Heparin-Induced Thrombocytopenia in Infants after Heart SurgeryFunding None.
10 November 2017
29 January 2018
01 April 2018 (online)
Background Heparin-induced thrombocytopenia (HIT) in infants is a rare disorder, and the diagnosis and management of HIT still remains challenging. Argatroban is a synthetic direct thrombin inhibitor (DTI) that is widely used for treating HIT. However, little is known about the efficacy of the activated clotting time (ACT) test in monitoring DTI treatment as an alternative to the routinely used activated partial thromboplastin time (aPTT).
Methods Between July 2013 and January 2015, four infants were diagnosed with HIT after surgical correction of congenital anomalies. In all cases, heparin was used during cardiopulmonary bypass (CPB). Diagnosis of HIT was based on the “4 Ts” pretest clinical scoring system, and platelet factor 4 (PF4) antibody was detected using enzyme-linked immunosorbent assay. Argatroban was used in treating HIT. When argatroban was infused, anticoagulation tests (aPTT, prothrombin time [PT], thrombin time [TT], and fibrinogen) were performed every 4 to 12 hours. ACT was used in addition to monitor the anticoagulation effect of argatroban. The target ACT was 1.5 to 3.0 times the baseline. ACT was measured every 2 to 4 hours and remeasured 1 hour after each dosage adjustment.
Results Thrombocytopenia (defined as a 50% decrease in platelet count) occurred during the 3rd to 6th day postoperatively. After the diagnosis of HIT, argatroban was started immediately, and platelet counts stabilized and gradually increased. Anticoagulation effect of argatroban was successful monitored by ACT and aPTT. Poor correlation between the ACT test and aPTT test (R = 0.270, p = 0.092) was noted in one patient. ACT values increased rapidly after 3 to 7 days on argatroban treatment. In most cases, low dosage of argatroban was given ranging from 0.04 to 5.00 μg/kg/min.
Conclusion Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study.
KeywordsInfant - heart surgery - heparin - thrombocytopenia - argatroban - activated coagulation time
Ethics Approval and Consent to Participate
Due its retrospective nature, the need of approval was waived by the Research and Ethical Committee of Xiangya Hospital of Central South University.
- 1 Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia: a historical perspective. Blood 2008; 112 (07) 2607-2616
- 2 Greinacher A. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373 (03) 252-261
- 3 Alsoufi B, Boshkov LK, Kirby A. , 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: 155-171
- 4 Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96 (05) 1703-1708
- 5 Seigerman M, Cavallaro P, Itagaki S, Chung I, Chikwe J. Incidence and outcomes of heparin-induced thrombocytopenia in patients undergoing cardiac surgery in North America: an analysis of the nationwide inpatient sample. J Cardiothorac Vasc Anesth 2014; 28 (01) 98-102
- 6 Kerendi F, Thourani VH, Puskas JD. , et al. Impact of heparin-induced thrombocytopenia on postoperative outcomes after cardiac surgery. Ann Thorac Surg 2007; 84 (05) 1548-1553 , discussion 1554–1555
- 7 Piednoir P, Allou N, Provenchère S. , et al. Heparin-induced thrombocytopenia after cardiac surgery: an observational study of 1,722 patients. J Cardiothorac Vasc Anesth 2012; 26 (04) 585-590
- 8 Yoon JH, Jang IK. Heparin-induced thrombocytopenia in cardiovascular patients: pathophysiology, diagnosis, and treatment. Cardiol Rev 2011; 19 (03) 143-153
- 9 Grouzi E. Update on argatroban for the prophylaxis and treatment of heparin-induced thrombocytopenia type II. J Blood Med 2014; 5: 131-141
- 10 Lewis BE, Wallis DE, Berkowitz SD. , et al; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103 (14) 1838-1843
- 11 Lind SE, Boyle ME, Fisher S, Ishimoto J, Trujillo TC, Kiser TH. Comparison of the aPTT with alternative tests for monitoring direct thrombin inhibitors in patient samples. Am J Clin Pathol 2014; 141 (05) 665-674
- 12 Demma LJ, Paciullo CA, Levy JH. Recognition of heparin-induced thrombocytopenia and initiation of argatroban therapy after cardiothoracic surgery in the intensive care unit. J Thorac Cardiovasc Surg 2012; 143 (05) 1213-1218
- 13 Obeng EA, Harney KM, Moniz T, Arnold A, Neufeld EJ, Trenor III CC. Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system. J Pediatr 2015; 166 (01) 144-150
- 14 Vakil NH, Kanaan AO, Donovan JL. Heparin-induced thrombocytopenia in the pediatric population: a review of current literature. J Pediatr Pharmacol Ther 2012; 17 (01) 12-30
- 15 Moffett BS, Teruya J. Trends in parenteral direct thrombin inhibitor use in pediatric patients: analysis of a large administrative database. Arch Pathol Lab Med 2014; 138 (09) 1229-1232
- 16 Mullen MP, Wessel DL, Thomas KC. , et al. The incidence and implications of anti-heparin-platelet factor 4 antibody formation in a pediatric cardiac surgical population. Anesth Analg 2008; 107 (02) 371-378
- 17 Young G, Boshkov LK, Sullivan JE. , et al. Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer 2011; 56 (07) 1103-1109
- 18 Risch L, Huber AR, Schmugge M. Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res 2006; 118 (01) 123-135
- 19 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 (04) 759-765
- 20 Avila ML, Shah V, Brandão LR. Systematic review on heparin-induced thrombocytopenia in children: a call to action. J Thromb Haemost 2013; 11 (04) 660-669
- 21 Lee GM, Arepally GM. Diagnosis and management of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am 2013; 27 (03) 541-563
- 22 Pouplard C, May MA, Iochmann S. , et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin : clinical implications for heparin-induced thrombocytopenia. Circulation 1999; 99 (19) 2530-2536
- 23 Bates D, Griffin S, Angel B. Clinical experience with argatroban for heparin-induced thrombocytopenia in a large teaching hospital. Can J Hosp Pharm 2009; 62 (04) 290-297
- 24 Linkins L, 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 (02) 495-530
- 25 Watson H, Davidson S, Keeling D. ; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012; 159 (05) 528-540
- 26 Koster A, Buz S, Hetzer R, Kuppe H, Breddin K, Harder S. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiovascular surgery with cardiopulmonary bypass: first results from the ARG-E03 trial. J Thorac Cardiovasc Surg 2006; 132 (03) 699-700
- 27 Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG. ; Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163 (15) 1849-1856
- 28 Lewis BE, Wallis DE, Hursting MJ, Levine RL, Leya F. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest 2006; 129 (06) 1407-1416
- 29 Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med 2004; 164 (04) 361-369
- 30 Carteaux JP, Gast A, Tschopp TB, Roux S. Activated clotting time as an appropriate test to compare heparin and direct thrombin inhibitors such as hirudin or Ro 46-6240 in experimental arterial thrombosis. Circulation 1995; 91 (05) 1568-1574