Successful administration of eltrombopag in preparation for peritoneal dialysis catheter placement in a girl with MYH9-related disease

Abstract

MYH9-related disease is an autosomal dominant disorder characterized by macrothrombocytopenia, nephropathy, inclusion bodies in leukocytes, sensorineural hearing loss, and cataract. Severe cases require kidney replacement therapy in the patient’s second decade of life; thrombocytopenia constitutes a major risk factor for hemorrhagic complications during dialysis initiation or kidney transplantation. Prophylactic platelet transfusion prior to surgery is commonly administered to affected patients in these cases. However, transfusion in such patients has limitations other than the general risk of allergic reactions and blood-borne infections; it may also trigger alloimmunization, leading to platelet transfusion resistance or the development of anti-donor antibodies in potential kidney transplant recipients. Here, we describe prophylactic administration of eltrombopag, an oral thrombopoietin receptor agonist, prior to laparoscopic peritoneal dialysis catheter placement in a 15-year-old girl with MYH9-related disease. Her platelet count was approximately 30 × 10³/μL at baseline; it increased to 61 × 10³/μL on the day before surgery, thereby avoiding the need for platelet transfusions. There were no major bleeding or adverse events associated with eltrombopag administration. Thus, eltrombopag may be a safe and effective alternative to prophylactic platelet transfusions in patients with MYH9-related disease.

Introduction

MYH9-related disease is an autosomal dominant disorder characterized by macrothrombocytopenia, nephropathy, inclusion bodies in leukocytes, sensorineural hearing loss, and cataract. It is caused by mutations in the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA. Although all affected patients exhibit macrothrombocytopenia, the other phenotypes are highly variable; consequently, this disease was regarded as four separate syndromes (May–Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome) prior to identification of the causative gene [1, 2]. Severe cases lead to end-stage kidney disease in the patient’s second decade of life; the risk of thrombocytopenia-related hemorrhagic complications is a major concern when initiating kidney replacement therapy.

Prophylactic platelet transfusion is commonly used to increase platelet count prior to surgery. However, the disadvantages of transfusion in patients with MYH9-related disease are not limited to the general risks of allergic reactions and blood-borne infections; they also include the risk of alloimmunization, which may result in platelet transfusion resistance or the development of anti-donor antibodies in potential kidney transplant recipients.

Recently, there have been reports regarding the use of eltrombopag, an oral thrombopoietin receptor agonist, for the treatment of thrombocytopenia or for surgical preparation in patients with MYH9-related disease [3–8]. In those reports, eltrombopag was generally effective and well tolerated; however, there is minimal literature focused on the pediatric. To our knowledge, there has been no report of patients beginning peritoneal dialysis (PD) during the administration of eltrombopag.

Here, we describe prophylactic administration of eltrombopag prior to laparoscopic PD catheter placement in a 15-year-old girl with MYH9-related disease. The treatment avoided the need for platelet transfusion without causing adverse effects.

Case report

A 15-year-old girl was referred to our institution for the initiation of PD. She exhibited normal physical and mental development. Proteinuria was first detected during a routine school urinalysis when she was 6 years old, and further evaluation showed macrothrombocytopenia. MYH9-related disease was suspected based on platelet morphology. When the patient was 9 years old, genetic testing revealed a heterozygous R702C missense mutation in the motor domain of the MYH9 gene; this mutation is responsible for the most severe phenotype, including nephropathy that progresses to end-stage kidney disease in the second decade of life [9, 10]. The patient’s kidney function gradually declined, and she progressed to end-stage kidney disease at the age of 15 years. No inclusion bodies were present in the patient’s leukocytes, hearing was normal in both ears, and no cataract was observed in either eye. Although the patient had no family history of kidney disease or hematological disease, her father had died of pancreatic cancer at the age of 43 years.

The use of eltrombopag in this patient was approved by the Institutional Review Board for Off-Label Drug Use at Tokyo Women’s Medical University (No. 2022111). Platelet count and the dosage of eltrombopag over time are shown in Fig. 1. The patient’s platelet count at baseline was approximately 30 × 10³/μL. Three weeks prior to PD catheter placement, prophylactic use of eltrombopag was initiated at a dose of 25 mg daily, with a target platelet count of 50 × 10³/μL. Since there was no response, the dose was increased to 75 mg daily at 13 days prior to surgery. On the day before surgery, the patient’s platelet count had increased to 61 × 10³/μL, thereby avoiding the need for platelet transfusion. Laparoscopic PD catheter placement and partial omentectomy were performed as scheduled. Laparoscopic observation of the right internal inguinal ring showed a patent canal of Nuck, which is a potential cause for inguinal hernia and PD malfunction; it was concomitantly closed by open surgery. The estimated blood loss was 5 mL; the patient’s postoperative course was uneventful, without major bleeding or leakage around the PD catheter site. Eltrombopag was administered until postoperative day 5. PD was initiated on postoperative day 7 with a fill volume of 500 mL (316 mL/m²), which was gradually increased to 1600 mL (1017 mL/m²). There were no adverse events associated with eltrombopag administration.

Fig. 1.

Platelet count and dosage of eltrombopag over time. Dotted line indicates day of surgery. Baseline platelet count was approximately 30 × 10³/μL. Eltrombopag 25 mg daily was initiated 3 weeks prior to surgery, increased to 75 mg daily at 13 days prior to surgery, and continued at the same dose until postoperative day 5. Platelet count had increased to 61 × 10³/μL on the day before surgery

Discussion

Eltrombopag is an oral thrombopoietin receptor agonist approved by the Japanese Ministry of Health, Labour and Welfare for the treatment of chronic immune thrombocytopenic purpura and aplastic anemia. Recently, there have been studies regarding the use of short-term eltrombopag in patients with MYH9-related disease, with the goal of avoiding the risks of transfusion. Pecci et al. administered eltrombopag 50–75 mg daily for 3–6 weeks to 12 patients with platelet counts < 5 × 10³/μL [3]. A response in terms of platelet count was observed in 11 of 12 patients; remission of spontaneous bleeding was achieved in eight of the 10 patients who exhibited this symptom at baseline. Zaninetti et al. described 11 cases of surgical procedures in five patients who received prophylactic eltrombopag [4]. In 10 of 11 cases (four of five patients), the platelet count increased to a level that avoided the need for transfusion; the procedures were safely performed without bleeding complications. Zaninetti et al. also conducted a phase 2 clinical trial in which 24 patients with inherited thrombocytopenias, including nine with MYH9-related disease, received eltrombopag 50–75 mg/day for 3–6 weeks [5]; all patients with MYH9-related disease responded to treatment. In all three studies, eltrombopag was well tolerated with mild adverse effects. In addition to the cases described in these studies, three case reports have been published regarding patients with MYH9-related disease who received short-term eltrombopag prior to surgical procedures [6–8]. The need for transfusion was avoided in all three patients, and no hemorrhagic complications were observed.

Our patient received a similar dosage of eltrombopag with comparable outcomes and no adverse effects. No dosage adjustment for kidney dysfunction was necessary [11]. According to current guidelines, prophylactic platelet transfusion is suggested for patients with a platelet count < 50 × 10³/μL who are undergoing major elective surgery [12]. In previous reports, platelet responses were reproducible over time in patients who received eltrombopag multiple times [4]; thus, there is a strong possibility that our patient will achieve a platelet count above this threshold during the receipt of prophylactic eltrombopag for future surgical procedures. However, several case reports have described hemorrhagic complications in patients with MYH9-related disease who underwent kidney transplantation, although their platelet counts remained > 50 × 10³/μL [13, 14]. Therefore, a platelet count > 100 × 10³/μL during the perioperative period has been recommended for safe kidney transplantation in these patients [15]. With respect to our patient, eltrombopag may be insufficient as a sole treatment for achieving a platelet count > 100 × 10³/μL; nonetheless, it may help to reduce the volume of transfusion and mitigate the risk of hemorrhagic complications.

Exposure to human leukocyte antigens (HLAs) through transfusion may trigger anti-HLA antibody production. Kidney transplant recipients with preformed anti-HLA antibodies reactive against the donor (i.e., donor-specific antibodies) have higher risks of hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection [16]. In deceased-donor transplant candidates, the presence of anti-HLA antibodies increases the risk of a positive crossmatch with the donor; this increased risk may lead to prolonged waiting times for transplantation [17]. Therefore, patients with MYH9-related disease, particularly patients with a mutation in the motor domain, will benefit from avoiding the need for transfusion because they may require a kidney transplant in the future.

In summary, we have described a patient with MYH9-related disease who received prophylactic eltrombopag prior to laparoscopic PD catheter placement. Eltrombopag may be a safe and effective alternative to prophylactic platelet transfusions in patients with MYH9-related disease; it is particularly beneficial in potential kidney transplant recipients because it helps to reduce the risk of donor-specific antibody development.

Declarations

Conflict of interest

The authors have declared no conflict of interest.

Human and animal rights statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent for genetic testing and off-label use of eltrombopag was obtained from the patient and her guardian.