Post‐varicella thrombocytopenic purpura

Aims: The aim of the study was to characterize the clinical course of post‐varicella idiopathic thrombocytopenic purpura (ITP) and to asses the risk of acquiring ITP after varicella infection. Methods: A retrospective study of all children diagnosed with ITP in a tertiary medical centre during 1998–2008. Findings were compared with the Intercontinental Childhood ITP Study Group database. The risk of acquiring ITP after a varicella infection was assessed. Results: Ten children were diagnosed with post‐varicella ITP. The incidence of post‐varicella ITP was 1.9% amongst children diagnosed with ITP and 1.1% amongst children hospitalized for varicella. ITP was diagnosed, on average, 8.5 days after the onset of the varicella rash. The female‐to‐male ratio was 1:1.5. The average minimal platelet count was 9.5 × 10⁹ platelets/L. Post‐varicella ITP had an acute course in 80% of cases and a chronic course in the remaining 20%. Bleeding episodes occurred in three patients. During the follow‐up period, 11 patients with previously diagnosed ITP developed varicella. The infection had no apparent affect on the platelet count of the children with acute ITP, but caused a relapse in 71% of the patients with chronic ITP. Conclusions: Post‐varicella ITP has similar clinical features and course to non‐varicella associated ITP. The calculated risk of ITP as a complication of varicella infections is approximately 1:25 000.     

Romiplostim treatment allows for platelet transfusion‐free liver transplantation in pediatric thrombocytopenic patient with primary sclerosing cholangitis

Thrombocytopenia is a major risk factor for cirrhotic liver disease. Patients with thrombocytopenia may have esophageal or gastric varices secondary to portal hypertension, leading to variceal bleeding which exposes the liver to further damage. Here, we present a female pediatric patient with PSC and CD, whose progressive thrombocytopenia was successfully controlled by romiplostim, a TPO receptor agonist. The patient developed bloody diarrhea at four yr of age, and was subsequently diagnosed with PSC and CD when seven yr old. While CD was well‐controlled by immunomodulators, the patient's thrombocytopenia gradually progressed resulting in petechiae (platelet count of 11 × 10⁹/L) when she was 10 yr and four months old. She responded poorly to immunoglobulin and corticosteroids. Weekly subcutaneous injection of romiplostim was therefore initiated, and platelet counts were maintained over at 50 × 10⁹/L. She was able to undergo successful LDLT without platelet transfusion seven months after the initiation of romiplostim. Romiplostim was not required after LDLT with improved platelet counts. This case report suggests that romiplostim may be effective in the treatment of thrombocytopenic children with liver cirrhosis and portal hypertension, and in eliminating the need for platelet transfusion during the peri‐transplant period.     

Subcutaneous anti‐D treatment of idiopathic thrombocytopenic purpura in children

We investigated the effect of subcutaneous anti‐D IgG as platelet enhancing therapy in children with idiopathic thrombocytopenic purpura (ITP). Twenty‐three children were treated with subcutaneous anti‐D 50 µg/kg. The median platelet count increased from 7 × 10⁹ to 31 × 10⁹/L on day 3 (P < 0.01). The median decline in hemoglobin was 1.3 g/dl. Two children experienced minor fever and chills within 24 hr of treatment. Pain at the injection site was common but self‐limiting with no effect on activity level. These results suggest subcutaneous anti‐D IgG 50 µg/kg as an effective and well‐tolerated treatment option in childhood ITP. Pediatr Blood Cancer 2009; 53:1315–1317. © 2009 Wiley‐Liss, Inc.     

Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and SMARCAL1 splice mutation (IVS4-2 A>G) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described.     

Intravenous immune globulin versus intravenous anti-D immune globulin for the treatment of acute immune thrombocytopenic purpura

Objective  The purpose of this study was to compare the efficacy and side effects of intravenous immunoglobulin (IVIG) with intravenous anti-D immunoglobulin for treatment of newly diagnosed acute childhood Idiopathic thrombocytopenic purpura (ITP). Methods  Children (6 months to 14 years) with newly diagnosed acute ITP and platelet count below 20,000/ μL were randomized to receive single dose intravenous 75 μg/kg anti-D or 1g/kg IVIG for two consecutive days (total dose 2 g/kg). Response rate defined as a platelet count over 20,000 / μL 72 hours after initial treatment. Results  Eighty one patients (52 male and 29 female) with mean age of 5 years and 3 months randomly divided in anti-D group (n=42) and IVIG group (n=39). Mean baseline (pretreatment) platelet counts were 15406 / μL and 15230/ μL in anti-D and IVIG group, respectively. The response rate in IVIG group (98%) was more significant than anti-D group (76%); (P = 0.017). After 7 days the platelet counts of all patients in IVIG group were more than 20,000/ μL while in anti-D group 12% had platelet counts below 20,000/ μL. Conclusion  In acute childhood ITP, initial treatment with IVIG (2g/Kg in divided dose) increased platelet count more rapidly and more significant than intravenous anti-D (single dose of 75 μg/Kg) within the first 72 hours.     

Soluble P-selectin,interleukin 6, and thrombopoietin levels in children with acute and chronic idiopathic thrombocytopenic purpura and their relationship with mega-dose methylprednisolone therapy: a pilot study

We observed less severe symptoms in patients with chronic idiopathic thrombocytopenic purpura (ITP) than in patients with acute ITP with similar platelet counts. Thrombopoietin (TPO), soluble P-selectin, soluble P-selectin per platelet, and interleukin 6 (IL-6) were evaluated in children with ITP before treatment in 16 acute and 22 chronic cases and after treatment in 10 acute and chronic cases who received mega-dose methylprednisolone. The levels of IL-6, soluble P-selectin, soluble P-selectin per platelet, and platelet count were similar in acute and chronic ITP (P > 0.05) but TPO in acute ITP was higher than that of the patients with chronic ITP (P < 0.05). The posttreatment IL-6 and TPO declined (P < 0.05), but soluble P-selectin and platelet count increased (P < 0.05). Posttreatment soluble P-selectin per platelet levels were higher than the normal values (P < 0.05). These results suggest that IL-6, soluble P-selectin, and soluble P-selectin per platelet are not responsible for the milder symptoms in chronic than in acute ITP. Mega-dose methylprednisolone seems to keep the soluble P-selectin levels elevated.     

Steroid-free interval with anti-D in chronic idiopathic thrombocytopenic purpura

Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the antibody-mediated destruction of platelets. To maintain the platelets above the symptomatic level we administered 100 μg of anti-D for 5 consecutive days to 19 children with ITP. Four patients did not respond to the treatment. Fifteen responded with an increase in the average platelet number to 76 000/μL 7 days postinjection. However, the platelet count dropped within 45 days to 27 000/μL. Three months after this study, two patients from the study group were then administered monthly anti-D after reinjecting anti-D daily for 5 consecutive days, as previously performed. Platelet levels in these two patients were maintained above 30 000/μL for 5 and 6 months respectively. We concluded that anti-D administration for 5 consecutive days can induce an increase in platelets followed by a decrease below 30 000/μL after 30–45 days. However, monthly administration of anti-D after daily injections for 5 consecutive days can keep platelets above the symptomatic level and may provide a corticosteroid-free safe interval for nearly 5 months.     

Relationships among bleeding severity,health‐related quality of life,and platelet count in children with immune thrombocytopenic purpura

Important outcomes for children with immune thrombocytopenic purpura (ITP) include health‐related quality of life (HRQOL) and bleeding severity. A HRQOL instrument for children with ITP, the Kids' ITP Tools (KIT), was recently validated. Secondary analysis of the KIT database was performed to determine relationships among platelet count, bleeding severity and HRQOL. Bleeding severity grade correlated with platelet count in chronic ITP but not in acute ITP. Platelet count and bleeding severity failed to have any statistically significant correlations with the KIT scores. These findings suggest that relationships among outcome measures in children with ITP, using currently available instruments, remain poorly defined. Pediatr Blood Cancer 2009;53:652–654. © 2009 Wiley‐Liss, Inc.     

A novel compound heterozygous mutation of the <Emphasis Type="Italic">SMARCAL1</Emphasis> gene leading to mild Schimke immune-osseous dysplasia: a case report

Background

Schimke immune-osseous dysplasia (SIOD, OMIM 242900) is characterized by spondyloepiphyseal dysplasia, T-cell deficiency, renal dysfunction and special facial features. SMARCAL1 gene mutations are determined in approximately 50% of patients diagnosed with SIOD.

Case presentation

The case presented here is that of a 6-year-old boy who was born at 33 weeks to healthy, non-consanguineous Chinese parents. He presented with short stature (95 cm; <3rd percentile) and proteinuria. Initially suspected of having IgM nephropathy, the patient was finally diagnosed with mild Schimke immune-osseous dysplasia. One novel mutation (p.R817H) and one well-known mutation (p.R645C) was identified in the SMARCAL1 gene.

Conclusion

This report describes a clinical and genetic diagnostic model of mild SIOD. It also highlights the importance of molecular testing or clinical diagnosis and the guidance it provides in disease prognosis.

     

Favorable four‐yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation‐associated HUS

aHUS is a clinical challenge for successful renal transplantation. Case report: A 14‐yr‐old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH‐related protein (CFHR1/CFHR3) homozygous deletion‐associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation “under cover” of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post‐transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow‐up after transplantation. Conclusion: Specific pre‐ and post‐transplant management allowed successful renal transplantation in a CFH antibody‐positive patient.     

Using individual DSA titers to assess for accommodation after late humoral rejection

Management of late humoral rejection remains challenging, and DSA may persist. A case report illustrates how individual DSA titers using solid‐phase‐based assays may help to assess for accommodation. A male cystinosis patient received a cadaveric renal transplant at the age of 12 yr with a daclizumab, tacrolimus, MMF, and steroids‐based immunosuppression. After three acute rejection episodes over the first eight months, interstitial fibrosis/tubular atrophy (IF/TA) was diagnosed on biopsy, while the immunosuppression was left unchanged with a high target exposure for both tacrolimus and MPA. One yr later, AMR type III (C4d and DSA positive) was treated with daily plasmapheresis, IVIG 100 mg/kg and pulse steroids 5 mg/kg. DSA (DR 53, DQ4, and DQ 2) were not responding until the plasma volume was increased to 2.5 plasma volumes. A second rise of creatinine confirmed worse humoral rejection; daily plasma exchange was resumed, and two doses of rituximab (375 mg/m²) were given. Subsequently, all DSA dropped, but only DR53 DSA remained unchanged, whereas the DQ antibodies rebounded to very strong titers. With a follow‐up of over 120 days after recovery of the CD19 count, off all additional treatment and on identical immunosuppression with tacrolimus and MMF and prednisone, the patient's creatinine remained stable between 45 and 50 um while DQ DSA remain strong to very strong. We conclude that the patient is in a state of accommodation. DSA titers should be monitored when managing late humoral rejection.     

Durable engraftment and correction of hematological abnormalities in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation

The use of HSCT is the only potentially curative treatment for CAMT, but access is limited by the availability of suitable donors. We report five consecutive patients with CAMT who received MAC and partially HLA‐mismatched, UCBT (unrelated, n = 4). Median times to neutrophil (>500/μL) and platelet (≥20 000 and ≥50 000/μL) engraftment were 19, 57, and 70 days, respectively. Acute GvHD, grade II, developed in one patient, who subsequently developed limited chronic GvHD. At median follow‐up of 14 yr, all patients are alive with sustained donor cell engraftment. To our knowledge, this is the largest single‐center series of UCBT for patients with this disease and suggests that UCBT is a successful curative option for patients with CAMT.     

Idiopathic thrombocytopenic purpura in childhood: Twenty years of experience in a single center

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder with a variable clinical course. Methods: A retrospective analysis was carried out of ITP patients presenting to a pediatric hematology‐oncology department during a period of 20 years, with a focus on treatment and outcome. Results: One hundred and twenty‐four cases were recorded (mean patient age, 8.4 years). Forty‐nine children (39.5%) had platelet counts <10 000/µL at diagnosis. No episode of severe bleeding was observed. Peak incidence was observed during spring and summer. Respiratory infections proceeded in 58% of cases. Treatment consisted of i.v. immunoglobulin (IVIG) in 93 children at four dosing schedules. Sixteen children received corticosteroids, 10 children received anti‐D immunoglobulin and 14 received no treatment. Recovery was observed in 67% of children on IVIG and in 50% on anti‐D globulin. Eight patients did not respond initially and received corticosteroids. Three children with refractory thrombocytopenia received anti‐CD20 (rituximab). Fourteen children (11%) had persistent/chronic disease. In 10 of them recovery was observed in 13 months–8 years. Splenectomy was performed in six children with resistant/chronic disease. Conclusion: ITP has a benign course in the majority of cases. Anti‐D globulin can effectively be used as an alternative first‐line treatment. Rituximab can successfully be used in refractory cases, while splenectomy has currently limited indications.     

Rituximab resistant evans syndrome and autoimmunity in Schimke immuno-osseous dysplasia

Autoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency and role of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which is caused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletal dysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximab resistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a review of SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease. To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the first study of autoimmune disease in SIOD.     

High-dose dexamethasone therapy for a 14-month-old boy with refractory idiopathic thrombocytopenic purpura

A 14-month-old boy with refractory idiopathic thrombocytopenic purpura (ITP), who was successfully treated with pulsed high-dose oral dexamethasone therapy is reported. The platelet count increased after six scheduled courses of treatment (10 mg/day × 4 days, six courses). Twenty-four months later, the platelet count remained over 10.0 × 10⁴/μL. No obvious side effects were observed during or after the therapy. This treatment could be taken into consideration not only for adults but also for young children with refractory ITP. It is effective, safe, easy to administer, patient comfort is taken into consideration, and hospitalization duration and costs are minimized.     

The effect of peri‐transplant plasmapheresis in the prevention of recurrent FSGS

Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post‐transplant. But the effectiveness of this expensive, time‐consuming process of plasmapheresis in the prevention of FSGS recurrence is still unclear. We retrospectively reviewed all pediatric cases of FSGS in our center that received a kidney transplant and compared the transplant and patient outcomes of those transplanted after 2006 who received pretransplant plasmapheresis to those prior to 2006 who did not. Of the 57 children with FSGS, 31 and 26 were transplanted before and after 2006, respectively. The cohorts differed significantly in keeping with the center immunosuppression protocol changes, and prior to 2006, the recipients were significantly younger. All children with FSGS transplanted after 2006 underwent three and one sessions of 1.0 plasma volume/exchange plasmapheresis with fresh frozen plasma replacement prior to the transplant in living and deceased donors, respectively, in addition to five sessions of every other day post‐transplant pheresis. The incidence (27% vs 26%, P = 1.0) and time to recurrence of FSGS in the kidney allograft (P = .22) were not significantly different in patients that did and did not undergo prophylactic plasmapheresis. We need to re‐evaluate the role of preemptive plasmapheresis in the prevention of FSGS recurrence in a prospective multicenter study.     

Marked thrombocytopenia in a neonate is associated with anti‐HPA‐5b,anti‐HLA‐A31, and anti‐HLA‐B55 antibodies

Maternal antibodies against human platelet antigen (HPA) and/or human leukocyte antigen (HLA) cause fetal and neonatal alloimmune thrombocytopenia (FNAIT) in 0.09‐0.15% of live births. Severe cases account for 5‐31% and the frequency of multiple kinds of alloantibodies is 6.9‐9% of FNAIT. We present a case of severe FNAIT associated with anti‐HPA‐5b, anti‐HLA‐A31, and anti‐HLA‐B55 antibodies, successfully treated with immunoglobulin and platelet transfusion. The anti‐HLA‐B55 antibody was detected in the newborn's serum, but disappeared on the 20th day, which was followed by an increase of the platelet count. These findings suggested the potential involvement of an anti‐HLA antibody in the pathogenesis of FNAIT.     

Medullary nephrocalcinosis in Schimke immuno‐osseous dysplasia

Schimke immuno‐osseous dysplasia (SIOD) is a rare hereditary disease characterized by skeletal dysplasia, immune deficiency and progressive renal disease. Kidney involvement mainly determines the prognosis. The most common renal pathology is focal segmental glomerulosclerosis (FSGS). Medullary nephrocalcinosis refers to the diffuse deposition of calcium salts in renal medulla and has not previously been identified in SIOD. Here we report the first case of a pediatric patient having typical features of SIOD with medullary nephrocalcinosis.     

The impact of rituximab in ABO‐incompatible pediatric living donor liver transplantation: The experience of a single center

Previous studies have demonstrated the safety of ABO‐incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO‐incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO‐incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m² in two cases; second period: 50 mg/m² in two cases; and 200 mg/m² in eight cases). Two patients who received 375 mg/m² rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m² rituximab required retransplantation as a consequence of antibody‐mediated complications. All eight patients administered 200 mg/m² survived, and the mean CD20⁺ lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO‐incompatible LDLT, the administration of 200 mg/m² rituximab three wk prior to LDLT was safe and effective.     

Retrospective evaluation of children with immune thrombocytopenic purpura and factors contributing to chronicity

ObjectiveImmune thrombocytopenic purpura (ITP) is the most common cause of acquired thrombocytopenia children. The aim of this retrospective study is to describe presenting features and clinical characteristics of ITP and evaluate clinical course, treatment modalities, and complications and determine the effects of preceding infection history, age, gender, treatment modality, and admission platelet count on chronicity.MethodTwo hundred and eleven patients who were diagnosed ITP and followed-up in Department of Pediatric Hematology, Ankara Children Hematology Oncology Education and Research Hospital between January 2008 and September 2012 were included. Age of the patients, gender, date of admission, date of diagnosis, complaint in the application, previous infection and laboratory tests were recorded.ResultsMean age of the patients on diagnosis was 5.4 ± 4.1 years. The female/male ratio was 1.03. The clinical courses were determined as acute or chronic in 72% and 28% of patients respectively. Mean age at diagnosis was significantly higher in chronic ITP (p < 0.01). Chronic course was significantly higher in female patients (p < 0.05). The most frequent complaint was bruises on the skin (68%). The most common physical examination findings were petechiae, purpura and ecchymosis (89%). Patients with a history of past infection (53.6%) and who had serologically positive infection (15.6%) frequently had acute course (p < 0.01). The most common serologically positive infection was Rubella. The mean platelet count was significantly higher in chronic ITP (p < 0.01). In the initial treatment of patients admitted in the acute phase, megadose methylprednisolone (MDMP) was used in 31% of patients, intravenous immune globulin (IVIG) in 55% of patients and anti-D in 2% of patients while 12% did not receive any treatment. There were no significant differences between the recurrence rate and treatment modality (p > 0.05).ConclusionIn our study, in females and in patients without any history of past infection, platelet count >20 × 10⁹/L and initial diagnosis age > 10 years were found to increase the probability of chronic disease, which is compatible with the literature.