Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review.

BACKGROUND: The burden of severe bleeding in adults and children with immune thrombocytopenia (ITP) has not been established. OBJECTIVES: To describe the frequency and severity of bleeding events in patients with ITP, and the methods used to measure bleeding in ITP studies. PATIENTS/METHODS: We performed a systematic review of all prospective ITP studies that enrolled 20 or more patients. Two reviewers searched Medline, Embase, CINAHL and the Cochrane registry up to May 2014. Overall weighted proportions were estimated using a random effects model. Measurement properties of bleeding assessment tools were evaluated. RESULTS: We identified 118 studies that reported bleeding (n = 10 908 patients). Weighted proportions for intracerebral hemorrhage (ICH) were 1.4% for adults (95% confidence interval [CI], 0.9-2.1%) and 0.4% for children (95% CI, 0.2-0.7%; P < 0.01), most of whom had chronic ITP. The weighted proportion for severe (non-ICH) bleeding was 9.6% for adults (95% CI, 4.1-17.1%) and 20.2% for children (95% CI, 10.0-32.9%; P < 0.01) with newly-diagnosed or chronic ITP. Methods of reporting and definitions of severe bleeding were highly variable in primary studies. Two bleeding assessment tools (Buchanan 2002 for children; Page 2007 for adults) demonstrated adequate inter-rater reliability and validity in independent assessments. CONCLUSIONS: ICH was more common in adults and tended to occur during chronic ITP; other severe bleeds were more common in children and occurred at all stages of disease. Reporting of non-ICH bleeding was variable across studies. Further attention to ITP-specific bleeding measurement in clinical trials is needed to improve standardization of this important outcome for patients.

Implantable central venous access device procedures in haemophilia patients without an inhibitor: systematic review of the literature and institutional experience.

Elective surgical procedures involving central venous access devices (CVADs) in patients with haemophilia are often necessary for adequate factor delivery but there are few data regarding haemostatic coverage and acute complication rates accompanying these procedures. To describe experience with CVAD insertion, revision and removal in young haemophilia patients at our institution and in the literature and to assess acute complications following CVAD procedures. PubMed, Medline and Cochrane databases were searched for articles, which included a description of factor coverage during CVAD procedures. A retrospective review of our comprehensive haemophilia database identified patients undergoing CVAD placement, revision and removal between January 1993 and August 2005. Manual and electronic searches of the published literature yielded 14 articles, which met inclusion criteria. Peri-operative factor administration varied greatly among the reports. Mean acute infection and haematoma rates were 8% and 12.5% respectively. A retrospective review identified 49 CVAD placements, revisions, or removals meeting inclusion criteria. Most patients received outpatient bolus factor replacement to achieve a level of 100% preoperatively, immediately postoperatively and on postoperative days 1, 2, 3, 5 and 7. Thirty-six procedures were performed without hospitalization. Ten patients developed 11 (22%) minor haematomas postoperatively. Major haemorrhage, acute infection, or pneumothorax was not encountered. Few published data exist regarding haemostatic coverage and complications following CVAD procedures. Our institutional experience using a consistent management approach was favourable. Further studies are required to define optimal haemostatic coverage during minor surgical procedures in haemophilia.

Short-term oral corticosteroid therapy for acute haemarthrosis in haemophilia patients with high-titre inhibitors.

Treatment of acute bleeding events is unsatisfactory in patients with haemophilia and high-titre factor VIII (FVIII) inhibitors. In order to determine whether short-term corticosteroid therapy enhances resolution of the signs and symptoms of acute haemarthrosis, we performed a randomized, double-blind, placebo-controlled study in children with FVIII deficiency and high-titre inhibitors receiving Factor Eight Inhibitor Bypass Activity (FEIBA) for acute haemorrhagic events. At each haemarthrosis, patients were randomized to receive either prednisolone 2 mg kg(-1) day(-1) or placebo-divided t.i.d. for 2 days (six doses) in addition to FEIBA. The primary endpoint was the number of subsequent doses of FEIBA required. The effect of the study medication was also assessed subjectively by patients or parents, by physical examination and by repeated haemorrhages into the joint. During the study period, seven patients were enrolled with 45 evaluable events, 24 treated with prednisolone and 21 with placebo. An average of 2.08 and 1.86 doses of FEIBA were infused in the prednisolone- and placebo-treated patients, respectively. By Wilcoxon Rank Sum Test, there was no statistically significant difference in number of additional infusions of FEIBA or duration of symptoms between the corticosteroid and placebo arms. We conclude that there is no significant benefit of a 2-day course of oral corticosteroids as adjunctive therapy for haemarthrosis in patients with haemophilia and a high-titre inhibitor.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Fatal central venous catheter-related infection in haemophilia.

Central venous catheters (CVC) are frequently used in children with haemophilia to deliver factor infusions for the treatment or prophylaxis of bleeding. Complications of CVCs in patients with haemophilia include thrombosis and infection. We report a young boy with severe haemophilia A and an inhibitor who developed disseminated Staphylococcus aureus infection most likely related to a CVC. To our knowledge, this is the first reported case of fatal sepsis secondary to a CVC in a patient with haemophilia.

Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS).

BACKGROUND: Acute and chronic idiopathic thrombocytopenic purpura (ITP) is traditionally based on the duration of thrombocytopenia at the cut-off point of 6 months after diagnosis. Registry I evaluated the diagnosis, definition, management, and follow-up of childhood ITP. This report focuses on children with thrombocytopenia persisting more than 6 months. PROCEDURE: Data were collected by questionnaires to the physicians caring for children with ITP, at diagnosis, 6, and 12 months later. Data were compared regarding initial features and follow-up with emphasis on children with persistent thrombocytopenia, and those with ITP who recovered their platelet counts between 7 and 12 months from diagnosis. RESULTS: At 12 months from diagnosis, 79 of 308 (25.6%) evaluable children recovered from ITP and 229 had ongoing ITP. Children with recovered ITP were younger than children with ongoing ITP (P = 0.043) and exhibited a lower frequency of bleeding symptoms during the first 6 months after diagnosis (P = 0.018). Frequency of hospitalization, bone marrow aspiration, and drug treatment differed regionally. CONCLUSIONS: The high rate of recovery from ITP between 7 to 12 months demonstrates, that the cut-off point of 6 months for the definition of chronic ITP does not adequately differentiate chronic from acute ITP. The majority of children with ITP have variable time to recovery with gradual improvement of platelet counts and disappearance of bleeding signs. ITP is a heterogeneous disorder with a diverse natural history and diverse pattern of treatment response.

Consensus recommendations for use of central venous access devices in haemophilia.

Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.

Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia.

BACKGROUND: Traditionally, children with malignant disease who present with fever and neutropenia are hospitalized for parenteral antibiotics. More recently, outpatient strategies have been proposed for lower risk cohorts of such patients. The authors sought to identify clinical and laboratory parameters that are associated with a low risk of bacteremia in children with malignant disease who presented with febrile neutropenia. METHODS: A multicenter, retrospective cohort of children with malignant disease and fever with neutropenia was established in three pediatric oncology centers over a 5-year period. A total of 1171 episodes of febrile neutropenia (absolute neutrophil count [ANC] < 500 cells per mm(3)) were identified in children with malignant disease age > 1 year. The endpoints examined were 1) bacteremia and 2) intensive care unit admission or death related to bacteremia. The odds ratio was used to determine which of the following admission parameters and cut-off values were associated with the lowest risk for bacteremia: ANC, absolute phagocyte count (APC), absolute monocyte count (AMC), platelet count, and admission temperature. RESULTS: A total of 189 episodes of bacteremia were identified among the 1171 episodes of febrile neutropenia (14% bacteremia). Only 11 of 1171 episodes (0.9%) resulted in intensive care unit admission, and 3 of these patients died. All 11 patients had an AMC < 30 cells per mm(3). The lowest frequency of bacteremia (6.1%) occurred in the children with an admission AMC of > or = 155 cells per mm(3). None of the patients identified as low risk by AMC required an intensive care unit admission or died. No level of ANC, APC, temperature, or platelet count was associated with a statistically significant decrease in the risk for bacteremia in the patient population. CONCLUSIONS: Adverse outcomes due to bacteremia are infrequent in pediatric oncology patients who present with fever and neutropenia are treated with parental antibiotics. Patients with fever and neutropenia and an AMC value of > or = 155 cells per mm(3) have the lowest risk for bacteremia and may be potential candidates for outpatient management.

Catheter-related deep venous thrombosis in children with hemophilia.

Central venous catheters (CVCs) are a common adjunct to hemophilia therapy, but the risk of CVC-related deep venous thrombosis (DVT) in hemophiliacs is not well defined. In a previous study, 13 patients with CVCs had no radiographic evidence of DVT. However, recent abstracts and case studies demonstrate that DVT does occur. Therefore, this study sought to determine the frequency of DVT in children with hemophilia and long-term CVCs and to correlate venographic findings with clinical features. All hemophilia patients with tunneled subclavian CVCs in place for 12 months or more were candidates for evaluation. Patients were examined for physical signs of DVT and questioned about catheter dysfunction. Contrast venograms were obtained to identify DVT. Fifteen boys with severe hemophilia were evaluated, including 9 from the initially studied group of 13. Eight patients had evidence of DVT, 5 of whom previously had normal venograms. Five of 15 patients had clinical problems related to the CVC, all of whom had DVT. Four of 15 patients had suggestive physical signs; 3 had DVT. The mean duration of catheter placement for all patients was 57.5 months (range, 12-102 months). For patients with DVT, the mean duration was 66.6 +/- 7.5 months, compared to 49.5 +/- 7.2 months for patients without DVT (P =.06). No patient whose CVC was in place fewer than 48 months had an abnormal venogram. Many hemophilia patients with CVCs develop DVT of the upper venous system, and the risk increases with duration of catheter placement.

Oral megadose methylprednisolone therapy for refractory Diamond-Blackfan anemia. International Diamond-Blackfan Anemia Study Group.

PURPOSE: Several reports describe children with refractory transfusion-dependent Diamond-Blackfan anemia who responded to extremely large doses of methylprednisolone. Limitations in available data prompted further exploration of this treatment approach. PATIENTS AND METHODS: This prospective treatment protocol was designed to test the efficacy and toxicity of oral megadose methylprednisolone in children with Diamond-Blackfan anemia who had previously failed to respond to standard doses of prednisone and who were dependent on regular packed red blood cell transfusions. Patients were treated with oral methylprednisolone, starting at a dose of 100 mg/kg per day, tapering slowly to 5 mg/kg per day at the end of 4 weeks and to 2 mg/kg per day after 7 weeks of induction therapy. Therapy was continued for a total of 23 weeks. Efficacy was assessed by increase in peripheral blood reticulocytes and increase or stabilization in hemoglobin concentration, which was maintained during and after steroid tapering. RESULTS: Nine children with Diamond-Blackfan anemia were registered on the study, and all were evaluable. Disease in four of the children failed to respond to megadose methylprednisolone therapy. The other five patients demonstrated a partial or complete response during the initial 4 to 8 weeks of therapy, but all subsequently experienced relapse during the ensuing 2 months as the corticosteroid dose was tapered. All patients required resumption of transfusions, although one later remitted spontaneously. Toxicity of megadose methylprednisolone was modest. CONCLUSION: None of nine children with refractory Diamond-Blackfan anemia treated with oral megadose methylprednisolone exhibited a clinically significant response. Alternative therapeutic strategies are required.

Outcome measures and treatment endpoints other than platelet count in childhood idiopathic thrombocytopenic purpura.

Therapy for children with acute idiopathic thrombocytopenic purpura (ITP) has been controversial, in great part because it is not evidence based. Some physicians are activists, treaters, or interventionists with regard to therapy of ITP whereas others have been described as nontreaters or noninterventionists. Platelet count (which is often extremely low in ITP) has generally been employed as a surrogate measure of hemorrhagic risk even though life-threatening or fatal bleeding is rare. Virtually all of the randomized clinical trials conducted in childhood ITP have focused on platelet counts as the sole outcome measure. However, other determinants should influence clinical decision making, including assessment of bleeding tendency. Laboratory testing has not been helpful in this regard, but clinical assessment by means of semiquantitative bleeding scores may prove more useful than simply designating a patient as having a "dry" or "wet" purpura. The side effects as well as costs (direct and indirect) of therapy must also be considered when attempting to weigh the merits of drug therapy against their risks. Finally, the effect of ITP and its treatment on health-related quality of life should be determined. Measurement tools to assess each of these alternative outcome measures are in early stages of development. Employing them in addition to platelet counts in future clinical trials will allow treatment to be based more on scientific data than treatment philosophy.

Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia.

BACKGROUND: In view of the recent trend toward monotherapy in the treatment of bacterial infection, we evaluate the clinical efficacy and safety of cefepime vs. ceftazidime for the empiric treatment of febrile episodes in neutropenic pediatric cancer patients. METHODS: In a single site, open label study, 104 neutropenic pediatric cancer patients [96% with absolute neutrophil count (ANC) of <500 neutrophils/mm3] with a median age of 6 years were randomized (1:1) to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose every 8 h; < or = 6 g/day) for empiric treatment of fever (temperature >38.0 degrees C occurring at least twice in 24 h, or single >38.5 degrees C). Febrile episodes were classified as either microbiologically or clinically documented infection or fever of unknown origin. Therapy continued until the ANC was > or = 1,000 neutrophils/mm3 or there was an increasing ANC in low risk patients (maximum duration of treatment, 8 weeks). The primary efficacy endpoints assessed were clinical and microbiologic response to assigned drug therapy. Secondary outcome measures were rate of early discontinuation of study drug and use of concomitant antibiotic therapy to modify initial study drug regimen. RESULTS: Of 68 patients who could be evaluated for efficacy, 74% (26 of 35) of cefepime-treated patients and 70% (23 of 33) of ceftazidime-treated patients responded to treatment. The small number of study patients precluded statistical analysis of results. In a modified intent-to-treat analysis, 59% of the patients treated with cefepime and 47% of ceftazidime-treated patients responded to therapy. Cefepime patients developed fewer new infections than ceftazidime patients (9% vs. 21%, respectively) and early discontinuation of study drug therapy occurred slightly more often in the ceftazidime group. Further, the use of concomitant systemic antimicrobial therapy (mostly vancomycin) occurred less often in the cefepime-treated patients, as compared with the ceftazidime group [35% [17 of 49] vs. 44% (24 of 55), respectively]. No deaths or serious adverse events were considered to be related to study therapy. The most frequent adverse event was rash that was moderate in severity, and it occurred equally in both groups. CONCLUSION: Cefepime appears to be safe and effective compared with ceftazidime for initial empiric therapy of febrile episodes in neutropenic pediatric cancer patients.

Catheter-related thrombosis in children with cancer.

OBJECTIVE: The prevalence of asymptomatic catheter-related thrombosis of the upper venous system in children with cancer has not been determined. We evaluated patients with cancer and implantable central venous catheters (ports) for this complication. STUDY DESIGN: Children with cancer undergoing port removal were eligible for this study. Vessel patency was evaluated by contrast venography. We examined each child for physical stigmata of thrombosis and retrospectively assessed catheter-related mechanical difficulties and infections. RESULTS: Thirty-one ports had been placed in 24 children (aged 20 months to 18 years; median age, 9 years) with diagnoses of leukemia/lymphoma (n = 10), solid tumor (n = 12), and histiocytosis (n = 2). Venography showed abnormalities in 12 of the 24 patients. Physical examination revealed dilated superficial veins on the chest in 3 patients. Venograms showed abnormalities in all 3 children with prominent superficial thoracic veins. Nine of the 21 other patients had clinically occult central venous occlusion. CONCLUSION: Fifty percent (95% CI, 30% to 70%) of children who had implantable ports removed during or after treatment of cancer exhibited deep venous thrombosis at the site of catheter placement. Future studies should determine the contribution of inherited and other acquired risk factors for thrombosis and assess measures to prevent and/or treat catheter-related thrombosis in this population.

Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study.

BACKGROUND: Diagnosis and management of idiopathic thrombocytopenic purpura (ITP) have been based primarily on expert opinion and practice guidelines rather than on evidence. We have used a registry to prospectively survey the presenting features and the diagnostic evaluation and management practices used for children with ITP worldwide. METHODS: We used the Intercontinental Childhood ITP Registry which had been widely advertised. 209 physicians from 136 institutions in 38 countries participated by submitting data for each of their newly diagnosed patients. Data from 2031 children with ITP was registered between June, 1997, and May, 2000, and we analysed 6-month follow-up data from 1496 children. FINDINGS: There was a peak in occurrence of childhood ITP during spring and a nadir in the autumn. Mean initial platelet count was 15.4x10(9)/L (SD 19.7). 1447 (73%) of 1976 children were admitted to hospital. Initial management consisted of no drug treatment in 612 (31%), intravenous immunoglobulin in 576 (29%), corticosteroids in 651 (33%), or both in 137 (7%) patients. Intracranial haemorrhage was reported in two patients. INTERPRETATION: The variable approaches to management of childhood ITP demonstrate the need for prospective clinical trials, which should be feasible within such a study group.

Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia.

PURPOSE: To assess cardiovascular risk factors (CVRF) in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-six subjects (median age, 20.9 years; median interval since completion of therapy, 13.3 years) were evaluated. Ten participants had received cranial irradiation (CRT), whereas 16 had received only chemotherapy. Primary outcome measures included body mass index (BMI), blood pressure, fasting lipoprotein, glucose, and insulin levels. Secondary measures included insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 levels, physical activity index, a 7-day dietary recall, tobacco product use, and measurement of the intima-media thickness (IMT) of the common carotid artery. RESULTS: Sixty-two percent (16/26) of participants had at least one CVRF potentially related to their cancer treatment (obesity, dyslipidemia, increased blood pressure, or insulin resistance), with 30% (7/26) having more than two CVRF. Thirty-one percent (8/26) of subjects were obese (BMI > or = 30). Subjects who were treated with CRT (BMI, 30.4 +/- 6.7) had an increased BMI (P = 0.039) in comparison with those who received only chemotherapy (BMI, 25.4 +/- 5.1). Triglyceride and very low-density lipoprotein C levels were significantly higher in those treated with CRT (P = 0.027 and 0.022, respectively). The IGF-1 was inversely correlated with IMT (total group, -0.514, P = 0.009; females only, -0.729, P = 0.003). CONCLUSIONS: Young adult survivors of childhood ALL, especially those treated with CRT, are at risk for obesity and dyslipidemia, insulin resistance, hypertension, and cardiovascular disease. Further investigation of these risks is warranted.

Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia.

A multicenter investigation of allogeneic bone marrow transplantation for children with sickle cell disease was conducted that included 27 European and North American transplant centers. Fifty-nine patients who ranged in age from 3.3 to 15.9 years (median, 10.1 years) received HLA-identical sibling marrow allografts between September 1991 and April 2000. Fifty-five patients survive, and 50 survive free from sickle cell disease, with a median follow-up of 42.2 months (range, 11.8 to 115 months) after transplantation. Of the 50 patients with successful allografts, 13 developed stable mixed donor-host hematopoietic chimerism. The level of donor chimerism, measured > or =6 months after transplantation in peripheral blood, varied between 90% and 99% in 8 patients. Five additional patients had a lower proportion of donor cells (range, 11% to 74%). Among these 5 patients, hemoglobin levels varied between 11.2 and 14.2 g/dL (median, 11.3 g/dL; mean, 12.0 g/dL). In patients who had donors with a normal hemoglobin genotype (Hb), the Hb S fractions were 0%, 0%, and 7%, corresponding to donor chimerism levels of 67%, 74%, and 11%, respectively. Among patients who had donors with sickle trait, the Hb S fractions were 36% and 37%, corresponding to donor chimerism levels of 25% and 60%, respectively. Thus, allograft recipients with stable mixed chimerism had Rb S levels similar to donor levels, and only 1 patient required a red blood cell transfusion beyond 90 days posttransplantation. None of the patients have experienced painful events or other clinical complications related to sickle cell disease after transplantation. These observations strongly suggest that patients with sickle cell disease who develop persistent mixed hematopoietic chimerism after transplantation experience a significant ameliorative effect.

Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors.

A mutation in the gamma-glutamyl carboxylase gene leading to a combined congenital deficiency of all vitamin K-dependent coagulation factors was identified in a Lebanese boy. He is the first offspring of consanguineous parents and was homozygous for a unique point mutation in exon 11, resulting in the conversion of a tryptophan codon (TGG) to a serine codon (TCG) at amino acid residue 501. Oral vitamin K(1) administration resulted in resolution of the clinical symptoms. Screening of several family members on this mutation with an RFLP technique revealed 10 asymptomatic members who were heterozygous for the mutation, confirming the autosomal recessive pattern of inheritance of this disease. In 50 nonrelated normal subjects, the mutation was not found. This is the second time a missense mutation in the gamma-glutamyl carboxylase gene is described that has serious impact on normal hemostasis.