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Chapter 12 - Heparin-induced thrombocytopenia and thrombosis syndrome in children

from Section 2 - Special considerations in pediatric patients

Published online by Cambridge University Press:  18 December 2014

By
Courtney D. Thornburg
Edited by
Neil A. Goldenberg  and
Marilyn J. Manco-Johnson
Courtney D. Thornburg
Affiliation:
University of California San Diego and Rady Children’s Hospital
Neil A. Goldenberg
Affiliation:
The Johns Hopkins University School of Medicine
Marilyn J. Manco-Johnson
Affiliation:
Hemophilia and Thrombosis Center, University of Colorado, Denver
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Summary

Historical perspective

Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) are well-described phenomena, particularly in the adult population. These conditions were first described several decades ago [1,2]. At first, these syndromes were under-recognized, leading to limb and life-threatening thrombosis. Recently, due to increased recognition, testing, availability of novel anticoagulants and high concern for missing a case, the trend has shifted to over-diagnosis.

Pathophysiology

The HIT/HITTS condition requires the interaction between heparin, platelet factor 4 (PF4), immunoglobulin G (IgG) and an Fc receptor on the platelet. This interaction results in procoagulant activity of the platelets and a prothrombotic state. These complexes are most likely to be formed under proinflammatory conditions such as surgery, described by Warkentin as “point immunization” [3]. There is a high rate of thrombosis even once heparin is discontinued. This is because the HIT antibody can bind to heparin-PF4 complexes on the surface of endothelial cells, monocytes and polymorphonuclear (PMN) cells, and lead to vessel injury and inflammation, PMN activation and exposure of tissue factor on monocytes.

Special considerations in children

The pathophysiology of HIT/HITTS likely differs between adults and children. This may be related to differences in PF4 levels and immune response, which contribute to immune complex formation as well as platelet reactivity and underlying prothrombotic risk, which contribute to the incidence of thrombosis in the presence of HIT antibodies [4].

Diagnosis

Clinical symptoms

The primary manifestation of HITTS is thrombosis. Venous thrombosis occurs more often than arterial thrombosis. Thrombosis most often occurs within 5–10 days of initial heparin exposure, and if heparin has been given within the past 100 days, within 24 hours of repeat heparin exposure (rapid HITTS). Thrombosis may also occur weeks after heparin exposure (delayed HITTS). Other manifestations include heparin-induced skin necrosis and acute systemic reaction coincident with heparin infusion. Even in the presence of significant thrombocytopenia, bleeding is rare. In fact, bleeding with thrombocytopenia should decrease the suspicion of HIT.

Type
Chapter
Information
Pediatric Thrombotic Disorders , pp. 158 - 165
Publisher: Cambridge University Press
Print publication year: 2015

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References

Rhodes, GR, Dixon, RH, Silver, D. Heparin-induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet. 1973;136(3):409–16.Google ScholarPubMed
Weismann, RE, Tobin, RW. Arterial embolism occurring during systemic heparin therapy. AMA Arch Surg. 1958;76(2):219–25; discussion 25–7.CrossRefGoogle ScholarPubMed
Warkentin, TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011;9(Suppl 1):105–17.CrossRefGoogle ScholarPubMed
Takemoto, CM, Streiff, MB. Heparin-induced thrombocytopenia screening and management in pediatric patients. Hematology/the Education Program of the American Society of Hematology. 2011;2011:162–9.Google ScholarPubMed
Mullen, MP, Wessel, DL, Thomas, KC, Gauvreau, K, Neufeld, EJ, McGowan, FX, et al. The incidence and implications of anti-heparin-platelet factor 4 antibody formation in a pediatric cardiac surgical population. Anesth Analg. 2008;107(2):371–8.CrossRefGoogle Scholar
Warkentin, TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest. 2005;127(2 Suppl):35S–45S.CrossRefGoogle Scholar
Lo, GK, Juhl, D, Warkentin, TE, Sigouin, CS, Eichler, P, Greinacher, A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759–65.CrossRefGoogle Scholar
Cuker, A, Arepally, G, Crowther, MA, Rice, L, Datko, F, Hook, K, et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost. 2010;8(12):2642–50.CrossRefGoogle ScholarPubMed
Cuker, A. Update in the diagnosis and management of heparin-induced thrombocytopenia. Clin Adv Hematol Oncol. 2012;10(7):453–5.Google ScholarPubMed
Newall, F, Barnes, C, Ignjatovic, V, Monagle, P. Heparin-induced thrombocytopenia in children. J Paediatr Child Health. 2003;39(4):289–92.CrossRefGoogle ScholarPubMed
Schmugge, M, Risch, L, Huber, AR, Benn, A, Fischer, JE. Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics. 2002;109(1):E10.CrossRefGoogle ScholarPubMed
Ranze, O, Ranze, P, Magnani, HN, Greinacher, A. Heparin-induced thrombocytopenia in paediatric patients – a review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr. 1999;158(Suppl 3):S130–3.CrossRefGoogle Scholar
Klenner, AF, Lubenow, N, Raschke, R, Greinacher, A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost. 2004;91(4):719–24.Google ScholarPubMed
Murdoch, IA, Beattie, RM, Silver, DM. Heparin-induced thrombocytopenia in children. Acta Paediatr. 1993;82(5):495–7.CrossRefGoogle ScholarPubMed
Potter, KE, Raj, A, Sullivan, JE. Argatroban for anticoagulation in pediatric patients with heparin-induced thrombocytopenia requiring extracorporeal life support. J Pediatr Hematol/Oncol. 2007;29(4):265–8.CrossRefGoogle ScholarPubMed
Almond, CS, Harrington, J, Thiagarajan, R, Duncan, CN, LaPierre, R, Halwick, D, et al. Successful use of bivalirudin for cardiac transplantation in a child with heparin-induced thrombocytopenia. J Heart Lung Transplant. 2006;25(11):1376–9.CrossRefGoogle Scholar
Risch, L, Huber, AR, Schmugge, M. Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res. 2006;118(1):123–35.CrossRefGoogle ScholarPubMed
Spadone, D, Clark, F, James, E, Laster, J, Hoch, J, Silver, D. Heparin-induced thrombocytopenia in the newborn. J Vasc Surg. 1992;15(2):306–11; discussion 11–12.CrossRefGoogle ScholarPubMed
Severin, T, Sutor, AH. Heparin-induced thrombocytopenia in pediatrics. Semin Thromb Hemost. 2001;27(3):293–9.CrossRefGoogle Scholar
Alsoufi, B, Boshkov, LK, Kirby, A, Ibsen, L, Dower, N, Shen, I, et al. Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2004;7:155–71.CrossRefGoogle ScholarPubMed
Argueta-Morales, IR, Olsen, MC, DeCampli, WM, Munro, HM, Felix, DE. Alternative anticoagulation during cardiovascular procedures in pediatric patients with heparin-induced thrombocytopenia. J Extra Corpor Technol. 2012;44(2):69–74.Google ScholarPubMed
Raffini, L, Huang, YS, Witmer, C, Feudtner, C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124(4):1001–8.CrossRefGoogle ScholarPubMed
Setty, BA, O’Brien, SH, Kerlin, BA. Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases. Pediatr Blood Cancer. 2012;59(2):258–64.CrossRefGoogle ScholarPubMed
Boulet, SL, Grosse, SD, Thornburg, CD, Yusuf, H, Tsai, J, Hooper, WC. Trends in venous thromboembolism-related hospitalizations, 1994–2009. Pediatrics. 2012;130(4):e812–20.CrossRefGoogle ScholarPubMed
Raffini, L, Trimarchi, T, Beliveau, J, Davis, D. Thromboprophylaxis in a pediatric hospital: a patient-safety and quality-improvement initiative. Pediatrics. 2011;127(5):e1326–32.CrossRefGoogle Scholar
Fraser, CD, Jaquiss, RD, Rosenthal, DN, Humpl, T, Canter, CE, Blackstone, EH, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med. 2012;367(6):532–41.CrossRefGoogle ScholarPubMed
Hardikar, W, Poddar, U, Chamberlain, J, Teo, S, Bhat, R, Jones, B, et al. Evaluation of a post-operative thrombin inhibitor replacement protocol to reduce haemorrhagic and thrombotic complications after paediatric liver transplantation. Thromb Res. 2010;126(3):191–4.CrossRefGoogle ScholarPubMed
Arepally, GM, Ortel, TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355(8):809–17.CrossRefGoogle ScholarPubMed
Cuker, A, Cines, DB. How I treat heparin-induced thrombocytopenia. Blood. 2012;119(10):2209–18.CrossRefGoogle Scholar
Young, G. New anticoagulants in children: a review of recent studies and a look to the future. Thromb Res. 2011;127(2):70–4.CrossRefGoogle Scholar
Young, G, Boshkov, LK, Sullivan, JE, Raffini, LJ, Cox, DS, Boyle, DA, et al. Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer. 2011;56(7):1103–9.CrossRefGoogle ScholarPubMed
Young, G, Yonekawa, KE, Nakagawa, PA, Blain, RC, Lovejoy, AE, Nugent, DJ. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis. 2007;18(6):547–53.CrossRefGoogle ScholarPubMed
Young, G, Tarantino, MD, Wohrley, J, Weber, LC, Belvedere, M, Nugent, DJ. Pilot dose-finding and safety study of bivalirudin in infants < 6 months of age with thrombosis. J Thromb Haemost. 2007;5(8):1654–9.CrossRefGoogle ScholarPubMed
Gates, R, Yost, P, Parker, B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytopenia patients. Artif Organs. 2010;34(8):667–9.Google ScholarPubMed
Forbes, TJ, Hijazi, ZM, Young, G, Ringewald, JM, Aquino, PM, Vincent, RN, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheter Cardiovasc Interv. 2011;77(5):671–9.CrossRefGoogle ScholarPubMed
Wright, JM, Watts, RG. Venous thromboembolism in pediatric patients: epidemiologic data from a pediatric tertiary care center in Alabama. J Pediatr Hematol/Oncol. 2011;33(4):261–4.CrossRefGoogle ScholarPubMed
Hursting, MJ, Dubb, J, Verme-Gibboney, CN. Argatroban anticoagulation in pediatric patients: a literature analysis. J Pediatr Hematol/Oncol. 2006;28(1):4–10.CrossRefGoogle ScholarPubMed
Madabushi, R, Cox, DS, Hossain, M, Boyle, DA, Patel, BR, Young, G, et al. Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics. J Clin Pharmacol. 2011;51(1):19–28.CrossRefGoogle Scholar
Argatroban prescribing information 2008 [cited 2012 September 24]. Available from:
Hursting, MJ, Lewis, BE, Macfarlane, DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11(3):279–87.CrossRefGoogle ScholarPubMed
Cuker, A, Crowther, M. 2009 clinical practice guidelines on the evaluation and management of heparin-induced thromboctyopenia (HIT 2009) (cited 2012 September 17). Available from:
Chong, BH, Chong, JJ. Heparin-induced thrombocytopenia associated with fondaparinux. Clin Adv Hematol Oncol. 2010;8(1):63–5.Google ScholarPubMed
Young, G, Yee, DL, O’Brien, SH, Khanna, R, Barbour, A, Nugent, DJ. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer. 2011;57(6):1049–54.CrossRefGoogle ScholarPubMed
Monagle, P, Chan, AK, Goldenberg, NA, Ichord, RN, Journeycake, JM, Nowak-Gottl, U, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e737S–801S.CrossRefGoogle Scholar
Sachais, BS, Rux, AH, Cines, DB, Yarovoi, SV, Garner, LI, Watson, SP, et al. Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood. 2012;119(25):5955–62.CrossRefGoogle Scholar
Joglekar, MV, Quintana Diez, PM, Marcus, S, Qi, R, Espinasse, B, Wiesner, MR, et al. Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH). Thromb Haemost. 2012;107(4):717–25.CrossRefGoogle Scholar
Donoghue, M, Suh, KR, Facilitating Development of Anticoagulant Drugs for Use in Pediatric Patients. FDA Presentation to Pediatric Subcommittee of the Oncologic Drugs Advisory Committee. Food and Drugs Administration, 2011.Google Scholar
Food and Drugs Administration. Arixtra (fondaparinux sodium) prescribing information, September, 2013: Reference ID: 3372362.

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