Transition of care for pediatric and adult patients with venous thromboembolism: A National Quality Improvement Project from the American Thrombosis and Hemostasis Network (ATHN).

BACKGROUND: Transition of care (TOC) for management of anticoagulation from inpatient to outpatient setting for patients with acute venous thromboembolism (VTE) poses serious safety concerns. We implemented a national quality improvement educational initiative to address this issue. METHODS: Pediatric and adult patients admitted for their first VTE were prospectively enrolled at 16 centers from January 2016 to December 2018. Patient demographics, VTE diagnosis, risk factors, and treatment characteristics were collected. There were two phases: pre-intervention (PI) and quality intervention (QI). The PI phase assessed the quality and patient understanding and satisfaction of anticoagulation instructions given at hospital discharge and adherence to these instructions via a patient and/or caregiver feedback questionnaire (PFQ) and a patient knowledge questionnaire (PKQ) at 30 days. The QI phase provided patient and/or caregiver enhanced education regarding anticoagulation therapy and VTE at hospital discharge using a comprehensive discharge instruction module and a phone call follow-up at one week. Patient and/or caregiver knowledge at 7 and 30 days was assessed with the same PFQ and PKQ and compared to the PI baseline measures. RESULTS: Of the 409 study patients, 210 (51%) were adults, 218 (53%) females, and 316 (77%) White. Deep vein thrombosis (62.8%) and pulmonary embolism (47.9%) were the most common VTE in children and adults, respectively. Day 30 PFQ scores were significantly higher in the QI phase compared to the PI phase by 11% (p < 0.01). Day 30 PKQ demonstrated enhanced teaching (93.7% vs. 83.5%, p-value 0.004) and disease recognition (89.6% vs. 84.6% p = 0.03) in the QI phase than the PI phase. CONCLUSION: Comprehensive VTE discharge instructions followed by a 1-week post-discharge phone call strengthen patient and caregiver knowledge, satisfaction of education given and care provided, and disease recognition.

Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia.

Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis.

OBJECTIVES: In preparation for a pediatric randomized controlled trial on thromboprophylaxis, we determined the frequency of catheter-related thrombosis in children. We also systematically reviewed the pediatric trials on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials. PATIENTS/METHODS: We searched MEDLINE, EMBASE, Web of Science and the Cochrane Central Register for Controlled Trials for articles published until December 2013. We included cohort studies and trials on patients aged 0-18 years with central venous catheters who underwent active surveillance for thrombosis with radiologic imaging. We estimated the pooled frequency of thrombosis and the pooled risk ratio (RR) with thromboprophylaxis by using a random effects model. RESULTS: From 2651 articles identified, we analyzed 37 articles with 3128 patients. The pooled frequency of thrombosis was 0.20 (95% confidence interval [CI] 0.16-0.24). In 10 trials, we did not find evidence that heparin-bonded catheters (RR 0.34; 95%CI 0.01-7.68), unfractionated heparin (RR 0.93; 95% CI 0.57-1.51), low molecular weight heparin (RR 1.13; 95% CI 0.51-2.50), warfarin (RR 0.85; 95%CI 0.34-2.17), antithrombin concentrate (RR 0.76; 95% CI 0.38-1.55) or nitroglycerin (RR 1.53; 95%CI 0.57-4.10) reduced the risk of thrombosis. Most of the trials were either not powered for thrombosis or were powered to detect large, probably unachievable, reductions in thrombosis. Missing data on thrombosis also limited these trials. CONCLUSIONS: Catheter-related thrombosis is common in children. An adequately powered multicenter trial that can detect a modest, clinically significant reduction in thrombosis is critically needed. Missing outcome data should be minimized in this trial.

Risk-prediction tool for identifying hospitalized children with a predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule.

BACKGROUND: The prevalence of VTE is increasing in tertiary pediatric hospitals. Identification of high-risk populations using uniform criteria is required to develop evidence-based VTE prevention guidelines. OBJECTIVE: To develop a VTE risk prediction rule, the Peds-Clot clinical Decision Rule (PCDR), to identify high-risk children who were at increased risk of developing VTE. METHODS: This retrospective case-control study developed the PCDR using a derivation cohort (173 cases, 346 controls) and validated it on a separate validation cohort (100 cases, 100 controls). A uniform data collection strategy was applied to derive both the samples. Conditional logistic regression analyses were used to develop a risk-prediction model. Each significant predictor was assigned a score based on its beta coefficient and the PCDR was developed. ROC curves were derived to test the performance of the PCDR. RESULTS: Characteristics of derivation and validation cohorts were comparable. Six risk factors (positive blood stream infection, central venous catheter, direct admission to ICU/NICU, hospitalization for ≥ 7 days, immobilization for > 72 h, and use of birth control pills) formed the final risk prediction model (risk score range, 0.5-9.5). A risk score of 3 or more identified high-risk children at a sensitivity of 70% and specificity of 80% and AUC of 0.852 (95% confidence interval, 0.814-0.890). The application of a risk score to the validation sample showed sensitivity 57% and specificity 88% and an AUC of 0.875 (95% confidence interval, 0.82-0.924). CONCLUSION: Incorporation of the PCDR in routine clinical care can be an attractive strategy to identify high-risk hospitalized children with a predisposition for VTE. The clinical utility of the PCDR needs validation in prospective studies.

Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US).

The primary objective of the study was to examine the prevalence of cardiovascular disease (CVD) events and their known risk factors among persons with haemophilia (PWH). This cross-sectional study, covering a 5-year period, included PWH aged ≥35 years who were cared for at a single haemophilia treatment centre in the United States. Medical records were extensively reviewed to collect the information about CVD events and their risk factors such as obesity, hypertension, diabetes, hypercholesterolemia and smoking. Prevalence rates were compared with national population estimates and associations between risk factors and CVD events were examined using logistic regression. The study cohort comprised 185 PWH (102 haemophilia A and 83 haemophilia B). Lifetime prevalence of a CVD event was 19.5% (36/185, 95% confidence interval [CI] 13.8-25.2%). CVD mortality was 5.4% (10/185, 95% CI 2.7-8.1). Compared with US non-Hispanic White males (NHWH), PWH had about twice the prevalence of coronary artery disease, stroke and myocardial infarction. The prevalence of CVD risk factors for PWH was similar to that for US NHWM with 39.5% of PWH exposed to two or more of these risk factors. Both hypertension and smoking were associated significantly with CVD events, with odds ratios of 4.9 and 6.3, respectively. In conclusion, this study revealed that both CVD events and its risk factors were at least equally prevalent among PWH and might have been even higher than among the US NHWM in the United States. Therefore, it is imperative to implement strategies for CVD prevention among PWH.

Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C-->T mutation.

The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1-27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1-70 years); median bleeding score: 1 (range 0-8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score >/=3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 +/- 10.3% (95% CI 36.4-47.7) while a score >3 had involvement of /=3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation.

Activated B-cell immunophenotype might be associated with poor prognosis of primary central nervous system lymphomas.

Primary central nervous system (PCNS) diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma whose growth is restricted to the central nervous system and eye. Primary CNS DLBCL has a poor prognosis relative to other extranodal DLBCL. Recently DLBCL has been subclassified as germinal and non-germinal center B-cell types using microarray. Germinal center B-cell DLBCL is associated with better prognosis compared to non-germinal center B-cell group. The objective of the study was to subcategorize the PCNS DLBCL into germinal center and non-germinal center DLBCL using immunohistochemistry and to correlate its prognostic significance. 21 immunocompetent patients were diagnosed with PCNS DLBCL over last 20 years at William Beaumont Hospital. Clinical data on outcome were collected and their specimens were retrieved. Immunohistochemical staining was done using markers, CD20, CD10, Bcl-6, MUM-1, MIB-1, Bcl-2 and by molecular analysis of the immunoglobulin heavy chain gene (IgH) variable region. Immunohistochemistry showed 1/21 (positive cases/examined cases) for CD10, 19/21 for Bcl-6, 19/21 for MUM-1 and 15/21 for Bcl-2. The expression pattern of CD10(-) MUM-1(+) is corresponded to the non-germinal center DLBCL. The MIB-1 index ranged from 40--80% with a mean of 57%, indicating a high proliferation of lymphoma cells. The IgH gene variable region analysis showed monoclonality in 15 of 21 cases (71%). Primary CNS DLBCL has a non-germinal center B-cell phenotype in majority of cases and has a high Bcl-2 positivity and MIB-1 index. These features might be associated with poor prognosis.

Hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (also known as Osler-Weber-Rendu syndrome) is a relatively common, under-recognized autosomal-dominant disorder that results from multisystem vascular dysplasia. It is characterized by telangiectases and arteriovenous malformations of skin, mucosa and viscera. This article summarizes the clinical manifestations and the management of this disorder and its management. This review underscores an urgent need to conduct prospective multicentre studies to develop evidence-based management guidelines for this disease.

Primary thromboprophylaxis with heparins for arteriovenous fistula failure in pediatric patients.

BACKGROUND: To reduce the incidence of early arteriovenous fistula failure (AVF) due to thrombosis in pediatric hemodialysis (HD) patients, a primary thromboprophylaxis (PTP) protocol was initiated at author's institution in June 2005. The goal of this study is to report author's experience with this protocol one year later. METHODS AND RESULTS: 19 AVFs (14 patients, Historical group) and 8 AVFs (7 patients, PTP group) were created prior to and after initiation of PTP respectively. PTP consisted of unfractionated heparin (5-10 units/kg/hr) infusion postoperatively, followed by subcutaneous low molecular weigh heparin (LMWH) until AVF was matured. LMWH dosing was 'Prophylactic' (0.5 mg/kg/d, anti-factor Xa levels: peak 0.25-0.5 and trough < 0.3 units/mL) and 'Therapeutic' (1 mg/kg/d, anti-factor Xa level: peak 0.5-1 and trough < 0.5 units/mL) based on thrombosis predisposition. In Historical group, 12 AVFs did not receive thromboprophylaxis (No-treatment group), 5 received 81 mg aspirin/day (Aspirin group), and 2 received LMWH. In No-treatment group 10/12 AVFs failed: 9 thromboses and 1 stenosis. In Aspirin group 1/5 AVFs failed due to thrombosis. In PTP group 1/8 AVFs failed due to stenosis; the first 2 AVFs developed hematoma prompting a reduction in LMWH dose and monitoring trough anti-factor Xa levels, one AVF required thrombectomy after LMWH was transiently held. The incidence of thrombosis was less in PTP group (12.5%) when comparing to No-treatment group (83%) (p < 0.05). CONCLUSION: PTP is a feasible option to prevent early thrombosis at AVF. Close clinical and laboratory monitoring including trough anti-factor Xa levels is required to adjust optimum anticoagulation. Larger studies are needed to clarify safety and efficacy of our PTP protocol.

Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound.

Low molecular weight heparin (LMWH) is efficacious in preventing recurrent thromboembolic events (TEs) in children. The efficacy of LMWH in resolving thrombus in children is, however, unknown and may differ from what has been observed in adults due to known differences in the hemostatic system. We reviewed the ultrasound (US) scanning reports of children treated with LMWH in order to determine the rate and predictors of thrombus resolution. Of 245 children consecutively treated for a non-cerebral TE with enoxaparin (Lovenox, Aventis Pharma Inc., QC, Canada) for at least 5 consecutive days, 190 (78%) had serial ultrasound available for analysis. The mean follow-up time was 7 months (median 3 months, range 3 days to 6.6 years). The rate of complete thrombus resolution was 101/190 (53%, 95% confidence interval 46.2-60.2%). On univariate analysis, arterial and non-occlusive thrombus had an increased rate of resolution when compared with venous and occlusive thrombus. Age at time of TE (neonates vs. non-neonates), location of TE, initial treatment (unfractionated heparin vs. LMWH) and dose of enoxaparin were not related to outcome. On multivariate analysis, type of vessel (vein vs. artery) and occlusion (occlusive vs. non-occlusive thrombus) independently predicted outcome. In children, the rate of complete thrombus resolution is similar to the rate in adults. The clinical significance of residual abnormal vessels, specifically to the occurrence of post-thrombotic syndrome and for the diagnosis of recurrence, needs to be explored in prospective studies.

Allogeneic bone marrow transplantation vs chemotherapy for children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic bone marrow transplant (BMT) with an MRD in complete remission (CR)1 is the preferred treatment for children with Philadelphia-positive (Ph(+)) ALL. The role of MUD BMT in CR1 is still controversial. We compared the outcomes of two treatment strategies: BMT using an MRD or MUD vs chemotherapy in children with Ph(+) ALL in CR1. In total, 21 children were treated from 1985 to 2001. In all, 10 received chemotherapy and 11 received allogeneic BMT: four MRD, seven MUD. In the MRD group, one relapsed 12 months after BMT and died; the remaining three are long-term event-free survivors (median follow-up, 6.1 years). In the MUD group four died; the remaining three are long-term event-free survivors (median follow-up, 7.2 years). The 4-year event-free survival (EFS) for the BMT group was 53+/-15%. In the chemotherapy group, seven relapsed after a median period of 12.5 months and three remain in continuous CR (median follow-up, 2.4 years). Four chemotherapy patients received CR2 transplants; all died. The 4-year EFS for the chemotherapy and MUD groups was 33+/-17 and 35.7+/-20%, respectively. This difference was not statistically significant. We continue to support treating children with Ph(+) ALL with MRD BMT in CR1. The effectiveness of MUD BMT vs chemotherapy merits further study.

Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A.

BACKGROUND: Inhibitors are rare in boys with mild hemophilia A (MHA; factor (F)VIII:C > 5%) but may arise following intense FVIII exposure, e.g. continuous infusion (CI). OBJECTIVES: To determine the impact of intense FVIII exposure in inhibitor formation in MHA at our institution and to compare this with previous reports. PATIENTS AND METHODS: We reviewed FVIII exposure and inhibitor development in boys (ages 0-18 years) with MHA followed at our institution from 1996 to 2001 and conducted a Medline search (1966-2002) on the experience of inhibitor development following intensive/CI exposure to FVIII. RESULTS: We identified 54 boys with MHA. Twenty-nine (54%) had been exposed to FVIII. Seven had received FVIII by CI. Four developed inhibitors; three high titer (at ages 10 years, 16 years and 17 years) and one low titer (at 1 month old). All four had received a CI of recombinant (r) FVIII of at least 6 days within 6 weeks of developing inhibitors. Baseline FVIII levels fell to < 1% in all cases and the three with high-titer inhibitors developed severe bleeding. Immune tolerance therapy (ITT) was attempted in two boys and was successful in one. Our literature search identified 35 cases (only four children) with MHA developing inhibitors following intense FVIII exposure often in the context of surgery. CONCLUSIONS: The incidence of inhibitors in our MHA population was 7.4%. If expressed according to exposure the incidence was significantly higher: 14% (4/29) for any exposure to FVIII and 57% (4/7) for exposure by CI. A prospective study to address whether CI is associated with an increased incidence of inhibitor development in MHA is warranted.

Ganciclovir-induced encephalopathy in a bone marrow transplant recipient.

Ganciclovir is widely used as prophylactic and pre-emptive therapy, as well as treatment, for CMV infection following BMT. We report a case treated with ganciclovir 5 days a week. Following escalation of the ganciclovir dose to a twice daily dose to treat CMV antigenaemia, he developed encephalopathy. His encephalopathy resolved with withdrawal of ganciclovir. Ganciclovir encephalopathy has been described in other groups of patients but has not been reported following BMT to date. With its widespread use this complication is likely to be seen more often.