We report the case of a patient with type 2 Glanzmann thrombasthenia who underwent successful kidney transplant with his mother’s kidney. He started dialysis at 13 months. The patient had been diagnosed with Glanzmann thrombasthenia at 9 years old, after hemorrhagic shock, during which multiple transfusions were required and hyperimmunization had developed. At 12 years old, he received a kidney transplant. Before transplant, ABO- and HLA-compatible platelet donors were identified and convened to donate for the surgery and in case of emergency. Bleeding was prevented with prophylactic HLA-matched platelet transfusion and tranexamic acid. After transplant, diuresis started immediately with excellent graft function and no severe bleeding. However, after week 5, several episodes of macroscopic hematuria occurred, with obstruction and anuria. The double J ureteric stent was replaced 4 times in 2 months. Finally, the ureteric stent was removed 9 months later. At 22 months after kidney transplant, the patient has a normal graft function and no further bleeding has occurred, underlying the importance of multidisciplinary management.
Key words : Hematuria, Kidney transplant, Platelet dysfunction, Ureteric stent obstruction
For children and adults with end-stage renal disease (ESRD), kidney transplant is the best treatment; however, the procedure is associated with a significant risk of bleeding. Glanzmann thrombasthenia is a rare autosomal recessive1,2 disease caused by defects in the platelet membrane glycoprotein IIb/IIIa complex that can lead to platelet dysfunction.3,4 Incidences of spontaneous or traumatic bleeding usually begin during childhood, and mucocutaneous bleeding is common. The disease often leads to severe complications during surgeries or traumas.5,6 The surgical management of patients with the disease is thus complex due to the unpredictability of the hemorrhagic risk that is at times life threatening.7 Therefore, management of patients with Glanzmann thrombasthenia requires multidisciplinary team coordination and planning of preventive measures.8,9 Several articles have reported surgical interventions of patients with Glanzmann thrombasthenia,10 but none have reported patients with Glanzmann thrombasthenia who have received solid-organ transplant.9 Here, we report the case of a boy with a type 2 Glanzmann thrombasthenia and ESRD secondary to a genetic nephrotic syndrome. He underwent a successful kidney transplant with his mother’s kidney at the age of 12 years.
The patient was born in Algeria from consanguineous parents. The patient has 2 older sisters and 1 brother who died at age 16 months because of ESRD due to nephrotic syndrome. At 11 months of age, the patient was diagnosed with infantile steroid-resistant nephrotic syndrome. Years later, the patient was identified as having a homozygous mutation in the phospholipase C epsilon 1 gene. At 13 months old, he was started on peritoneal dialysis. The patient had several incidences of peritonitis and had 3 peritoneal catheter replacements, with a catheter ultimately placed into the right internal jugular vein. At 9 years old, he was switched to hemodialysis.
At 5 years old, the patient was explored for mild thrombocytopenia (with platelet count between 70 and 130 × 109/L). At 8 years old, he underwent surgery to change his peritoneal dialysis catheter and for posthectomy. During the surgery, he developed hemorrhagic shock, leading to the transfusion of 18 packed red blood cells and 6 platelet concentrates. He was then diagnosed with type 2 Glanzmann thrombasthenia by platelet function tests (platelet aggregation and flow cytometry) and a low glycoprotein IIb/IIIa expression of 20%. A homozygous missense mutation in exon 13 of the ITGB3 gene coding for glycoprotein IIIa was found when the patient and his family moved to France. Once in France, he underwent surgery to remove his peritoneal dialysis catheter. Perioperative bleeding was prevented with the administration of 4 platelet concentrations 1 hour before the surgery and the subsequent detection of transfused platelets, which were monitored by flow cytometry (using glycoprotein IIb/IIIa expression, with an objective of more than 40%). Surgery went well, with adequate glycoprotein IIb/IIIa quantification. Nevertheless, 48 hours after surgery, a wall hematoma appeared, and he needed 2 more surgeries for removal. Platelet transfusions could not maintain a sufficient glycoprotein IIb/IIIa expression, and he was treated with antifibrinolytic (tranexamic acid) and recombinant activated factor VII.
The patient required kidney transplant to limit ESRD morbidity and to improve his quality of life. The initial proposal was to perform transplant with his father’s kidney. The choice of a living donor was mandatory to prevent perioperative hemorrhage. Unfortunately, after the patient received platelet concentrates and packed red blood cells, donor-specific antibodies (DSAs) appeared and crossmatch was positive, thus not allowing this transplant. After multidisciplinary discussions with the French Reference Center for constitutional platelet diseases, pediatric nephrologists, anesthesiologist, and surgeons, a living donation from his mother was accepted.
The patient received immunosuppressive therapy according to the presence before transplant of 3 DSAs (with mean fluorescence intensities of 2158, 3228, and 1785) and negative crossmatch. He was thus treated with 5 days of thymoglobulins, steroids, immunoglobulins, tacrolimus, and mycophenolate mofetil. To prepare for hematologic treatment and platelet concentrate needs, the French Blood Establishment identified platelet donors who were ABO- and HLA-compatible due to our patient’s HLA immunization. These donors were asked to be ready to donate so that fresh platelets (< 48 h before transfusion) were available for the surgery.
The protocol used to prevent the risk of severe bleeding in our patient is outlined in Table 1. Briefly, it consisted of platelet transfusion before surgery and every 8 to 12 hours after surgery during the first 72 hours. The objectives were that the patient needed to have more than 100 × 109/L platelets and an expression of glycoprotein IIb/IIIa by flow cytometry over 40%. Platelet transfusions were then progressively stopped. In total, 8 platelet concentrates were transfused. The efficacy of HLA-matched platelet transfusion was monitored by daily platelet count and flow cytometry (Figure 1). Patient care included treatment with tranexamic acid via continuous intravenous perfusion during surgery (at 10 mg/kg/h), which was continued orally for 10 days (at 30 mg/kg/day). The patient started diuresis immediately at the end of transplant. No severe bleeding was noted during transplant or during the weeks that followed. The patient was discharged 25 days after transplant with normal creatinine level (67 μmol/L) and without any other complication.
At week 5 posttransplant, the patient had multiple episodes of hematuria with blood clots and anuria. During episodes of hematuria, he received daily platelet concentrates (ABO- and HLA-compatible), and tranexamic acid was given orally. In addition, he needed several new double J catheters. The hematuria stopped after the use of a larger double J catheter (removed 9 months after renal transplant), and discontinuation of tranexamic acid was possible 2 months after the first episode. The prevention of bleeding was done with fresh ABO- and HLA-compatible platelet transfusions and tranexamic acid. After 22 months, the patient had normal renal function (serum creatinine level of 54 μmol/L) and no proteinuria. During the first year after renal transplant, DSAs were negative. One DSA became positive again 18 months after kidney transplant, with low mean fluorescence intensity of 1399. We did not perform any systematic graft biopsy due to the high hemorrhagic risk. Interestingly, the platelet transfusion yield was higher after the patient started immunosuppressive treatment and antiplatelet antibodies became concomitantly negative.
To our knowledge, we describe the first case of successful kidney transplant in a pediatric patient with type 2 Glanzmann thrombasthenia. The challenges were double, as the patient had a high hemorrhagic risk and high immunization rate due to previous transfusions. Interestingly, the antiplatelet antibodies became negative after transplant, most likely due to the immunosuppressive treatment he received before and after transplant, leading to a higher platelet transfusion yield.
Multidisciplinary management and coordination efforts between the different teams involved (hematologists, nephrologists, anesthesiologists surgeons, and the blood bank) made this transplant possible. In addition, the use of a living donor allowed our group to anticipate the different complications and to recruit HLA- and ABO-compatible blood donors to provide fresh platelets. In patients with diseases that may lead to solid-organ transplant, the addition of another disease affecting the coagulation process adds complexity to treatment management. When both diagnoses are made early enough, transfusions should be avoided as much as possible, as they can lead to immunization and lower chances of getting a compatible donor.11 This was not the case in our patient due to the hemorrhagic shock he had suffered from before being diagnosed with Glanzmann thrombasthenia.
For patients with Glanzmann thrombasthenia who must undergo surgeries that have a high risk of hemorrhage, platelet transfusions are recommended in association with tranexamic acid. For patients who are refractory to platelet transfusions, other strategies should be considered to prevent bleeding and to reduce the immunologic risk. Indeed, recombinant activated factor VII therapy (NovoSeven, Novo Nordisk Health Care, Bagsvaerd, Denmark) is now available on the market and is effective in preventing the risk of severe hemorrhage in patients with Glanzmann thrombasthenia who must undergo surgery.12 Nevertheless, surgical teams should anticipate unexpected severe bleeding during surgery and have ABO- and HLA-compatible platelets available in advance. A multidisciplinary management approach is of course recommended in all patients with severe platelet dysfunction.13
DOI : 10.6002/ect.2019.0174
From the 1Pediatric Department of Nephrology and Transplantation, Robert Debré Hospital, APHP, Paris, France, the 2Department of Pediatric Surgery and Urology, Robert Debré Hospital, APHP, Paris, France, the 3Etablissement Français du Sang (EFS), Robert-Debré Hospital, Paris, France, the 4Biological Hematology Department, Robert Debré Hospital, APHP, Paris, France, and the 5Centre de Référence des Pathologies Plaquettaires Constitutionnelles, Robert Debré Hospital, APHP, Paris, France
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Paul Bastard, Pediatric Department of Nephrology and Transplantation, Robert Debré Hospital (48 boulevard Sérurier), Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
Table 1. Protocol to Prevent Risk of Severe Bleeding in Study Patient
Figure 1. Monitoring of Transfused Platelets by Flow Cytometry