Key words : Childhood, Deoxyguanosine kinase deficiency, Literature review, Splenic embolization, Thrombopoietin

Introduction
Thrombocytopenia, defined as platelet count <150 × 10⁹/L, is a common problem among recipients of orthotopic liver transplant (LT). Thrombocytopenia, which develops or advances in 50% to 90%^1-3 of LT recipients, will start within the first 2 weeks^1,2 and sometimes immediately after LT.³ Platelet count reduces by 60%³ and reaches nadir on days 3 to 5^3,4 and then increases^1,2 to preoperative levels³ by day 30,^1,2 starting after the first⁴ or second³ week, if no complication develops.⁴

Posttransplant thrombocytopenia that persists for more than 30 days is due to causes such as residual portal hypertension, hypersplenism,¹ medications,³ impaired thrombopoietin production because of graft dysfunction, viral infections,³ decreased production of ADAMTS13 in the graft, and extravasated platelet aggregation after living donor LT (LDLT).³ Posttransplantation thrombocytopenia has been found to be associated with allograft dysfunction, poor graft regeneration, infections (bacterial, fungal⁴) in both LDLT and deceased donor LT and biliary anastomotic stricture.³

In LDLT, platelets play 2 ambivalent roles in “liver regeneration” through the release of various mediators like serotonin, hepatocyte growth factor, insulin growth factor, and vascular endothelial growth factor, the latter stimulating neoangiogenesis,^3,4 and in “ischemia reperfusion” phases. Therefore, higher preoperative platelet count for deceased donor LT and higher postoperative platelet count in LDLT are associated with reperfusion injury after graft ischemia.

Although overall higher platelet counts are considered beneficial because their effects on liver regeneration outweigh the associated risk of ischemia-reperfusion injury (mostly during the early post-LDLT period³), some physicians prefer postoperative low platelet count rather than high count against the risk of thrombosis.

Immune thrombocytopenia (ITP) is a rare complication after transplantation in childhood [shown to occur in 1.3% of pediatric LT recipients (n = 158)²] versus only in 1 to 6.4 per 100?000 general pediatric population.⁵ The disease is characterized by premature destruction of opsonized platelets by the immune system and can result in severe thrombocytopenia.

Thrombopoietin, a glycoprotein hormone that is mainly synthesized by the liver and to a lesser extent by the kidneys, stimulates the production and maturation of platelets through its action on hematopoietic stem cells and megakaryocytes. Synthetic analogs of thrombopoietin (romiplostim and eltrombopag) have been used to treat thrombocytopenia in conditions like ITP and aplastic anemia.⁶

Herein, we present an 8-year-old boy who developed recurrent ITP after LT during immunosuppressive therapy and was successfully treated after a second episode with the thrombopoietin receptor agonist eltrombopag, a second-line therapy, before partial splenic embolization (PSE). We reviewed the literature on development of ITP in pediatric patients after LT and reviewed the diagnostic criteria and therapy choices of ITP in patients who underwent LT. We aimed to understand the characteristics of posttransplant ITP among other causes of post-transplant thrombocytopenia.

Case Report
The patient was the fourth child born by cesarean section to second-degree consanguineous parents (birth weight of 2440 g). He presented with jaundice at aged 1 year and was diagnosed with cryptogenic cirrhosis. He underwent LT at 16 months of age and later was diagnosed with autism. Whole exome sequencing analysis showed homozygous deoxyguanosine kinase deficiency (DGUOK; NM_080916.3:c.679G>A[p.Glu227Lys]), which is a mitochondrial DNA depletion syndrome associated with neonatal hepatocerebral syndrome.

At aged 8 years, 6 years after LT while on tacrolimus (1.5 mg) therapy, the patient was admitted to our center because of diffuse petechial lesions. The patient had history of upper respiratory tract infection 2 weeks previously. He had no previous history of recurrent epistaxis, gingival bleeding, or hematuria. Biochemical tests were significant for platelet count (13 × 10⁹/L), elevated immunoglobulin G (IgG) levels (20.54 g/L), and positive direct Coombs (IgG). Viral serological tests (cytomegalovirus, Epstein-Barr virus, parvovirus, and hepatitis C and B viruses) were negative. Peripheral blood smear showed thrombocytopenia with large platelets (Table 1). The patient was further evaluated for ITP, and bone marrow aspiration was performed. Bone marrow smear was compatible with ITP, showing a remarkable increase in megakaryocytes, most of which were immature. Blast cells, storage cells, malignant infiltration, and parasites were not detected. Post-transplant lymphoproliferative disorder was also excluded. Treatment with mega-level dose pulse methylprednisolone (1 × 30 mg/kg/day) for 3 days was initiated. Methylprednisolone treatment (1 × 20 mg/kg/day) was maintained for another 4 days. After treatment, the patient’s petechial lesions resolved and platelet count increased to 132 × 10⁹/L.

The platelet count remained stable (221-327 × 10⁹/L) during the following 21 months. After this stable period, the patient was again admitted to our hospital because of another ITP episode, which occurred 7 days after a mild upper respiratory tract infection. Physical examination revealed diffuse petechial lesions, mucosal purpura, and autistic self-mutilation behavior. On the day of admission, platelet count was 16 × 10⁹/L. Bone marrow aspiration was compatible with ITP. Viral serological markers and indirect and direct (IgG, C3d) Coombs tests were negative. Serum IgG levels were within the normal range (Table 1). Treatment with methylprednisolone was initiated; however, the patient showed no response. Treatment with human intravenous IgG (IVIG) (800 mg/kg) was initiated. Following IVIG therapy, platelet count was 7 × 10⁹/L. The laboratory findings were not compatible with previously published diagnostic criteria of transplant-associated thrombotic microangiopathy.^7-11 Corrected count increment (CCI), which was calculated at the first hour after an irradiated and leukocyte-depleted platelet suspension was transfused (1-hour CCI) showed result of 2631 (<7500), indicating immune-mediated destruction of platelets; however, a second test was not possible, in accordance with its definition.¹² The patient was switched from tacrolimus to cyclosporine treatment, since switching from tacrolimus to an alternate agent like sirolimus or cyclosporine has been reported to give 100% response in some children who developed ITP following solid-organ transplant.¹³

After cessation of tacrolimus, the patient still showed no recovery in platelet count. Because platelet count remained exceedingly low, additional treatment with rituximab (375 mg/m²/day) was initiated; the patient received 3 doses of rituximab. Rituximab-induced interstitial lung disease developed after the second dose; moreover, no substantial response to rituximab treatment (platelet 6 × 10⁹/L) was attained.

Treatment with thrombopoietin receptor agonist eltrombopag was initiated at 25 mg/day approximately 1 month after the second episode and was increased to 50 mg/day and then to 75 mg/day. Because cyclosporine decreases the effect of eltrombopag, cyclosporine treatment was ceased and switched to sirolimus. Little recovery of platelet count was shown 7 days after eltrombopag treatment was started (from 6 × 10⁹/L to 33 × 10⁹/L); the patient then underwent PSE (~50% of spleen volume) about 1 month later. Ten days after PSE, eltrombopag treatment was ceased when platelet count reached 445 × 10⁹/L. Platelet count gradually decreased and reached to 72 × 10⁹/L 10 days after cessation of eltrombopag; thus, eltrombopag treatment (25 mg/kg/day) was reinitiated and then tapered to 25 mg/kg at every-other-day dosing. Eltrombopag treatment was ceased after 45 days when platelet counts were between 247 and 40 × 10⁹/L. The patient experienced no discernible side effects throughout the course of eltrombopag treatment and remained free of further episodes during the follow-up period (Figure 1).

Literature Review
Literature review of pediatric patients who developed new-onset ITP after LT revealed 17 cases in total. However, several of these pediatric cases were not compatible with definition of ITP^1,2,14-16 because of coexistent hepatosplenomegaly and agranulocytosis,¹⁴ no response to IVIG and high-dose steroids but resolution only after antiviral (ganciclovir) therapy¹⁵ because of underlying cytomegalovirus infection, poor response to IVIG, anti-D and spontaneous resolution after 13 months after reduced dose of tacrolimus,²-case 4 hypersplenism (which had developed posttransplant because of chronic rejection²-review-,¹⁶ case 2 from splenomegaly and concomitant leukopenia/anemia and poor or no response to therapies like IVIG, corticosteroids, rituximab, vincristine but only splenectomy), suggesting the diagnosis of hypersplenism¹-case 7,²-review/hypersplenism¹⁷ misdefined as ITP.¹

In a case shown in Miloh and colleagues,² the patient developed splenomegaly associated with CMV and responded to high-dose steroids. We excluded cases with Evans syndrome (ITP + autoimmune hemolytic anemia) and ITP that developed before LT.^1,18 Those who developed ITP before LT displayed no occurrences¹ or multiple recurrences of ITP after LT before they attained remission.¹⁸

In our review of the literature for pediatric cases who developed ITP, we thus found only 9 cases.^16,18-23 Mean age was 60.6 ± 61.8 months (median of 36 mo; range, 7-156 mo); 4 patients were females and 5 were males. Primary liver disease included biliary atresia (n = 6), progressive familial intrahepatic cholestasis (n = 1), hepatoblastoma (n = 1), and Wilson disease (n = 1). Mean age at LT was 45.11 ± 58.09 months (median of 11 mo, range, 4-159 mo). Immunosuppression regimen consisted of tacrolimus and corticosteroids (n = 4), tacrolimus (n = 3), rapamycin and corticosteroids (n = 1), and tacrolimus after shift from cyclosporine (n = 1). None of the patients received eltrombopag or was administered PSE. Time from LT to the onset of ITP was 15.88 +13.52 months (median of 13 mo, range, 2-42 mo). Etiology of ITP included cytomegalovirus infection (n = 2), human herpes virus 6 (n = 2), parvovirus (n = 1), influenza vaccine (n = 1), and pregnancy-associated ITP in the donor⁴ and unclear etiology (n = 2). The mean platelet count at diagnosis of ITP was 5.52 ± 2.49 × 10⁹/L (median of 5 × 10⁹/L; range, 2-10 × 10⁹/L). Treatment modalities included IVIG + corticosteroids (n = 4), IVIG (n = 3), corticosteroid (n = 1), and polyclonal anti-D antibody (n =1). Five patients had ITP relapse, and 4 had no recurrence. Mean ITP-free survival was 13.75 ± 16.21 months (median of 6 mo; range, 2-50 mo) (Table 2).

Discussion
Herein, we described a pediatric patient who developed 2 ITP attacks 72 and 93 months after LT. Although the first attack responded to steroids, the second was resistant to classical treatment modalities, such as steroids, IVIG, and rituximab; however, the patient responded to eltrombopag as a bridging regimen for PSE and also as a maintenance therapy, making this case different from those in the literature. Having the DGUOK gene mutation as primary liver pathology^1,2,16,18-23 and development of ITP after LT at a period longer than shown in the literature are other unique features of our patient. In our literature search of pediatric patients who underwent LT for DGUOK, ITP as a posttransplant complication was not shown.²⁴

Diagnosis of ITP depends on development of mucocutaneous bleeding without any other symptoms and findings of systemic diseases and isolated thrombocytopenia in a well-appearing child. Therefore, ITP is a clinical diagnosis, and mandatory exclusion of other causes of thrombocytopenia is needed.⁵ However, patients may have little or no sign of purpura or bleeding (resulting in why immune thrombocytopenic purpura was changed to immune thrombocytopenia but preserving the acronym ITP²⁵). However, the following criteria have been defined for patients with atypical findings to be fulfilled completely⁵: (1) platelet count <100 × 10⁹/L; (2) normal white cell count, hemoglobin, reticulocyte count, and normal differential white blood cell count; (3) no abnormalities on the peripheral blood smear, particularly no blasts or no finding of hemolysis (virocytes or transformed lymphocytes from viral activation are agreeable); (4) history and physical examination showing no fever, anorexia, bone or joint pain, headaches, or weight loss; no prolonged history of thrombocytopenia or atypical bleeding; no family history of thrombocytopenia or bleeding of unknown etiology; no history of clinically significant systemic disease; no enlargement of lymph nodes, liver, or spleen (although the spleen may be mildly enlarged in as many as 10% of cases); no abnormal thumbs or forearms and/or hyper- or hypopigmented skin lesions (suggestive of Fanconi anemia). In addition, patients should have (5) unquestionable response to standard ITP treatments (eg, IVIG and anti-D immune globulin), even if the response is transient, which helps to confirm the diagnosis.

We believe that these criteria are useful in diagnosis of ITP in patients with LT, who may exhibit persistent splenomegaly, drug effects, and infections as complications of LT. Indeed, a few case reports of ITP were not included in our review depending on these criteria.

Classically, pathogenesis of ITP involves specific autoantibodies (typically, IgG), most often directed against platelet membrane glycoproteins such as GPIIb/IIIa, causing accelerated phagocytosis and destruction mainly by splenic macrophages.⁵ However, testing for antiplatelet antibodies is not recommended because their presence does not confirm the diagnosis (is neither sensitive nor specific).^5,26 Therefore, in our literature review, we did not take into account presence of antiplatelet antibodies. Immune mechanisms are likely to play a role as well, including increased cytotoxic T cells,²⁷ helper TH1 cells,²⁸ and TH17 cells (subtypes for autoimmune response) and the cytokines secreted by them,^27,29 reduced natural killer cells,²⁷ and reduced and dysfunctional T and B regulatory cells.^27,28

Paradox of developing ITP while taking immunosuppressives
Our patient and nearly all those in the literature who developed ITP after transplant were already on calcineurin inhibitor therapy, which blocks T-cell cytokine production,³⁰ alone or in combination. Putative causes of development of autoimmune disorders like ITP even under such potent immunosuppressives are: 1) Production of alloantibodies by lymphocytes from the donor or graft-versus-host disease.^16,31 Early-onset ITP after LT (during the first 3 months) may be from passive transfer of antibodies directed against platelet antigens from the donor to the patient (recipient)¹ (within the first post-transplant weeks). We found 3 patients who had received kidney and liver transplant from the same donor who developed alloimmune severe thrombocytopenia.³¹ We also found 1 patient who developed ITP from pregnancy-associated ITP from the donor 3 months after LT.¹⁸ Antibodies may also be transfusion dependent.¹ 2) Infections are high levels of immunosuppressive drugs that recipients receive during the early posttransplant period may reactivate cytomegalovirus, Epstein-Barr virus, and varicella viruses¹ (called early-onset ITP^1,18). Antibodies that develop in response to viral infections may have molecular mimicry with antiplatelet antibodies and crossreact with natural antigens that are present on platelets.²³ Hence, 6 of 9 cases in our review had a history of viral infection or vaccination before development of ITP. Our case patient also showed an upper respiratory infection 14 and 7 days before the first and second ITP attacks. Donor-derived viral infections can also induce ITP.³³) Autoimmunity induced by calcineurin inhibitors (tacrolimus, cyclosporine). Calcineurin inhibitors may interfere with negative T-cell selection in the thymus, rendering autoreactive T cells proliferate clonally. This mechanism may occur in children more than that in adults. Calcineurin inhibitors may prevent T-cell receptor-induced apoptosis, which is essential for elimination of activated T cells. Therefore, autoreactive T cells cannot be eliminated and survive long. These inhibitors suppress not only CD4 and CD8 T cells but also T regulatory cells, abolishing their inhibitory effect.¹⁶ 4) Dose reduction of immunosuppressive drugs. Antirejection drugs are effective in treatment of ITP.³² Development of ITP when the immunosuppressives are tapered (to maintenance doses) suggest that defective immunoregulation, which already constitutes the pathophysiology of the underlying disease, becomes unmasked, such as with primary biliary cirrhosis.³² Neither our patient nor those found in the literature had history of dose reduction of immunosuppressants. 5) Type of underlying liver pathology. Biliary atresia, which comprised most of the cases in our literature review, is an immune dysregulation disorder characterized by decreased regulatory T cells and increased Th1 and Th17 cells,³³ similar to ITP.²⁸ Hence, in biliary atresia, ITP may develop before transplant¹⁸ and may present with concomitant food allergies and angioedema.¹⁶ However, the underlying liver pathology in many patients who underwent LT did not have any autoimmune features.¹ In fact, our review did not reveal any patient with primary biliary cirrhosis or primary sclerosing cholangitis, unlike shown in reports in adults.^1,34,35 When diagnosed before diagnosis of liver pathology or transplant, ITP may pursue a chronic course.^18,35

Therapy
Corticosteroids are the first-line treatment modality for ITP in children with response rates of 50% to 90%. Second-line therapies (rituximab, thrombopoietin agonists, splenectomy) are indicated in patients unresponsive to or dependent on steroid therapy.³⁶ However, some children are refractory to both first-line and second-line therapies being more susceptible to bleeding. Although our patient showed a response to steroid therapy in the first episode, the second episode was resistant to steroids, IVIG, and rituximab. Our patient had a heightened risk of bleeding because of self-mutilation that necessitated prompt management of thrombocytopenia.

Splenectomy can be an effective therapy for refractory ITP, showing remissions rates as high as 50% to 70%.³⁷ However, splenectomy is an invasive procedure with unpredictable outcomes. Use of PSE is an alternative procedure to splenectomy in refractory ITP patients with favorable long-term outcomes.³⁸ Eltrombopag increases platelet counts, decreases bleeding risk, and minimizes the requirement for concomitant ITP therapies in children with chronic ITP with few side effects.⁶ Short-term (2 week) eltrombopag treatment before invasive procedures increased platelet counts and reduced the need for platelet transfusion in patients with cirrhosis and thrombocytopenia.³⁹ Our patient had severe refractory thrombocytopenia; thus we opted to abstain from proceeding with splenectomy. Short-term eltrombopag treatment (9 days) resulted in a dramatic increase in platelet counts, and the PSE procedure was performed safely without any complications. Our patient could have derived advantages from eltrombopag treatment without PSE; however; the decision-making process involved carefully weighing and considering the high bleeding risk and effects of PSE.

The tapering and discontinuation of eltrombopag treatment in ITP cases are still controversial with no established guidelines. Durable platelet response after eltrombopag discontinuation was reported in nearly 15% of adult ITP patients.⁴⁰ Discontinuation of eltrombopag in our patient resulted in a drop in platelet count; thus, we decided to continue eltrombopag treatment and tapered it gradually after durable platelet counts were achieved. The paucity of available ITP reports after LT in children impedes the ability to determine effective management strategies. Because of the variability in patient responses, the approach to managing refractory ITP is often individualized.⁴¹ Our case patient showed that short-term eltrombopag can be used as a bridging therapy before invasive procedures in children with refractory ITP.

Our patient did not develop any major infectious complication despite ongoing immunosuppressive therapy during the 3-year follow-up after PSE. Moreover, our patient had coexistent severe autism as a component of DGUOK deficiency in which psychomotor retardation with or without other neurological abnormalities are typical.⁴²

Characteristics of ITP compared with other causes of thrombocytopenia that develop after LT
Platelet sequestration in the liver graft^1,3,4 is proposed as the main mechanism.^3,4 Although not completely understood,³ adhesion of activated platelets to activated sinusoidal endothelium after liver graft, which has been preserved in cold, may undergo subsequent cold and warm ischemia after reperfusion.⁴³ The activated platelets that give rise to apoptosis of sinusoidal endothelial cells⁴³ are destructed by Kupffer cells³ and the circulating platelets decrease by 30% to 55%.⁴ Other causes are thrombopoietin deficiency³ and immune causes (primary or secondary ITP,¹ transplant of liver from donors who previously developed ITP^1-44 or had had platelet antibodies against platelet antigens,¹ platelet consumption from thrombosis [disseminated intravascular coagulation, thrombotic microangiopathy, or venous thromboembolism], sepsis, and viral infections or a combination of these processes).³ Ingestion of drugs like azathioprine, mycophenolate mofetil,^1,3 antithymocyte globulin,³ calcineurin inhibitors (cyclosporine, tacrolimus),^1-3 ganciclovir, valganciclovir, trimethoprim sulfamethoxazole,³ and heparin¹ may cause thrombocytopenia through various mechanisms (eg, inhibiting hematopoiesis, T-cell lymphopoiesis, causing microangiopathic hemolytic anemia, causing bone marrow toxicity or inducing antibodies). Factors such as low pre-operative platelet counts, massive intraoperative platelet transfusions, retransplant, and poor general preoperative conditions such as need for dialysis in deceased donor LT have been found to be associated with posttransplant thrombocytopenia.

Although almost all causes, including immune causes, were reported to give rise to thrombocytopenia in early phases after transplant,⁴ our literature review displayed that ITP is generally a late complication of LT (2-93 mo after LT); moreover, ITP is not associated with allograft dysfunction, poor regeneration, or severe complications and infections.³ We did not have the opportunity to compare the incidence of ITP with all of the aforementioned causes of post-transplant thrombocytopenia since incidence by cause was not available in the literature; however, when we consider that the incidence of early thrombocytopenia, starting within 2 weeks after LT, develops in 50% to 90% of transplanted cases,^2,3 the incidence of posttransplant ITP seems low. Actually, our case is the first ITP case of 335 children who received LT in our clinic from 2001 to 2024, displaying an incidence of 0.29%, much lower than that of Miloh and associates² (3% of 158 LT children) and in the general childhood population (1-6.4 per 100?000 general childhood population).⁵

Our study showed that diagnosis of ITP may be difficult; thus, the diagnostic criteria of ITP for atypical cases can be used, and, in cases refractory to therapy, eltrombopag can be used as a bridging agent for PSE and also as maintenance in success. Further research is required to shed light on its pathogenesis.

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