Pharmcokinetics of Fondaparinux by Anti-Xa Levels and Clinical Response to Anticoagulation in a 4-Month Old Congenital Cardiac Patient with Heparin-Induced Thrombocytopenia (HIT) and Established Venous Thrombosis Transitioned from Argatroban to Fondaparinux.

Abstract

Our group has recently reported on heparin-induced thrombocytopenia (HIT) as an emerging cause of morbidity and mortality in pediatric cardiac surgery patients (Alsoufi, Ped Card Surg Ann of Sem Thorac Cardiovasc Surg 2004: 7: 155). This has included our experience with the off-label use of the antithrombin argatroban as an initial alternative anticoagulant to heparin in neonates and young children with HIT. Our findings indicate the incidence of HIT in pediatric patients undergoing congenital cardiac surgery to be 1–2% with a thrombotic rate of 50–60%. As with adults, children > 1 year with HIT-related thrombosis needing intermediate-to-longterm anticoagulation can be transitioned to warfarin. However stable warfarinization of children < 1 year is difficult, particularly given the feeding difficulties seen in sick congenital cardiac patients. In one such 4 month old, reported here, we successfully used the pentasaccharide fondaparinux, verifying dosage according to fondaparinux levels as measured by a specific fondaparinux curve. A 3 month old 3 kg girl with Down's syndrome underwent cardiac surgery with cardiopulmonary bypass at our institution (complete atrio-ventricular canal repair, closure of patent ductus arteriosus and patent foramen ovale). Platelets did not rise to baseline levels post-operatively and functional HIT assay was positive on postoperative day (POD) 8. All heparin was stopped and anticoagulation with argatroban initiated after obtaining parental informed consent. Due to IV access issues and necessity for pacemaker insertion argatroban was administered with interruptions. On POD 11 the patient thrombosed a PICC line in her left thigh. The line was surgically removed, but residual non-occulsive thrombus was noted by vascular ultrasound in the left common and proximal femoral veins, which persisted on reimaging 1 week later despite sustained therapeutic argatroban infusion. To facilitate outpatient management a decision was made to attempt transition to fondaparinux. Renal function was normal. After obtaining parental informed consent therapy with fondaparinux ( t 1/2 =17−l20 hr) was initiated at 0.15 mg/kg q 24 hrs on POD 23. Anti-Xa levels were drawn at 2, 4, 8 hr post injection and then at intervals on days 2, 3, 4 and 7 of fondaparinux therapy (see table). Values were referenced against both a fondaparinux and a low molecular weight heparin (lovenox) curve. Coefficient of correlation between curves: r = 0.939. The patient did well clinically on fondaparinux with no evidence of bleeding and was discharged on POD 30. Vascular ultrasound showed complete resolution of thrombus at the time of discharge. Platelets remained stable. The patient continued on outpatient fondaparinux therapy for 3 months with stable platelet counts and no clinical evidence of bleeding or rethrombosis.Response to fondaparinux by anti-Xa levelsDay of therapyHour post injectionFondaparinux Level (fondaparinux curve)Corresponding level on LMWH curveDay 120.330.4140.470.5080.60.60Day 220.70.7340.660.6980.510.51Day 3pre0.180.1950.670.60Day 4pre0.180.3320.710.72Day 520.77not done