ABSTRACT
INTRODUCTION: The incidence of thromboembolic (TE)-pediatric pulmonary embolism (PPE) is increasing. We sought to evaluate current practice patterns and gaps in the management of TE-PPE. MATERIALS AND METHODS: After Institutional Review Board approval, SurveyMonkey® questions were sent to members of the Pediatric/Neonatal Thrombosis and Hemostasis Subcommittee, of the International Society on Thrombosis and Haemostasis and the Hemostasis and Thrombosis Research Society. RESULTS: Of 442 members of the two groups, 134 (30%) responded, and 125 (28%) complete responses were analyzed. Eighty percent practiced at a pediatric facility, 88% at academic centers, and 59% in the USA. Computed tomography pulmonary angiography (CTPA) was the preferred diagnostic modality (89%). D-dimer testing was variably used; 22% used clinical diagnostic prediction models and 8% had specific clinical care pathways for TE-PPE management. Prognostic stratification models were used to guide therapy by 4%. Indications for thrombolytic therapy varied considerably; 40% had a standardized protocol for thrombolysis, employing various modalities (45% systemic, 25% catheter-directed, 19% pharmaco-mechanical) and tissue plasminogen activator dose intensities. Duration of anticoagulation was variable with 58% prescribing anticoagulation for duration of >3â¯months-6â¯months; 61% followed for long-term adverse outcomes. CONCLUSION: This multinational survey of thrombosis/hemostasis specialists mainly based at pediatric academic centers demonstrates that antithrombotic management of TE-PPE (including duration of anticoagulation and use/non-use of thrombolysis) varies considerably. Furthermore, standardized care pathways to facilitate acute evaluation and management decisions are in place in a minority of centers. These findings help to inform the design of future clinical trials in TE-PPE.
Subject(s)
Pulmonary Embolism/diagnosis , Pulmonary Embolism/therapy , Thromboembolism/diagnostic imaging , Thromboembolism/diagnosis , Humans , Pulmonary Embolism/pathology , Surveys and QuestionnairesABSTRACT
Essentials The once-daily dosing of tinzaparin provides an advantage over other low molecular weight heparins. The recommended age-dependent doses of tinzaparin in children have not previously been validated. Once-daily administration of tinzaparin is a safe and effective treatment of childhood thrombosis. Recommended doses are appropriate but monitoring may be required due to inter-individual variation. SUMMARY: Background The recommended starting doses of tinzaparin for the treatment of thrombosis in children have not previously been validated. There are few data to support the efficacy and safety of once-daily tinzaparin dosing in children with thrombosis. Objectives To investigate the use of tinzaparin for the treatment of childhood thrombosis, and to evaluate the age-dependent dosing recommendations and define outcomes in terms of efficacy and safety. Methods This was a retrospective cohort study of children aged 0 to < 16 years treated for thrombosis at a large teaching hospital in the UK between 2008 and 2015. Medical records were reviewed to evaluate tinzaparin dosing, anti-activated factor X (FXa) levels, and patient outcomes. Results Seventy-nine children were identified as having received tinzaparin. Dosing information was available for 57. Younger children required higher doses to reach a therapeutic level. The therapeutic dose requirement varied within age groups, supporting the use of anti-FXa monitoring. Over a median follow-up of 35 months, there were 13 (16%) bleeding episodes (two major; seven clinically relevant but non-major; and four minor). There were two (3%) recurrent episodes of thrombosis. Children were treated for a median duration of 3 months, and the majority (86%) remained on tinzaparin for the duration of their anticoagulant therapy. Conclusion Once-daily tinzaparin is a safe and effective treatment for childhood thrombosis, with rates of recurrence and bleeding similar to those for other anticoagulants used in children. The recommended starting doses are appropriate, but anti-FXa monitoring may be required, owing to interindividual variability in the therapeutic dose requirement.
Subject(s)
Fibrinolytic Agents/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Thrombosis/drug therapy , Adolescent , Age Factors , Child , Child, Preschool , Cohort Studies , Drug Administration Schedule , Factor Xa Inhibitors/blood , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Thrombosis/blood , Tinzaparin , Treatment OutcomeSubject(s)
Compartment Syndromes/diagnosis , Exercise/physiology , Hemophilia A/complications , Female , Humans , Male , Upper ExtremitySubject(s)
Anticoagulants/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Blood Coagulation/drug effects , Mixed Function Oxygenases/genetics , Warfarin/pharmacokinetics , Adolescent , Age Factors , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/blood , Aryl Hydrocarbon Hydroxylases/metabolism , Biotransformation , Child , Child, Preschool , Cross-Sectional Studies , Cytochrome P-450 CYP2C9 , Drug Monitoring/methods , England , Female , Gene Frequency , Genetic Predisposition to Disease , Hemorrhage/chemically induced , Hemorrhage/genetics , Humans , Infant , International Normalized Ratio , Male , Mixed Function Oxygenases/metabolism , Ontario , Pharmacogenetics , Phenotype , Retrospective Studies , Risk Factors , Vitamin K Epoxide Reductases , Warfarin/administration & dosage , Warfarin/adverse effects , Warfarin/bloodSubject(s)
Anticoagulants/pharmacology , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , International Normalized Ratio , Male , Risk , Time Factors , Treatment Outcome , Warfarin/pharmacologySubject(s)
Fontan Procedure , Postoperative Complications , Thrombosis/drug therapy , Thrombosis/etiology , Tricuspid Atresia/therapy , Adolescent , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Male , Point-of-Care Systems , Retrospective Studies , Warfarin/administration & dosage , Warfarin/adverse effectsABSTRACT
SUMMARY BACKGROUND: Excessive bruising and mucocutaneous bleeding are frequent presenting symptoms in childhood. A detailed bleeding history can distinguish children who may have an inherited bleeding disorder from those who are normal. There is a lack of standardization of such history taking in pediatric practise. OBJECTIVES: To assess the performance of a Pediatric Bleeding Questionnaire (PBQ), an adaptation of a standardized adult bleeding questionnaire and score that includes pediatric-specific bleeding symptoms, in a cohort of children with von Willebrand disease (VWD). PATIENTS/METHODS: Bleeding scores were determined by interview, for children with a previous diagnosis of VWD and a control group of unaffected siblings. RESULTS: Bleeding scores were obtained for 100 children with VWD, median age 10.9 years (range, 0.8-17.8 years), and 21 unaffected siblings. Median bleeding score in children with VWD was 7.0 (range, 0-29) and in the control group was 0 (range, -1-2). Bleeding score varied within and between each VWD type: definite type 1, n = 40, median, 9.0 (range, 2-18); possible type 1, n = 38, median, 2.0 (0-15); type 2, n = 6, median, 14.0 (3-17); and type 3, n = 16, median, 12.0 (4-29). Bleeding scores in affected children correlated with age (Spearman's correlation coefficient, 0.35; P = 0.0004). The most frequent clinically significant bleeding symptoms were surgical bleeding, bleeding after tooth extraction and menorrhagia. Post-circumcision bleeding, cephalohematoma, macroscopic hematuria and umbilical stump bleeding were clinically significant in 32% (of circumcised males), 4%, 4% and 3% of children, respectively. CONCLUSIONS: The PBQ provides a standardized quantitation of bleeding severity in children with VWD.
Subject(s)
Hemorrhage , von Willebrand Diseases/physiopathology , Child , Humans , Surveys and QuestionnairesABSTRACT
BACKGROUND: Childhood pulmonary embolism (PE) causes significant mortality and evidence suggests that it is under-diagnosed. Clinical probability scores and D-dimer estimation to assess pre-test probability have not been studied in children with suspected PE. PATIENTS/METHODS: This retrospective cohort study evaluated Wells simplified probability score for PE in 50 children with PE and 25 PE negative control patients, and D-dimer values in 27 PE positive and 12 PE negative children. RESULTS: PE positive and PE negative groups had similar rates of risk factors for venous thromboembolism (VTE). Wells simplified probability score showed a small difference between PE positive and PE negative children (median score: PE positive, 4.5; PE negative, 4; P = 0.009), children with PE are more likely to obtain a 'PE likely' score (score > 4), P = 0.012. The difference was of slightly greater significance when the Wells score was adjusted to account for pediatric normal ranges for heart rate, P = 0.007, and signs/symptoms of upper limb DVT, P = 0.006. Children with PE were as likely as PE negative patients to have a D-dimer value within the normal range (PE positive, 15%; PE negative, 25%; P = 0.654). A combination of a 'PE unlikely' score and normal D-dimer value occurred in 1/12 (8%) of PE negative children. CONCLUSIONS: The Wells clinical probability score and D-dimer estimation may lack utility in the determination of pre-test probability of PE in children. Validation of a pediatric clinical probability score, incorporating D-dimer estimation, by prospective study, would be difficult as a result of the rarity of childhood PE.
Subject(s)
Fibrin Fibrinogen Degradation Products/analysis , Pulmonary Embolism/diagnosis , Adolescent , Biomarkers , Catheterization, Central Venous/adverse effects , Child , Child, Preschool , Cohort Studies , Female , Heart Defects, Congenital/blood , Heart Defects, Congenital/complications , Humans , Immobilization/adverse effects , Infant , Infant, Newborn , Male , Neoplasms/blood , Neoplasms/complications , Postoperative Complications/blood , Predictive Value of Tests , Probability , Pulmonary Embolism/blood , Pulmonary Embolism/etiology , Recurrence , Retrospective Studies , Risk Factors , Tachycardia/etiology , Venous Thromboembolism/epidemiologyABSTRACT
Prophylaxis is standard of care for boys with severe haemophilia A. Indications for prophylaxis in adulthood, non-severe haemophilia A, haemophilia B and haemophilia with inhibitors are less well defined. This survey, conducted in 2006, aimed to describe prophylaxis use in patients of all ages and severities with haemophilia A or haemophilia B in Canada. Data on 2663 individuals (2161 haemophilia A; 502 haemophilia B), including 78 inhibitor-positive patients, were returned by 22/25 Canadian haemophilia treatment centres. This represented 98% of the Canadian haemophilia population. Frequency of prophylaxis use, defined as infusion of factor VIII/IX concentrate at least once weekly for >/=45 weeks of the year, was highest in individuals with severe haemophilia A (69%). It was lower in individuals with severe haemophilia B (32%), moderate haemophilia A (18%) or B (5%) and mild haemophilia A (1%) or B (1%). Among individuals with severe haemophilia A, the frequency of prophylaxis use was 84% in children (=18 years) and 55% in adults (>18 years). Thirteen per cent of inhibitor-positive individuals were receiving prophylaxis with bypassing agents. Comparison with data obtained from a 2002 Canadian survey showed a greater use of prophylaxis in children =5 years of age with severe haemophilia A (73% vs. 49%). Prophylaxis is no longer confined to children with severe haemophilia A, but is used in a significant proportion of adults with severe haemophilia A and individuals with severe haemophilia B or moderate haemophilia A. Prophylaxis is being started earlier in boys with severe haemophilia A.
Subject(s)
Factor IX/administration & dosage , Factor VIII/administration & dosage , Hemarthrosis/prevention & control , Hemophilia A/drug therapy , Hemophilia B/drug therapy , Adolescent , Adult , Aged , Cohort Studies , Drug Administration Schedule , Drug Utilization/statistics & numerical data , Factor IX/immunology , Factor IX/therapeutic use , Factor VIII/immunology , Factor VIII/therapeutic use , Health Care Surveys , Hemarthrosis/etiology , Hemophilia A/complications , Hemophilia A/immunology , Hemophilia B/complications , Hemophilia B/immunology , Humans , Isoantibodies/blood , Male , Middle Aged , Young AdultABSTRACT
We report the use of rituximab (MabThera); Roche Grenzach-Wyhlen, Germany) in a 6-year-old boy with severe haemophilia A and a high titre alloimmune factor VIII (FVIII) antibody, which had failed to respond to standard immune tolerance therapy. Rituximab was administered in 4 weekly doses with concurrent high-dose i.v. immunoglobulin (Flebogamma); Grifols, Barcelona, Spain) followed by daily high-dose recombinant FVIII concentrate (Recombinate); Baxter, CA, USA). Despite a fall in CD20 positive cell count to undetectable levels the inhibitor persisted. We discuss the possible reasons for failure of immune tolerance induction and review the literature concerning the use of rituximab for this indication.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Factor VIII/immunology , Hemophilia A/drug therapy , Immune Tolerance/drug effects , Immunologic Factors/therapeutic use , Antibodies/immunology , Antibodies, Monoclonal, Murine-Derived , Factor VII/immunology , Factor VII/therapeutic use , Factor VIII/therapeutic use , Factor VIIa , Hemophilia A/immunology , Humans , Infant , Male , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use , Rituximab , Treatment FailureABSTRACT
BACKGROUND AND OBJECTIVES: Recombinant activated factor VII (rFVIIa/NovoSeven) has been advocated in the treatment of life-threatening haemorrhage, but appropriate clinical indications remain uncertain. The aim of this study was to detect factors predictive of outcome and to incorporate them into a prognostically significant scoring system. MATERIALS AND METHODS: Thirty-six patients received rFVIIa for uncontrolled surgical, traumatic or obstetric bleeding in the Northern Region of the UK over a 45-month period. Clinical, laboratory and outcome data were examined. Characteristics of survivor and non-survivor groups were compared. A prognostic scoring system was evaluated retrospectively according to the presence of coagulopathy, renal impairment, hypothermia, greater than 10 units of red cell transfusion, advanced age and obstetric indication, with patients allocated to low, intermediate and high-risk groups. RESULTS: Clinical response occurred in 26 patients (72%) with a reduction in prothrombin time and blood product requirements. Death occurred in 19 (53%). Four patients (11%) suffered thrombotic events. Survivors were younger than non-survivors and less likely to have coagulopathy, renal impairment or hypothermia at the time of administration. Survivors were more likely to have had an initial clinical response in terms of an immediate reduction in haemorrhage. Non-survivors were transfused a greater number of red cell units prior to administration. Survival varied according to prognostic score; low-risk patients had a survival rate of 85%, intermediate-risk patients had a survival rate of 50% and high-risk patients had a survival rate of 18%. CONCLUSIONS: FVIIa has a role in the cessation of haemorrhage, but may not improve survival. Use of a clinical scoring system may help to predict outcome.
Subject(s)
Blood Loss, Surgical/prevention & control , Erythrocyte Transfusion , Factor VII/administration & dosage , Adolescent , Adult , Age Factors , Aged , Blood Loss, Surgical/mortality , Child , Child, Preschool , Erythrocyte Transfusion/adverse effects , Erythrocyte Transfusion/methods , Erythrocyte Transfusion/mortality , Factor VIIa , Female , Humans , Infant , Male , Middle Aged , Recombinant Proteins/administration & dosage , Treatment OutcomeABSTRACT
Bleeding owing to portal hypertensive colopathy, a form of large bowel angiodysplasia, as a cause of increased blood transfusion requirement is described in a 74 year old man with idiopathic myelofibrosis. The proposed mechanism and the potential therapeutic options for this rare complication of myelofibrosis are discussed.
Subject(s)
Angiodysplasia/complications , Colonic Diseases/complications , Hypertension, Portal/complications , Primary Myelofibrosis/complications , Splenomegaly/complications , Aged , Angiodysplasia/pathology , Angiodysplasia/therapy , Blood Transfusion , Colon , Colonic Diseases/pathology , Colonic Diseases/therapy , Fatal Outcome , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/pathology , Gastrointestinal Hemorrhage/therapy , Humans , Hypertension, Portal/pathology , Hypertension, Portal/therapy , Intestinal Mucosa/blood supply , Intestinal Mucosa/pathology , Male , Primary Myelofibrosis/pathology , Primary Myelofibrosis/therapy , Splenomegaly/pathology , Splenomegaly/therapyABSTRACT
We report a 71-year-old man who presented with severe subcutaneous and later psoas muscle haemorrhage in the presence of a raised white cell count and hepatosplenomegaly. A circulating factor VIII (FVIII) inhibitor was detected and bone marrow morphology confirmed the presence of a myeloproliferative/myelodysplastic disorder. Initial treatment with high dose FVIII followed by recombinant factor VIIa was unsuccessful. Haemorrhage was controlled by the administration of activated prothrombin complex concentrate (FEIBA; Baxter healthcare, CA, USA) in combination with prednisolone, cyclophosphamide and i.v. immunoglobulin. The inhibitor became undetectable 14 weeks after presentation. The white cell count responded initially to hydroxyurea and later to cyclophosphamide. There have been only two previous reports of acquired haemophilia A in association with myelodysplastic disorders and no previous report of an association with a myeloproliferative disorder.