Low-Molecular-Weight HeparinInduced Thrombocytopenia in a Child

William E Dager and Richard H White

OBJECTIVE: To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy. CASE SUMMARY: An 11-year-old African American female with Crohns disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 103/mm3, significantly lower than the count of 550700 103/mm3 5 months previously and the count of 433 103/mm3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 103/mm3. Over the next 4 months, there was no further thrombosis. DISCUSSION: HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults. CONCLUSIONS:

Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.

KEY WORDS: enoxaparin, heparin-induced thrombocytopenia, lepirudin, low-molecular-weight heparin, warfarin.

Ann Pharmacother 2004;38:247-50. Published Online, 23 Dec 2003, www.theannals.com, DOI 10.1345/aph.1D308

of immune-mediated heparin-induced The incidence(UFH)(HIT) in patients receivingbased on thrombocytopenia unfractionated heparin is approximately 15% data collected in adults.1 The incidence of HIT attributed to low-molecular-weight heparin (LMWH) is significantly lower, estimated to be <1%.2 Much less is known about the incidence of HIT in pediatric patients. The paucity of pediatric cases with documented venous thrombosis and the minimal use of UFH limit the size of the population at risk for HIT. Essentially no information is available about the incidence of HIT in pediatric patients treated with an LMWH. We present a case of probable HIT in a child with Crohns disease.

Case Report
An 11-year-old African American girl (44 kg) was admitted in September 2003 for evaluation of right lower-quadrant pain of 3 4 weeks duration. A computed tomographic study of the abdomen revealed extensive thrombosis of the inferior vena cava from the iliac veins to the hepatic vein, as well as a possible right lower-quadrant mass. The next day she underwent a laparotomy, which revealed an inflammatory mass approximately 4 cm in diameter next to the small bowel in the region of the iliocecal valve. The appendix was normal, but significant mesenteric lymphadenopathy was present. Crohns disease was diagnosed at that time. After resection of the mass and construction of an ilio-cecostomy, she was treated with antibiotics and anticoagulated for 9 days using intravenous UFH. A workup for a thrombophilic disorder showed a weakly positive antinuclear antibody test, with no evidence for anticardiolipin antibody. Factor V Leiden and prothrombin gene mutation were not present, and homocysteine and antithrombin levels were normal. Anticoagulation was continued using warfarin after the surgery. International normalized ratio (INR) values over the 3-month period of warfarin treatment were consistently in the range of 2.03.0.
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Author information provided at the end of the text.

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In January 2003, warfarin was discontinued prior to an elective colonoscopy; enoxaparin 1.5 mg/kg once daily was started at that time. Repeat abdominal computed tomography showed a phlegmon in the right lower quadrant, as well as evidence of thrombosis from the iliac veins to the hepatic vein, with interval development of extensive collaterals. Compared with the earlier study, there were signs suggesting the thrombus may have extended into the right hepatic vein; otherwise, there was no evidence of new thrombosis. After the colonoscopy, the patient remained on a therapeutic dose of enoxaparin 60 mg (1.5 mg/kg) subcutaneously once a day. In March 2003, 6 weeks after starting enoxaparin treatment, she began to have right facial swelling and bilateral ankle swelling. An ultrasound examination showed that the thromboses had extended to the superior vena cava, with right axillary and right jugular thrombosis. In addition, the thrombus had propagated distally into the femoral veins bilaterally. The patient was readmitted to the hospital and treated for 2 days using intravenous UFH, which was switched to enoxaparin 40 mg twice daily for 3 days during the time when warfarin therapy was initiated. However, an anticoagulation service consultation noted that the patients platelet count had dropped to 280 103/mm3 at the time of admission, decreasing further to 233 103/mm3 during intravenous heparin therapy, which represented a significant fall from previous values of 550700 103/mm3 in September and October 2002 and 468 103/mm3 in January 2003. The possibility of HIT was entertained just as the patient was being discharged. A quantitative d-dimer level (Advanced, Dade-Behring) showed an elevation at just below 2 times the upper limit of normal (2.9 mg/L, normal 1.5). An enzyme-linked immunosorbent assay (ELISAGTI Industries, Brookfield, WI) for HIT-associated antibody to heparinplatelet factor 4 was strongly positive. When the HIT antibody test result returned, the patient was immediately readmitted to the hospital. She was started on intravenous lepirudin, without a bolus dose, at a rate of 0.1 mg/kg/h titrated to 0.13 mg/kg/h to maintain an activated partial thromboplastin time (aPTT) 1.52.5 times control. Because the INR was elevated at 2.8 at the time lepirudin was started, intravenous vitamin K 2 mg was given. After 3 days of lepirudin, the d-dimer fell to 1.4 mg/L and the platelet count increased to 300 330 103/mm3. Warfarin was restarted on day 4 of lepirudin therapy, and the patient eventually was discharged after a therapeutic INR was achieved. Over the next 2 months, there was no clinical or ultrasound evidence of clot extension, and repeat d-dimer testing revealed normal values, as well as therapeutic INR values.

Discussion Because of the limited need to use heparin in pediatric patients, cases of HIT and descriptions of the use of direct thrombin inhibitors (DTIs) are rare. In fact, the incidence of HIT in the pediatric age group is largely unknown. A retrospective review evaluated the incidence of HIT or HIT antibody in 612 patients admitted to a pediatric intensive care unit who received at least 5 days of heparin therapy.3 Serologic confirmation of the presence of the HIT antibody was done using an enzyme-linked absorbance assay (ELISA; Asserachrom, Diagnostica, Asnieres-sur-Seine, France). The incidence of HIT with associated thrombosis was 2.3% (14 pts.). The median platelet nadir was 58 103/mm3 (range 27191 103/mm3), and thrombosis occurred a median of 10 days (range 5 45) after the start of heparin therapy. Death or limb amputation did not occur in any of the patients. The majority of these children had undergone open-heart surgery. Details of treatment were not provided. In a retrospective analysis of a large pediatric tertiary care center population over a 2-year period, the author suggested that the incidence might be lower.4 Published information on the management of HIT in pediatric patients is limited. Danaparoid has been successfully used in children with HIT aged 12 days to 15 years.4-10
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Several of the patients were successfully transitioned to warfarin.6-8 Unfortunately, danaparoid is not available in the US, and given its long half-life, lack of an easy means to monitor its anticoagulation effects, as well as no available reversal agent, limits it as a preferable agent. In adults, DTIs (argatroban or lepirudin) are considered the preferred initial treatment for adults with HIT based on beneficial outcomes observed compared with historical controls.11,12 Very little information is available on the use of DTIs in pediatric patients. There are reports of 3 children with HIT who were treated with argatroban: a 6month-old infant who underwent cardiac catheterization13 and 2 neonates on extracorporeal membrane oxygenation (ECMO) treated for 6 and 78 days, respectively.14 Continuous intravenous argatroban was administered at doses ranging from 0.5 to 10 g/kg/min to maintain activated clotting time (ACT) values of approximately 200 seconds. There was no evidence of intracranial bleeding or cannula site hemorrhage and no need to replace the oxygenator or ECMO circuit. Argatroban is eliminated by the liver and may be preferred in patients with renal failure. However, argatroban is also associated with false elevations in INR values, making the transition to warfarin challenging.15 Bivalirudin is another DTI with a shorter elimination halflife that has potential for use in HIT once in vivo supportive data are gathered. Bivalirudin has been studied in vitro for anticoagulation of neonatal ECMO circuits. No change in the ACT was noted during ECMO.16 Presently, experience with the use of bivalirudin in treatment of HIT is limited. In one case report, a 12-year-old child with HIT and associated thrombosis was managed using a bolus dose of lepirudin 0.2 mg/kg followed by an infusion dose that ranged from 0.1 to 0.7 mg/kg/h to maintain the aPTT around 5080 seconds for 8 days.17 Another case involved an 11-year-old child with HIT and thromboembolism. Lepirudin was infused at 0.150.22 mg/kg/h for 58 days.18 A 30-week gestational neonate with positive HIT antibodies unresponsive to danaparoid 2.0 2.4 units/kg/h (with anti-Xa levels 0.20.4 units/mL) was successfully treated with lepirudin 0.03 0.05 mg/kg/h (aPTT 1.52 control).19 No serious adverse events occurred in either case. In our patient, HIT was highly suspected (rated as possible on the Naranjo probability scale) as the likely cause of the thrombosis that occurred during treatment using therapeutic doses of enoxaparin.20 The Naranjo probability scale may not, however, serve as an accurate tool to test for HIT. Another pretest probability tool specifically developed for HIT has been recently proposed. Using this tool, a high probability for HIT was calculated.12 Vitamin K was given to reverse the warfarin effects out of concern for hemorrhage with the combined therapy, to remove any effect warfarin had on the aPTT for accurate dosing assessment for the lepirudin, and to avoid any potential for warfarin-associated venous gangrene. Lepirudin was initiated at a lower infusion rate of 0.1 mg/kg/h secondary to concerns for bleeding because the patient had been treated with warfarin and had an INR of 2.8. This dose of lepirudin was selected based on reports of the efwww.theannals.com

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fectiveness of this dose in isolated (nonthrombotic) HIT and our desire to minimize the risk of bleeding.21 After a slight increase of the lepirudin dose to 0.13 mg/kg/h, the aPTT values remained in the target range of 1.52.5 times the control value. The dosing was consistent, if not slightly higher, with the aPTT dose response seen in adults.11,21 Lepirudin is primarily excreted by the kidney and has a volume of distribution of 1219 L, indicating that most of the drug distributes to extracellular fluid.18,22 Based on this, one can postulate that higher doses on a milligram per kilogram basis may be needed in younger pediatric patients who have a higher proportion of their body weight as extracellular fluid and higher renal drug clearance compared with adults. Summary

4. 5.

6.

7.

8.

9.

10.

As reported in adults, this case illustrates the fact that HIT can develop in a pediatric patient with platelet counts in the normal range. The platelet count had fallen to 233 103/mm3 from higher values in the range of 468 103/mm3 6 weeks previously. Thus, although the value was normal, the platelet count had fallen approximately 50% from the earlier elevated level, which is one of the principal criteria for HIT. This emphasizes the fact that the relative fall in the platelet count may be a better measure of the effect of HIT antibody than the absolute value of the platelet count. Based on adult data, DTIs appear to be the most effective initial treatment for HIT. Careful, frequent monitoring is, of course, necessary. Since there are few data regarding use of DTIs in the pediatric age group, it is not clear whether there are any potential advantages or disadvantages with any single agent currently available.
We acknowledge the assistance of TE Warkentin MD in grading the HIT probability of this case.

11. 12. 13.

14.

15.

16.

17.

William E Dager PharmD FCSHP, Pharmacist Specialist, Department of Pharmaceutical Services, University of California, Davis Medical Center, Sacramento, CA; Clinical Professor of Pharmacy, School of Pharmacy, University of California at San Francisco; Associate Clinical Professor of Medicine, University of California, Davis School of Medicine Richard H White MD, Professor of Medicine; Medical Director, Anticoagulation Service, University of California, Davis Medical Center; Professor of Clinical Medicine, University of California, Davis School of Medicine Reprints: William E Dager PharmD FCSHP, Department of Pharmaceutical Services, University of California, Davis Medical Center, 2315 Stockton Blvd., Sacramento, CA 95817-2201, fax 916/7034031, william.dager@ucdmc.ucdavis.edu

18. 19.

20.

21.

22.

thrombocytopeniaassociated thrombosis in pediatric intensive care patients. Pediatrics 2002;109:E10. Newall F, Barnes C, Ignjatovic V, Monagle P. Heparin-induced thrombocytopenia in children. J Paediatr Child Health 2003;39:289-92. Neuhaus TJ, Goetschel P, Schmugge M, Leumann E. Heparin-induced thrombocytopenia type II on hemodialysis: switch to danaparoid. Pediatr Nephrol 2000;14:713-6. Wilhelm MJ, Schmid C, Kececioglu D, Mollhoff T, Ostermann H, Scheld HH. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using ORG 10172. Ann Thorac Surg 1996;61:920-4. Klement D, Rammos S, von Kries R, Kirschke W, Kniemeyer HW, Greinacher A. Heparin as a cause of thrombus progression. Heparin-associated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts. Eur J Pediatr 1996; 155:11-4. Saxon BR, Black MD, Edgell D, Noel D, Leaker MT. Pediatric heparininduced thrombocytopenia: management with danaparoid (Orgaran). Ann Thorac Surg 1999;68:1076-8. Zohrer B, Zenz W, Rettenbacher A, Covi P, Kurnik K, Kroll H, et al. Danaparoid sodium (Orgaran) in four children with heparin-induced thrombocytopenia type II. Acta Paediatr 2001;90:765-71. Ranze O, Ranze P, Magnani HN, Greinacher A. Heparin-induced thrombocytopenia in paediatric patientsa review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr 1999;158(suppl 3):S130-3. Dager WE, White RH. Pharmacotherapy of heparin-induced thrombocytopenia. Expert Opin Pharmacother 2003;4:919-40. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003;121:535-55. Boshkov LK, Thomas G, Kirby A, Shen I, Swanson V, Burch G, et al. Pharmacokinetics of argatroban infusion in a 6 month old congenital cardiac patient with previously diagnosed heparin-induced thrombocytopenia (HIT) (abstract). Blood 2002;100:269a. Kawada T, Kitagawa H, Hoson M, Okada Y, Shiomura J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin North Am 2000;14:445-57. Hursting MJ, Zehnder JL, Joffrion JL, Becker JC, Knappenberger GD, Schwarz RP. The international normalized ratio during concurrent warfarin and argatroban anticoagulation: differential contributions of each agent and effects of the choice of thromboplastin used. Clin Chem 1999; 45:409-12. Yonekawa KE, Nugent DJ, Young G. Use of bivalirudin for anticoagulation of a neonatal extracorporeal membranous oxygenation (ECMO) circuit (abstract). Blood 2002;100:129b. Schiffman, Unterhalt M, Harms K, Figulla HR, Volpel H, Greinacher A. [Successful treatment of heparin-induced thrombocytopenia (HIT) type II in childhood with recombinant hirudin.] German. Monatsschr Kinderheilkd 1997;145:606-12. Prescribing information. Refludan (lepirudin (rDNA) for injection). Wayne, NJ: Berlex Laboratories. Nguyen TN, Gal P, Ransom JL, Carlos R. Lepirudin Use in a neonate with heparin-induced thrombocytopenia. Ann Pharmacother 2003;37: 229-33. DOI 10.1345/aph.1C224 Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. Lubenow N, Eicher P, Lietz T, Greinacher A. Meta-analysis of the three prospective studies of lepirudin in the prevention of thrombosis in patients with heparin-induced thrombocytopenia (abstract). Blood 2002;100: 501a-2b. Vanholder R, Camez A, Veys N, van Loo A, Dhondt AM, Ringoir S. Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients. Thromb Haemost 1997;77:650-5.

References
1. 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;96:1703-8. 2. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with lowmolecular weight heparin or unfractionated heparin. N Engl J Med 1996;101:502-7. 3. Schmugge M, Risch L, Huber AR, Benn A, Fischer JE. Heparin-induced
EXTRACTO
OBJETIVO: Reportar un caso de trombosis venosa aguda probable causada por trombocitopenia inducida por heparina (TIH) en una paciente peditrica con un contaje normal de plaquetas luego de terapia prolongada con enoxaparina. RESUMEN DEL CASO: La paciente es una nia de 11 aos en la cual ocurri trombosis extensa de la vena cava concurrentemente con el diagnstico

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de enfermedad de Crohn. Su trombosis de vena profunda (TVP) fue tratada con heparina intravenosa no fraccionada seguida por terapia ambulatoria extendida con warfarina. Cuatro meses despus, la warfarina fue descontinuada y substituida por enoxaparina subcutnea 1.5 mg/kg una vez al da antes de 1 colonoscopa electiva. Ella se readmiti 6 semanas despus con TVP aguda y contaje de plaquetas de 233 103/mm3, el cual era significativamente menor que un contaje de 550700 103/mm3 obtenido 5 meses antes y un ltimo contaje de 468 103/mm3. Una prueba ELISA para medir anticuerpos de heparina factor 4 de plaquetas fue positivo y un d-dmero estuvo elevado a 2.9 mg/L (normal <1.5). La paciente fue tratada con lepirudina seguida por warfarina. Esto se hizo cuando el d-dmero repetido al tercer da estaba normal, la prueba de ultrasonido repetida no demostr extensin del cogulo, y el contaje de plaquetas haba aumentado sobre 300 103/mm3. No hubo trombosis adicionales dentro de los prximos 4 meses. DISCUSIN: La TIH parece ser rara en la poblacin peditrica y slo unos pocos casos tratados con un inhibidor directo de trombina han sido reportados. Una caracterstica interesante de este caso es el desarrollo de TIH a pesar de un contaje normal de plaquetas, lo cual es raro, pero ha sido reportado en adultos. CONCLUSIONES: Este es un caso de trombosis asociada a TIH probable que se desarroll en una paciente joven que estaba siendo tratada con enoxaparina. El tratamiento con el inhibidor directo de trombina, lepirudina, fue exitoso con control de trombosis y regreso a valores ms altos del contaje de plaquetas.
Juan F Feli
RSUM

Une patiente de 11 ans, souffrant de la maladie de Crohn, a prsent une thrombose extensive de la veine cave. La thrombose veineuse profonde (TVP) a t traite initialement avec de lhparine intraveineuse non fractionne suivie dune anticoagulothrapie orale la warfarine. Quatre mois plus tard, la warfarine tait cesse en prvision dune colonoscopie lective et un traitement lnoxaparine souscutane (1.5 mg/kg 1 fois par jour) tait alors dbut. La patiente fut radmise 6 semaines plus tard avec une TVP. A ce moment, le dcompte des plaquettes tait de 233 103/mm3, une valeur normale mais significativement plus basse que celle note 5 mois plus tt (550 700 103/mm3). Un test ELISA permettant la dtection des anticorps antihparine/facteur-4-plaquettaire tait fortement positif et les d-dimres taient augments 2.9 mg/L (normale <1.5). Elle fut traite avec de la lpirudine puis de la warfarine. Au jour 3, les d-dimres staient normaliss, lchographie dmontrait labsence dextension du caillot, et le dcompte des plaquettes tait suprieur 300 103/mm3. Aucun vnement thrombotique nest survenu au cours des 4 mois suivants. DISCUSSION: La TIH est rare dans la population pdiatrique et seuls quelques cas traits avec un inhibiteur direct de la thrombine ont t rapports. Ils sagirait du premier cas pdiatrique de TIH associe lnoxaparine. Une caractristique intressante dans le prsent cas est la survenue dune TIH avec dcompte normal des plaquettes, un phnomne rare mais rapport chez ladulte. CONCLUSIONS: Les patients pdiatriques recevant une hparine de bas poids molculaire sont aussi risque de prsenter une TIH. Le traitement initial de la TIH devrait impliquer lutilisation dun inhibiteur direct de la thrombine afin de traiter la thrombose et ce jusqu ce que le dcompte des plaquettes retourne des valeurs plus leves. Par la suite, un relais avec la warfarine pourra tre envisag pour le traitement long terme de la thrombose.
RSUM:

Rapporter un cas probable de thrombose veineuse cause par une thrombocytopnie lhparine (TIH) survenue suite un traitement prolong lnoxaparine chez une patiente pdiatrique avec dcompte normal des plaquettes.
OBJECTIF:

Alain Marcotte

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