Heparin-induced thrombocytopenia (HIT) is a problem at any cardiac surgery center, but there are few reports of the management of pediatric patients with HIT requiring cardiac surgery (1,2). We report a case of an infant with HIT requiring a bidirectional Glenn shunt who was successfully managed using lepirudin (r-hirudin, Refludan; Aventis, Bridgewater, NJ), a direct thrombin inhibitor. Dosing and monitoring of anticoagulation proved difficult.
A 4-mo-old, 5.7-kg male patient with hypoplastic left heart syndrome who had had a modified Norwood procedure with right ventricle (RV) to pulmonary artery conduit presented with cyanosis. An echocardiogram revealed a thrombus in the right atrium with decreased conduit flow, and heparin therapy was instituted. When thrombocytopenia (39 × 109/L) was identified, studies were requested for heparin/platelet factor 4 (PF4) antibodies. The patient had been exposed to heparin during the initial cardiac surgery and in the line flushes during the recovery phase. He had been discharged on aspirin therapy.
Cardiac catheterization demonstrated a RV end-diastolic pressure of 5 mm Hg and bilateral femoral vein occlusion. The right femoral vein occlusion had been identified at the time of the first hospitalization. Heparin/PF4 antibodies were reported and heparin was discontinued. A lepirudin infusion was established and the activated partial thromboplastin time (aPTT) was maintained at 50 s. It was decided to proceed with a superior cavopulmonary anastomosis (bidirectional Glenn shunt) to allow improved pulmonary blood flow without increasing ventricular volume work. The platelet count at that time was 223 × 109/L.
Anticipating cardiopulmonary bypass (CPB), it was decided to use lepirudin for anticoagulation, and the normal plasma-modified activated clotting time (ACT-NP), for intraoperative monitoring of anticoagulation (3). As the dissection proceeded, the surgeon determined that he would be able to perform the procedure without CPB. The patient was then given 0.25 mg/kg lepirudin. (Table 1.) Activated clotting time (ACT) (Hemochron, Edison, NJ), ACT-NP, and aPTT were measured at baseline, 10 minutes after each lepirudin bolus, and at the end of the procedure (Table 1). When the anastomosis was completed, the lepirudin infusion was stopped, and restarted 1 h later when the aPTT was within the preoperative target range. The estimated blood loss was 50 mL.
There was no significant bleeding in the postoperative period. The patient’s late postoperative course was complicated by concerns of necrotizing enterocolitis for which he returned to the operating room for exploration. During his hospitalization, he continued lepirudin therapy for his thrombi and was eventually transitioned to warfarin. He recovered after several weeks and was discharged on aspirin and warfarin. On a follow-up outpatient echocardiogram, the atrial thrombus was noted to have resolved, and warfarin was discontinued.
HIT Type II is an immune-mediated complication of heparin therapy that can cause thrombotic complications. It differs from Type I by the presence of antibodies and the severity of thrombocytopenia (4). Although there is substantial literature concerning adults with HIT undergoing CPB (5–9), there is no consensus for therapy and there is minimal literature addressing the issue in infants (1,2).
Alternatives to heparin anticoagulation for patients with HIT include direct thrombin inhibitors, such as lepirudin, bivalirudin, and argatroban, and heparin with platelet inhibition (using prostacyclin or tirofiban) to prevent heparin-related platelet activation and aggregation. Danaproid has been used but is not available in the United States. These lack the predictability, ease of monitoring, and reversibility of heparin. Lepirudin is a recombinant hirudin, which is an anticoagulant produced by the salivary gland of the leech. It binds thrombin at the fibrinogen-binding and catalytic sites, binding both free and clot-bound thrombin (10). Bivalirudin is a synthetic peptide that also directly binds the fibrinogen binding site and the catalytic site of thrombin. It is distinguished from lepirudin by its reversible binding and shorter half-life. It is now being investigated for use in CPB (10). Argatroban is another synthetic molecule that directly inhibits thrombin. Its use was recently reported for CPB in an infant with HIT; the patient experienced extensive bleeding and continuing coagulopathy, and difficulty monitoring the extent of anticoagulation (1). Lepirudin has been shown to be safe for adults requiring CPB and has been used in the therapy of HIT in pediatrics (11,12). Preoperatively our patient had a therapeutic response by anticoagulation testing (aPTT maintained at 50 seconds).
The dosing of lepirudin in adults for CPB varies (5,6,13,14), and the dosing in children is not defined. The most frequently reported adult dose is 0.25 mg/kg IV bolus with 0.2 mg/kg added to the CPB priming solution (5,6,15). Based on the adult dosing, and considering the increased volume of distribution for infants, we planned a bolus of 0.5 mg/kg before CPB and 5 mg added to the pump prime (approximate volume, 900 mL). Without CPB, we administered 0.25 mg/kg of lepirudin, resulting in an ACT of 259 seconds and an ACT-NP of 258 seconds. After repeating the dose, the ACT was 281 seconds and the ACT-NP was 325 seconds; these were expected to be adequate for vascular surgery.
Our anticoagulation measurements suggest that monitoring anticoagulation at the large concentrations of lepirudin required for CPB (4) would have been difficult. The aPTT is adequate for antithrombotic therapy but not for CPB because of the long measurement time (frequently more than 1 hour) and a range limited to low anticoagulation levels (10,14,16). Similarly, the range of the ACT is inadequate to resolve high lepirudin levels (3). The ECT (Ecarin clotting time) (14) is no longer available. Use of Ecarin with the ACT II device has also been reported (17). The ACT-NP has been reported (3,13) to be a point-of-care coagulation test that is returned rapidly, is easy to perform using available equipment, and is relatively linear in the range of anticoagulation we needed. We attempted to use the ACT-NP, which involves diluting the blood sample one-to-one with pooled normal plasma, then measuring a standard ACT. The addition of plasma to patient blood is to ameliorate the dilutional effects of CPB on prothrombin levels (3) and to produce a more linear dose-response curve in the therapeutic range for lepirudin.
The ACT-NP did not correlate with the other tests as predicted (3). Based on the reported dose-response curves, we predicted that the ACT would be higher for the doses of lepirudin given. Without CPB, the infant’s blood volume was not hemodiluted, and the addition of plasma was likely unnecessary. The pooled normal plasma was fresh, so there should not have been degradation of clotting factors.
This case emphasizes the need to define alternatives for anticoagulation methods and monitoring for infants requiring cardiovascular surgery. Lepirudin doses have not been established for infants, with or without CPB. In our patient, significantly larger-than-reported doses would have been necessary if CPB had been required. At large concentrations of lepirudin, commonly used monitors are inadequate. If the ECT test becomes available, it has not been characterized in infants. The ACT-NP might be a reasonable alternative, but a standardized method of performing this test must be defined. In our opinion, alternatives to lepirudin should be considered until there is a reliable method of monitoring the degree of anticoagulation with lepirudin.
The authors thank Dr. James Robotham and Dr. Denham Ward for assistance preparing the manuscript.
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