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Epoprostenol Therapy for a Pediatric Patient With Subacute Heparin-Induced Thrombocytopenia and a Ventricular Assist Device Undergoing Heart Transplant: A Case Report

Navaratnam, Manchula MBChB, FRCA*; Williams, Glyn D. MBChB, FFA (SA)*; Shuttleworth, Paul BSN, MBA, CCP; Almond, Chris MD; Maeda, Katsuide MD, PhD§

doi: 10.1213/XAA.0000000000000818
Case Reports
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Concerns remain regarding the use of direct thrombin inhibitors for cardiopulmonary bypass anticoagulation in pediatric patients with heparin-induced thrombocytopenia undergoing complex cardiac surgery. We describe the safe and effective use of epoprostenol sodium as an alternative therapy before heparin exposure for a pediatric patient with subacute heparin-induced thrombocytopenia and a ventricular assist device undergoing heart transplant.

From the *Department of Anesthesiology, Perioperative and Pain Medicine

Department of Cardiovascular Perfusion, Stanford Hospital and Clinics

Division of Cardiology, Department of Pediatrics

§Department of Cardiothoracic Surgery, Stanford Children’s Hospital, Stanford University Medical Center, Palo Alto, California.

Accepted for publication May 8, 2018.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Manchula Navaratnam, MBChB, FRCA, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford Children’s Hospital, Stanford University Medical Center, Palo Alto, CA. Address e-mail to manchuln@stanford.edu.

Heparin-induced thrombocytopenia (HIT) is a complex, immune-mediated interaction between heparin and platelets resulting in thrombocytopenia and a prothrombotic state.1 HIT has a 1%–3% incidence rate in pediatric patients with congenital heart disease after a 1-week exposure to unfractionated heparin and a thrombotic mortality and morbidity rate of 22% and 66%, respectively.2

There is no consensus on the optimal management of HIT in pediatric patients requiring cardiopulmonary bypass (CPB). Expert guidelines recommend bivalirudin (a direct thrombin inhibitor [DTI]) as the anticoagulant of choice instead of heparin during urgent CPB in adult patients who are HIT antibody positive.3 DTIs have a relatively long half-life and lack specific reversal agents. Adult studies have shown a 5%–10% risk of clinically significant bleeding associated with DTIs.4 Although DTIs such as bivalirudin and argatroban have been used successfully for pediatric cardiac surgery, there are limited published data on the use of these agents for pediatric CPB with varying dosing strategies and a lack of validated monitoring to guide dosing.5 A recent pediatric case report described extracorporeal circuit thrombus formation and massive post-CPB hemorrhage associated with the use of a DTI for CPB.5

Epoprostenol sodium (Flolan GlaxoSmithKline, Research Triangle Park, NC) is a prostaglandin (PGI2), which inhibits intracellular adenylyl cyclase resulting in decreased platelet aggregation.6 It has a short half-life of 6 minutes7 and has been reported in the adult literature as a safe, alternative therapy for HIT antibody-positive patients undergoing CPB.8 To date there is only 1 published case report describing its use during CPB for a pediatric patient with HIT.9 We describe pretreatment with epoprostenol sodium before heparin exposure for CPB in a pediatric patient with subacute HIT and a left ventricular assist device (LVAD) undergoing orthotopic heart transplant. Written consent was obtained for publication of this case report.

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CASE DESCRIPTION

A 15-year-old, 43-kg boy with Becker muscular dystrophy, dilated cardiomyopathy, and decompensating heart failure underwent urgent implantation of a continuous flow LVAD (Heartware II, Framingham, MA) using CPB. He was extubated on postoperative day (POD) 2. An unfractionated heparin infusion was started on POD 4 at 10 IU/kg/h and heparin activity level checked every 4 hours with a goal level of 0.1–0.3 U/mL, as per our institute’s protocol. Oral warfarin sodium anticoagulation commenced on POD 5. Platelet count decreased from 212 × 10−9/L on POD 4 to 46 on POD 6. HIT was diagnosed on POD 7 with a positive platelet factor 4 antibody (PF4Ab) IgG optical density (OD) of 3.115 and a positive HIT functional assay (serotonin release assay [SRA]) without clinically detected thrombi. The heparin infusion was immediately discontinued and LVAD anticoagulation maintained with warfarin and omega III fatty acids. Platelets returned to baseline on POD 10. Six weeks post–ventricular assist device (VAD) implantation, he was discharged to outpatient care with a brief readmission for a transvenous implantable cardioverter defibrillator for ventricular tachyarrhythmias.

He was readmitted 2 months later for heart transplant at which time the preoperative PF4Ab IgG remained positive with an OD of 1.69 despite a normalized platelet count of 326 × 10−9/L categorizing this patient as subacute HIT.3 The most recent SRA (1 week before transplant) was negative. Other preoperative laboratory results included an international normalized ratio of 2.0, fibrinogen 229, activated partial thromboplastin time 37, and hematocrit 32%. On the basis of his elevated PF4Ab titers and history of HIT, we decided to take precautions to prevent HIT recurrence. Because of concerns for irreversible bleeding associated with DTIs, combined with bleeding risks from repeat sternotomy, adhesions, and chronic LVAD anticoagulation, we opted to use intravenous epoprostenol before heparin anticoagulation for CPB as part of an alternative HIT protocol.

During setup of the operating room, we ensured that all arterial and venous flushes were heparin naive. After placement of all hemodynamic monitoring lines, an intravenous infusion of epoprostenol sodium was commenced at 15 ng/kg/min and increased by 5 ng/kg/min every 5 minutes to a goal dose of 30 ng/kg/min. Norepinephrine infusion was started at 0.02 µg/kg/min and titrated to maintain mean arterial pressure >60 mm Hg. The dose of norepinephrine ranged from 0.02 to 0.2 µg/kg/min with the higher dose requirements seen only during CPB. After visualization of the donor heart and before the recipient’s sternotomy, the implantable cardioverter defibrillator was disabled and the international normalized ratio reversed with 10 mg vitamin K and 25 IU/kg of a 4-factor prothrombin complex concentrate (PCC) (Kcentra, CSL Behring, King of Prussia, PA). The patient also received a prophylactic antifibrinolytic agent (aminocaproic acid).

The patient received 450 IU/kg of unfractionated heparin and an activated clotting time (ACT) >400 seconds confirmed before commencing CPB. Anticoagulation on CPB was monitored with the HepCon HMSplus system (Medtronic, Minneapolis, MN), which estimates heparin dose, ACT, and heparin dose response. The total CPB time was 144 minutes with a core temperature of 32°C. The patient received 30 mg/kg methylprednisolone on CPB and an antibody-mediated rejection desensitization protocol with plasmapheresis at the time of CPB initiation (1.5 × volume plasma exchange) and intravenous immunoglobulin 2 g/kg post-CPB. The donor ischemic time (288 minutes) was protracted because of delays at the retrieval hospital. After removal of the aortic cross-clamp and reperfusion of the donor heart, the patient separated from CPB with dopamine 3 µg/kg/min, epinephrine 0.03 µg/kg/min, milrinone 0.5 µg/kg/min, and calcium 20 mg/kg/h as per the standard practice at our institute. Norepinephrine was stopped before CPB termination due to adequate mean arterial pressures. An intraoperative transesophageal echocardiography confirmed good cardiac function and patent venous anastomoses and heparin was reversed with protamine (4.7 mg/kg). Post protamine, the ACT returned to baseline with a heparin concentration of 0. Fifteen minutes after heparin reversal, the epoprostenol infusion was decreased by 5 ng/kg/min every 5 minutes until termination. Post-CPB hemostasis was achieved with 5 mL/kg cryoprecipitate, 16 mL/kg platelets, 10 mL/kg red blood cell concentrate, and 2 doses of 10 IU/kg of 4-factor PCC (FEIBA, Baxter, Deerfield, IL).

During the first 24 hours in the intensive care unit, the total chest tube output was only 9 mL/kg. The patient received 9 mL/kg of red blood cell concentrate but no additional coagulation products. Platelet count was 313 × 10−9/L on POD 0 with a nadir of 159 on POD 3 and increased to 305 × 10−9/L by POD 6. Posttransplant PF4Ab IgG on POD day 10 was 0.686 and decreased to 0.2 by 3 months. There were no thrombi detected clinically or by echocardiography for the first 30 days postoperatively. The patient was extubated on POD 1, discharged from intensive care unit on POD 7, and from hospital on POD 16. The patient is alive and doing well at the time of manuscript writing.

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DISCUSSION

This report describes the safe and effective use of intravenous epoprostenol sodium before heparin exposure for CPB in a pediatric patient with subacute HIT and a LVAD undergoing heart transplant. The CPB flow rate remained stable with no evidence of thrombosis and post-CPB bleeding was not increased, consistent with literature from the adult cardiac surgical population.8 This case report did not find any obvious markers of hypoperfusion while receiving norepinephrine infusion such as reduced urine output or decreased cerebral oximetry. The use of PCCs to reverse warfarin, augment hemostasis after CPB, and reduce blood product exposure has become a common management strategy for complex pediatric heart transplant patients at our institution. This case report also illustrates no complications associated with the use of PCCs and epoprostenol in a patient with subacute HIT.

HIT may be an underestimated cause of morbidity and mortality in the pediatric cardiac population.2 HIT is an immune-mediated reaction involving antibodies (usually IgG) to heparin-PF4 complexes, resulting in platelet consumption, excess thrombin generation, and a prothrombotic state.10 HIT is diagnosed with a clinical scoring system (including timing and extent of platelet count fall and arterial or venous thrombosis) and laboratory testing.3 Two main types of diagnostic testing used are immunoassays that identify heparin-PF4Ab and functional assays such as SRA that evaluate the capacity of PF4Ab to activate platelets.11 Immunoassays (enzyme-linked immunosorbent assay) that only detect IgG appear to have better specificity for HIT because IgM and IgA antibodies are unlikely to cause HIT.3 Although SRA is considered the most sensitive and specific functional assay, it may not be confirmatory in the presence of high heparin-PF4Ab titers12 and is not readily available at all institutions.

The 2012 consensus guidelines from American College of Chest physicians categorize HIT into acute (thrombocytopenic and HIT Ab positive) and subacute HIT (platelet count recovered but remains HIT Ab positive) and state that patients with a history of HIT who remain Ab positive are still at risk of developing rapid-onset HIT on heparin reexposure unless the enzyme-linked immunosorbent assay is only weakly positive (OD <1).3

An increasing number of pediatric patients are bridged to heart transplant with a VAD. These patients are at increased risk for developing HIT due to repeated heparin exposure and platelet activation during CPB.13 The correct diagnosis and treatment choice for HIT has important implications for these patients especially when they present for urgent heart transplant. They are predisposed to significant perioperative bleeding at the time of orthotopic heart transplant due to repeat sternotomy, adhesions, complex vascular reconstructions (if congenital heart disease), liver dysfunction, and chronic VAD anticoagulation. The use of DTIs subjects them to an additional risk of major perioperative bleeding. The use of prostacyclins such as epoprostenol sodium before heparinization for CPB has been well described in adult HIT patients undergoing cardiac surgery,8 but the published pediatric data are limited to 1 case report.9 Epoprostenol may be protective for patients with HIT when heparin is given by inhibiting the heparin antibody-associated aggregation of platelets and thereby reducing the risk of HIT thrombosis and thrombocytopenia. This antiplatelet effect can be seen at doses starting at 10–15 ng/kg/min.14

Prostacyclins before heparin exposure may have a better risk/benefit profile than replacing heparin with DTIs for complex pediatric cardiac surgery in HIT patients. Potential benefits include ease of administration, rapid onset, ability to manage CPB anticoagulation with established methods, reversible protection of platelets, reduced platelet adhesion to the fibers of the CPB membrane oxygenator,15 and reduced perioperative bleeding. The hypotensive side effect of intravenous prostacyclins can be easily mitigated with intravenous norepinephrine.

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CONCLUSIONS

This case report illustrates that pretreatment with epoprostenol sodium before heparin exposure for CPB is a safe and effective therapy for a pediatric patient with a VAD and subacute HIT undergoing heart transplant. Further studies are needed to assess the risk/benefit profile of prostacyclins compared with DTIs for HIT antibody-positive pediatric patients undergoing complex cardiac surgery where the risk of refractory perioperative bleeding is a significant concern.

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DISCLOSURES

Name: Manchula Navaratnam, MBChB, FRCA.

Contribution: This author helped care for the patient and prepare the manuscript.

Name: Glyn D. Williams, MBChB, FRCA.

Contribution: This author helped edit the manuscript.

Name: Paul Shuttleworth, BSN, MBA, CCP.

Contribution: This author helped care for the patient and edit the manuscript.

Name: Chris Almond, MD.

Contribution: This author helped care for the patient and edit the manuscript.

Name: Katsuide Maeda, MD, PhD.

Contribution: This author helped care for the patient and edit the manuscript.

This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.

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REFERENCES

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