Anthony Kam Chuen Chan

Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease

Summary.  Venous thromboembolic events (VTEs) in children are usually associated with underlying clinical conditions. The added contribution of prothrombotic conditions to the occurrence of VTEs in children is not clear. This study reports the prevalence of prothrombotic conditions in 171 consecutive children with VTE followed in the Hospital for Sick Children Thrombosis Outpatient Clinic. The median age of the children at the time of VTE was 2.3 months (range 1 day to 16.5 years). An underlying medical condition and a central venous line (CVL) were present in 156 (91%) and 132 (77%) of 171 children, respectively. A positive family history was present in 8% of children. The prevalence of factor V Leiden was 4.7%, prothrombin G20210A polymorphism was 2.3%, protein S deficiency was 1.2%, protein C deficiency was 0.6% and increased plasma lipoprotein (a) concentration (>30 mg dL−1) was 7.5% (tested in 107 children). The overall frequency of inherited prothrombotic coagulation proteins was 13% (95% confidence interval 7 to 19%) and the frequency was not significantly different between neonates and older children with VTE. Inherited prothrombotic coagulation proteins were not associated with gender, CVL‐related VTE, a positive family history of thrombosis or spontaneous VTE in neonates. Increased frequency of inherited prothrombotic coagulation proteins was, however, found in older children with spontaneous VTE (60%) compared with older children with VTEs secondary to an underlying medical condition (10%) (P = 0.02). In conclusion, this study indicates that inherited prothrombotic coagulation proteins do not contribute significantly to the pathogenesis of VTEs in neonates and children, in whom the most significant etiological factors are the presence of a CVL and/or other medical conditions.

Clinical probability score and D‐dimer estimation lack utility in the diagnosis of childhood pulmonary embolism

Summary.  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.

Musculoskeletal health of subjects with hemophilia A treated with tailored prophylaxis: Canadian Hemophilia Primary Prophylaxis (CHPS) Study

Full‐dose prophylaxis is very effective at minimizing joint damage but is costly. Tailored prophylaxis has been proposed as a way of reducing costs while still protecting joints.

Definition of post‐thrombotic syndrome following lower extremity deep venous thrombosis and standardization of outcome measurement in pediatric clinical investigations

N. A . GOLDENBERG,* L . R . BRANDÃO,§ J . J OURNEYCAKE ,– S . R . KAHN,** P . MONAGLE , S . REVEL -V I LK , A. SHAR ATHKUMA R,§ § and A . K . C . C HA N–– ON BEH ALF OF TH E PER I NA TAL AND P AEDIAT R IC H AEMOSTA S IS SUB COMMITT EE OF THE SC IENT I F IC A ND ST AN DA RD IZA T ION COMMITT EE OF THE INTERNAT I ONA L SOCI ETY O N THROMBOS IS AND HAEMOSTAS IS *Section of Hematology/Oncology/Bone Marrow Transplantation, Department of Pediatrics; Division of Hematology/Oncology, Department of Medicine, Children s Hospital Colorado, The Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado; CPC Clinical Research, Aurora, CO, USA; §Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada; –Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA; **Center for Clinical Epidemiology and Community Studies, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada; Department of Clinical Haematology, Royal Children s Hospital, University of Melbourne, Melbourne, Vic., Australia; Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, Jerusalem, Israel; §§Division of Hematology/Oncology and Stem Cell Transplantation, Children s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; and ––Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada

Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti‐factor Xa levels

Summary.  Background: Unfractionated heparin (UFH) is a widely used anticoagulant. Current American College of Chest Physicians guidelines for infants extrapolated from adults recommend 28 U kg−1 h−1 of UFH to achieve an anti‐factor Xa level of 0.35–0.7 IU mL−1. Objective: To assess the profile of anti‐FXa‐based UFH dosing guidelines in infants. Patients/Methods: We included all infants aged < 6 months treated with per‐protocol intravenous UFH at the Hospital for Sick Children, Toronto, over a 3.5‐year period. Results: Of 100 infants, 11% achieved sustained therapeutic anti‐FXa levels with current dose recommendations. Only 15% achieved target anti‐FXa levels within 24 h with per‐protocol dose escalations. Seventeen per cent of patients never achieved therapeutic anti‐FXa levels, despite up to 60 days of therapy and triple the recommended dose. The median dose needed to achieve therapeutic anti‐FXa levels in the remaining 83 infants was 33 U kg−1 h−1 (interquartile range, 30–36). Two in three infants had decreased thrombus size at completion of therapy and no thrombus progression/recurrence, and 11/100 infants suffered major bleeding. Without exclusion of extracorporeal membrane oxygenation patients, an activated partial thromboplastin time (APTT) of > 180 s was detected as a risk factor for major bleeding. Conclusions: UFH monitoring is challenging in infants. Despite their delay in reaching therapeutic anti‐FXa levels, infants monitored with the adult‐based anti‐FXa range have a high thrombus resolution rate, no thrombus progression, but a relatively high bleeding rate. Extreme APTT elevation may contribute to this bleeding risk, particularly in critically ill patients. Current UFH guidelines for young infants may still be inadequate, and laboratory methods with age‐appropriate ranges may be required to further improve clinical outcomes within this population.

Standardization of post‐thrombotic syndrome definition and outcome assessment following upper venous system thrombosis in pediatric practice

S . REVE L -V I LK , * L . R . BRANDÃ O, J . J O U RNEYC AKE , A. GOLDENBERG,§ P . MONAGLE ,– A. S H ARA TH K UMA R ** and A . K . C . CH AN , , O N BEHA LF OF TH E PER I NA TAL AN D P AED IAT R IC HAEMOSTAS I S SUBCOMMITTEE OF THE SC IENT IF I C AND STANDARDIZ AT ION COMMITTEE OF THE IN TERN AT IONA L SOC IETY ON TH ROMBOS IS AN D H AEMOSTA S IS *Department of Pediatric Hematology/Oncology, Hadassah Hebrew-University Hospital, Jerusalem, Israel; Division of Hematology/Oncology/ Bone Marrow Transplantation, Department of Paediatrics, Hospital for Sick Children, Toronto, Canada; Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; §Division of Hematology/Oncology, Department of Pediatrics, Section of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, the Mountain States Regional Hemophilia and Thrombosis Center, and CPC Clinical Research, Children s Hospital Colorado, University of Colorado, Aurora, CO, USA; –Department of Clinical Haematology, Royal Children s Hospital, University of Melbourne, Melbourne, Australia; **Division of Hematology/Oncology and Stem Cell Transplantation, Ann and Rober H. Lurie Children s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; and Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, Canada

Effect of a novel covalent antithrombin-heparin complex on thrombin generation on fetal distal lung epithelium.

Respiratory distress syndrome is characterized by fibrin deposition in the lung. Fibrin adversely affects surfactant function and stimulates proliferation of fibroblasts. There is evidence that these properties may be important to the development of bronchopulmonary dysplasia. Despite successful initial treatment of neonatal respiratory distress syndrome with surfactant, the incidence of bronchopulmonary dysplasia has not decreased. In previous studies, it has been demonstrated that rat fetal distal lung epithelium (FDLE) possesses both procoagulant and anticoagulant properties. In this report, we have demonstrated (using factor VII-deficient plasma) that tissue factor is expressed on the FDLE surface and promotes thrombin generation. To regulate thrombin within this procoagulant environment, we have developed a novel anticoagulant, antithrombin-heparin covalent complex (ATH) that can be retained within the lung after intrapulmonary instillation. We have demonstrated that ATH was superior to antithrombin plus standard heparin in suppressing thrombin generation ( P < 0.001) and prothrombin consumption ( P < 0.01) in recalcified defibrinated plasma on the surface of FDLE. Further studies with ATH in vivo need to be performed.Respiratory distress syndrome is characterized by fibrin deposition in the lung. Fibrin adversely affects surfactant function and stimulates proliferation of fibroblasts. There is evidence that these properties may be important to the development of bronchopulmonary dysplasia. Despite successful initial treatment of neonatal respiratory distress syndrome with surfactant, the incidence of bronchopulmonary dysplasia has not decreased. In previous studies, it has been demonstrated that rat fetal distal lung epithelium (FDLE) possesses both procoagulant and anticoagulant properties. In this report, we have demonstrated (using factor VII-deficient plasma) that tissue factor is expressed on the FDLE surface and promotes thrombin generation. To regulate thrombin within this procoagulant environment, we have developed a novel anticoagulant, antithrombin-heparin covalent complex (ATH) that can be retained within the lung after intrapulmonary instillation. We have demonstrated that ATH was superior to antithrombin plus standard heparin in suppressing thrombin generation (P < 0.001) and prothrombin consumption (P < 0.01) in recalcified defibrinated plasma on the surface of FDLE. Further studies with ATH in vivo need to be performed.

Recommendations for developing uniform laboratory monitoring of heparinoid anticoagulants in children

F . NEWALL ,* § A . K . CH A N ,– V . IG NJA TOVIC ,* § and P . MO NA GLE , * § O N B EHA LF O F TH E PER I NA TAL A ND PAEDIA TR IC HA EMOSTA S IS SUBCOMMIT TEE OF THE SC IE NT I F IC A ND STANDARDIZAT ION COMMITTEE OF THE I NTERNAT I ONAL SOCI ETY FOR THR OMBOS I S A ND HAEMOSTAS I S *Clinical Haematology Department, Royal Children s Hospital, Melbourne; Department of Paediatrics, University of Melbourne, Melbourne; Department of Nursing, University of Melbourne, Melbourne; §Haematology Research Group, Murdoch Childrens Research Institute, Melbourne, Australia; and –Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Canada

Recommendations for standardized risk factor definitions in pediatric hospital‐acquired venous thromboembolism to inform future prevention trials: communication from the SSC of the ISTH

B . R . BRANCHFORD,* A . MAHAJER IN ,† L . RAFF IN I ,‡ E . CHALMERS ,§ C. H . VAN OMMEN, ¶ A. K . C . CHAN,** N . A . GOLDENBERG††‡‡§§¶ ¶ and FOR THE SUBCOMMITTEE ON PED IATR IC/ NEONATAL HEMOSTAS I S AND THROMBOS IS *Department of Pediatrics, Section of Hematology/Oncology and the Hemophilia and Thrombosis Center, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO; †Division of Hematology CHOC Children’s Specialists, Orange, CA; ‡Department of Pediatrics Division of Hematology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; §Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK; ¶Department of Pediatric Haematology, Emma Children’s Hospital/Academic Medical Centre, Amsterdam, the Netherlands; **Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada; ††Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; ‡‡Johns Hopkins Medicine Pediatric Thrombosis Program Johns Hopkins All Children’s Hospital, St. Petersburg, FL; §§Johns Hopkins Children’s Center Baltimore, MD; and ¶¶All Children’s Research Institute, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA