaxis, depending on the specific trigger and its particular mode of pathogenesis [22]. Indeed, this new study of Matsuo and colleagues helps to provide further evidence implicating high levels of IgG antibodies as a key factor in the pathogenesis of HIT-associated acute systemic reactions. Conflict of interest statement T.E.W. has received lecture honoraria from GlaxoSmithKline, Pfizer Canada, and Sanofi-Aventis, has provided consulting services to, and/ or has received research funding from, Canyon Pharmaceuticals, GenProbe GTI Diagnostics, GlaxoSmithKline, and Paringenix, and has provided expert witness testimony relating to HIT. References [1] Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 2009;8: 129–44. [2] Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th edition. New York: Informa Healthcare USA, Inc.; 2007. p. 21–66. [3] Hillis C, Warkentin TE, Taha K, Eikelboom JW. Chills and limb pain following administration of low-molecular-weight heparin for treatment of acute venous thromboembolism. Am J Hematol 2011;86:603–6. [4] Ling E, Warkentin TE. Intraoperative heparin flushes and subsequent acute heparin-induced thrombocytopenia. Anesthesiology 1998;89:1567–9. [5] Hewitt RL, Akers DL, Leissinger CA, Gill JI, Aster RH. Concurrence of anaphylaxis and acute heparin-induced thrombocytopenia in a patient with heparin-induced antibodies. J Vasc Surg 1998;28:561–5. [6] Warkentin TE, Hirte HW, Anderson DR, Wilson WEC, O'Connell GJ, Lo RC. Transient global amnesia associated with acute heparin-induced thrombocytopenia. Am J Med 1994;97:489–91.
[7] Ansell JE, Clark Jr WP, Compton CC. Fatal reactions associated with intravenous heparin [letter]. Drug Intell Clin Pharm 1986;20:74–5. [8] Mims MP, Manian P, Rice L. Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Eur J Haematol 2004;72:366–9. [9] Ebo DG, Bosmans JL, Couttenye MM, Stevens WJ. Haemodialysis-associated anaphylactic and anaphylactoid reactions. Allergy 2006;61:211–20. [10] Matsuo T, Wanaka K, Miyasita K, Prechel M, Walenga JM. Clinical evaluation of acute systemic reactions and detection of IgG antibodies against PF4/heparin complexes in hemodialysis patients. Thromb Res in press. [11] Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286–92. [12] Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost in press. [13] Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzymeimmunoassays. J Thromb Haemost 2008;6:1304–12. [14] Greinacher A, Ittermann T, Bagemühl J, Althaus K, Fürll B, Selleng S, et al. Heparininduced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010;8:2025–31. [15] Baroletti S, Hurwitz S, Conti NAS, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med 2011 Nov 8. [Electronic publication ahead of print]. [16] Zwicker JI, Uhl L, Huang WY, Shazi BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004;2:2133–7. [17] Altuntas F, Metavosyan K, Burner J, Shen YM, Sarode R. Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia. Eur J Haematol 2008;80:429–35. [18] Warkentin TE, Soutar RL, Panju A, Ginsberg JS. Acute systemic reactions to intravenous bolus heparin therapy: characterization and relationship to heparininduced thrombocytopenia. Blood 1992;80(Suppl. 1):160a [Abstract]. [19] Tejedor Alonso MA, López Revuelta K, Garcí Bueno MJ, Casas Losada ML, Rosado Ingelmo A, Gruss Vergara E, et al. Clin Nephrol 2005;63:236–40. [20] Tholl U, Greinacher A, Overdick K, Anlauf M. Life-threatening anaphylactic reaction following parathyroidectomy in a dialysis patient with heparin-induced thrombocytopenia. Nephrol Dial Transplant 1997;12:2750–5. [21] Greinacher A, Lubenow N, Eichler P. Anaphylatic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003;108:2062–5. [22] Levy JH, Adkinson Jr NF. Anaphylaxis during cardiac surgery: implications for clinicians. Anesth Analg 2008;106:392–403.
Theodore E. Warkentin Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. Tel.: +1 905 527 0271x46139; fax: +1 905 577 1421. E-mail address: [email protected] 25 October 2011
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Hemodialysis-Associated Acute Systemic Reactions and Heparin-Induced Thrombocytopenia
Hemodialysis results in the exposure of patient blood to anticoagulation—usually with heparin—and to contact with the dialyzer artificial surfaces. Either can result in the patient developing one or more untoward symptoms or signs termed “acute systemic reactions” (or “anaphylactoid”) reactions, due to at least two distinct mechanisms [1]. One mechanism is immune heparin-induced thrombocytopenia (HIT); here, in vivo platelet activation occurs due to the consequences of heparin-dependent platelet-activating antibodies that recognize complexes of platelet factor 4 (PF4) bound to heparin. Through poorly-defined mechanisms, abrupt HIT antibody-induced platelet activation upon heparin bolus administration can result in a variety of clinical adverse effects [2], including fever, chills [3,4], flushing, tachycardia, blood pressure changes, dyspnea [4,5], unusual neurologic sequelae (transient global amnesia) [6], and sometimes even pulmonary or cardiac arrest [1,7,8]. Such HIT-associated acute systemic reactions differ from the usual prothrombotic effects of HIT, such as venous and arterial thrombosis (although some patients may suffer from both HIT-associated thrombosis and HIT-associated acute systemic reactions [4–6]). However, other patients with hemodialysis-associated acute systemic reactions do not have HIT but rather develop symptoms and signs due to exposure of their blood to the dialyzer membranes. Dialysis systems expose patients to immunogenic materials besides heparin (e.g., latex, formaldehyde) [9]. In addition, the large negatively-charged artificial surfaces of the dialyzer can activate the contact system, especially in patients with other risk factors (such as treatment with angiotensin-converting enzyme inhibitors). Indeed, hemodialysis patients represented one of the main patient groups affected by the epidemic of heparin-induced anaphylaxis due to contamination of heparin by oversulfated chondroitin sulfate (OSCS) [1]. Although OSCS directly contributed to contact system activation, the disproportionate occurrence of OSCS-associated anaphylaxis in the hemodialysis population likely reflected the additional contribution of dialyzer-mediated potentiation of contact system activation [1]. In this issue of Thrombosis Research, Matsuo and colleagues have performed the first systematic study of the role of HIT antibodies as an explanation for acute systemic reactions in the setting of hemodialysis [10]. They evaluated 27 patients who developed hemodialysis-associated acute systemic reaction; to meet study eligibility, the patients also needed to have a minimum 30% fall in platelet count associated with hemodialysis performed either with unfractionated or low-molecular-weight heparin anticoagulation, and the reaction(s) needed to occur within 3 months of commencing new treatment with hemodialysis (this last criterion reflecting the known propensity of HIT antibodies to develop 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.11.004
within two weeks of an immunizing heparin exposure and—once generated—to remain subsequently detectable at clinically-important concentrations for only approximately 2 or 3 months [11]). All of the study patients underwent systematic clinical evaluation of their hemodialysisassociated symptoms and signs. They also underwent systematic evaluation for presence of heparin-dependent antibodies, using two different types of immunoassays to detect anti-PF4/heparin antibodies, as well as two different kinds of platelet activation assays to detect “functional” (i.e., platelet-activating) antibodies. A fundamental tenet of HIT research over the past decade is that only the minority of anti-PF4/heparin antibodies with platelet-activating antibodies have the potential to cause clinically-evident HIT [12]. Platelet-activating antibodies were detected in approximately half (13/27 [48%]) of the patients. However, of these 13 patients, only 8 (62%) were judged by the investigators to have developed HITassociated acute systemic reactions (the others were judged to be hemodialysis-associated). Nevertheless, even if one assumes that all the study patients with detectable platelet-activating antibodies had acute systemic reactions that were at least partly related to HIT mechanisms, that still means approximately half the patients with hemodialysis-associated acute systemic reactions developed these due to non-HIT-related mechanisms. This study of Matsuo and colleagues also provides additional support for a quantitative relationship between the magnitude of a positive PF4-dependent immunoassay result and the probability of platelet-activating antibodies being detectable [13,14]. These investigators found that median (IQR) anti-PF4/heparin IgG levels were much higher when platelet-activating antibodies were present compared with when they were non-detectable: 846.7 (513.6, 2115.7) versus 48.7 (10.7, 105.9) μg/mL; p = 0.0001. Higher OD levels do not merely predict for presence of platelet-activating antibodies, but also for greater risk of clinically-significant complications such as HITassociated thrombosis [15–17] and, it now appears, HIT-associated acute systemic reactions. One point of interest is that Matsuo and coworkers noted blood pressure changes in their patients with acute systemic reactions to manifest usually as hypotension, rather than as hypertension. This differs from patients with HIT-associated acute systemic reactions that I have observed in my own practice, where patients (unless they developed cardiopulmonary arrest) usually evinced hypertension [18]. However, the report by Matsuo and colleagues only studied hemodialysis patients, and it is possible that this patient population is at greater risk for bradykinin-mediated hypotension (due to exposure to the dialyzer), compared with post-heparin bolus acute systemic reactions that occur in non-hemodialysis patient settings (such as the one I practice in). Indeed, other case reports of acute systemic
406
Editorial
reactions in the setting of hemodialysis have also emphasized the occurrence of hypotension [19,20]. This study of HIT-associated acute systemic reactions also helps to implicate IgG class antibodies in the pathogenesis of this type of “anaphylactoid” reaction. Many clinicians incorrectly assume that anaphylaxis/anaphylactoid reactions invariably involve IgE antibodies. However, IgE antibodies have never been implicated in HIT, and one study that specifically sought the presence of IgE antibodies in a patient with a HIT-associated anaphylactic reaction failed to find IgE anti-PF4/ heparin antibodies (rather, IgG class antibodies were detected) [5]. Lepirudin-associated hypersensitivity reactions are another example of a well-documented IgG-mediated adverse event [21]. Indeed, as pointed out by Levy and Adkinson, both IgG and IgE class antibodies can cause anaphylaxis, depending on the specific trigger and its particular mode of pathogenesis [22]. Indeed, this new study of Matsuo and colleagues helps to provide further evidence implicating high levels of IgG antibodies as a key factor in the pathogenesis of HIT-associated acute systemic reactions. Conflict of interest statement T.E.W. has received lecture honoraria from GlaxoSmithKline, Pfizer Canada, and Sanofi-Aventis, has provided consulting services to, and/ or has received research funding from, Canyon Pharmaceuticals, GenProbe GTI Diagnostics, GlaxoSmithKline, and Paringenix, and has provided expert witness testimony relating to HIT. References [1] Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 2009;8: 129–44. [2] Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. 4th edition. New York: Informa Healthcare USA, Inc.; 2007. p. 21–66. [3] Hillis C, Warkentin TE, Taha K, Eikelboom JW. Chills and limb pain following administration of low-molecular-weight heparin for treatment of acute venous thromboembolism. Am J Hematol 2011;86:603–6. [4] Ling E, Warkentin TE. Intraoperative heparin flushes and subsequent acute heparin-induced thrombocytopenia. Anesthesiology 1998;89:1567–9. [5] Hewitt RL, Akers DL, Leissinger CA, Gill JI, Aster RH. Concurrence of anaphylaxis and acute heparin-induced thrombocytopenia in a patient with heparin-induced antibodies. J Vasc Surg 1998;28:561–5. [6] Warkentin TE, Hirte HW, Anderson DR, Wilson WEC, O'Connell GJ, Lo RC. Transient global amnesia associated with acute heparin-induced thrombocytopenia. Am J Med 1994;97:489–91.
[7] Ansell JE, Clark Jr WP, Compton CC. Fatal reactions associated with intravenous heparin [letter]. Drug Intell Clin Pharm 1986;20:74–5. [8] Mims MP, Manian P, Rice L. Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Eur J Haematol 2004;72:366–9. [9] Ebo DG, Bosmans JL, Couttenye MM, Stevens WJ. Haemodialysis-associated anaphylactic and anaphylactoid reactions. Allergy 2006;61:211–20. [10] Matsuo T, Wanaka K, Miyasita K, Prechel M, Walenga JM. Clinical evaluation of acute systemic reactions and detection of IgG antibodies against PF4/heparin complexes in hemodialysis patients. Thromb Res in press. [11] Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286–92. [12] Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost in press. [13] Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzymeimmunoassays. J Thromb Haemost 2008;6:1304–12. [14] Greinacher A, Ittermann T, Bagemühl J, Althaus K, Fürll B, Selleng S, et al. Heparininduced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010;8:2025–31. [15] Baroletti S, Hurwitz S, Conti NAS, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med 2011 Nov 8. [Electronic publication ahead of print]. [16] Zwicker JI, Uhl L, Huang WY, Shazi BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004;2:2133–7. [17] Altuntas F, Metavosyan K, Burner J, Shen YM, Sarode R. Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia. Eur J Haematol 2008;80:429–35. [18] Warkentin TE, Soutar RL, Panju A, Ginsberg JS. Acute systemic reactions to intravenous bolus heparin therapy: characterization and relationship to heparininduced thrombocytopenia. Blood 1992;80(Suppl. 1):160a [Abstract]. [19] Tejedor Alonso MA, López Revuelta K, Garcí Bueno MJ, Casas Losada ML, Rosado Ingelmo A, Gruss Vergara E, et al. Clin Nephrol 2005;63:236–40. [20] Tholl U, Greinacher A, Overdick K, Anlauf M. Life-threatening anaphylactic reaction following parathyroidectomy in a dialysis patient with heparin-induced thrombocytopenia. Nephrol Dial Transplant 1997;12:2750–5. [21] Greinacher A, Lubenow N, Eichler P. Anaphylatic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003;108:2062–5. [22] Levy JH, Adkinson Jr NF. Anaphylaxis during cardiac surgery: implications for clinicians. Anesth Analg 2008;106:392–403.
Theodore E. Warkentin Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. Tel.: +1 905 527 0271x46139; fax: +1 905 577 1421. E-mail address: [email protected] 25 October 2011