Tina Biss

Clinical features and outcome of pulmonary embolism in children

Pulmonary embolism (PE) is rare in childhood but evidence suggests it is under‐recognised. Children diagnosed with PE at a large tertiary centre over an 8‐year period were retrospectively reviewed. Fifty‐six children with radiologically proven PE were identified, 31 males and 25 females, median age 12 years. Eighty‐four per cent had symptoms of PE. Risk factors for thromboembolism were present in 54 patients (96·4%); most commonly immobility (58·9%), central venous line (35·7%) and recent surgery (28·6%). Investigation revealed a thrombophilic abnormality in 14/40 patients (35%). Concurrent deep vein thrombosis was confirmed in 31 patients (55·4%), predominantly lower limb. D dimer was elevated at presentation in 26/30 patients (86·7%). Eight patients underwent systemic thrombolysis. An inferior vena cava filter was placed in five patients. Therapy was complicated by major haemorrhage in 12 patients (21·4%). The majority (82·1%) had complete or partial resolution of PE following a median of 3 months anticoagulation. Seven patients had a recurrent thromboembolic event and 12 patients died (mortality 21·4%); five due to thromboembolism (8·9%) and two due to haemorrhage. Risk factors for PE in children are distinct from adults and morbidity and mortality is significant. Multicentre prospective studies are required to determine optimal treatment and long‐term outcome of childhood PE.

Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire.

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.

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Use of a quantitative pediatric bleeding questionnaire to assess mucocutaneous bleeding symptoms in children with a platelet function disorder

is a common complication following splenectomy in patients with malignant haematological diseases. Eur J Haematol 2006; 77: 203–9. 11 van t Riet M, Burger JW, van Muiswinkel JM, Kazemier G, Schipperus MR, Bonjer HJ. Diagnosis and treatment of portal vein thrombosis following splenectomy. Br J Surg 2000; 87: 1229–33. 12 Winslow ER, Brunt LM, Drebin JA, Soper NJ, Klingensmith ME. Portal vein thrombosis after splenectomy.Am J Surg 2002; 184: 631–5. 13 Parker HH III, Bynoe RP, Nottingham JM. Thrombosis of the portal venous system after splenectomy for trauma. J Trauma 2003; 54: 193– 6. 14 Peacock AJ. Pulmonary hypertension after splenectomy: a consequence of loss of the splenic filter or is there something more? Thorax 2005; 60: 983–4. 15 Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among post-splenectomy patients. J Infect 2001; 43: 182–6. 16 Cullingford GL, Watkins DN, Watts AD, Mallon DF. Severe late postsplenectomy infection. Br J Surg 1991; 78: 716–21. 17 Ejstrud P, Kristensen B, Hansen JB, Madsen KM, Schonheyder HC, Sorensen HT. Risk and patterns of bacteraemia after splenectomy: a population-based study. Scand J Infect Dis 2000; 32: 521–5. 18 Schwartz PE, Sterioff S, Mucha P, Melton LJ III, Offord KP. Postsplenectomy sepsis andmortality in adults. JAMA 1982; 248: 2279–83. 19 Mellemkjoer L, Olsen JH, Linet MS, Gridley G, McLaughlin JK. Cancer risk after splenectomy. Cancer 1995; 75: 577–83. 20 Frank L Epidemiology. When an entire country is a cohort. Science 2000; 287: 2398–9. 21 Wiseman J, Brown CV, Weng J, Salim A, Rhee P, Demetriades D. Splenectomy for trauma increases the rate of early postoperative infections. Am Surg 2006; 72: 947–50. 22 Boxer MA, Braun J, Ellman L. Thromboembolic risk of postsplenectomy thrombocytosis. Arch Surg 1978; 113: 808–9. 23 Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Mannucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol 2000; 111: 467–73. 24 Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338: 1169– 73. 25 KniffinWD. Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861–6. 26 Larsen TB, Johnsen SP, Moller CI, Larsen H, Sorensen HT. A review of medical records and discharge summary data found moderate to high predictive values of discharge diagnoses of venous thromboembolism during pregnancy and postpartum. J Clin Epidemiol 2005; 58: 316–9. 27 Goldhaber SZ. Pulmonary embolism. Lancet 2004; 363: 1295–305. 28 Kyrle PA, Eichinger S. Deep vein thrombosis.Lancet 2005; 365: 1163– 74. 29 Sorensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370: 1773–9. 30 Schmidt LM, Foli-Andersen NJ, Rasmussen HM, Wille-Jorgensen PA. Thrombo-prophylaxis in Danish surgical departments. Status 2005 and 25 years development. Ugeskr Laeger 2008; 170: 947– 51.

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.

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified “pathogenic” or “likely pathogenic” variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.

Recombinant Activated Factor VII (rFVIIa) in the Management of Major Obstetric Haemorrhage: A Case Series and a Proposed Guideline for Use

Major obstetric haemorrhage remains a significant cause of maternal morbidity and mortality. Previous case reports suggest the potential benefit of recombinant activated factor VII (rFVIIa: NovoSevenR) as a haemostatic agent. We performed a retrospective review of the use of rVIIa in major obstetric haemorrhage in the Northern Region between July 2004 and February 2007. Fifteen women received rFVIIa. The median patient age was 34 years. Major haemorrhage occurred antepartum (5 patients), intrapartum (1), and postpartum (9). All women received an initial dose of 90 mcg/kg rFVIIa and one received 2 further doses. Bleeding stopped or decreased in 12 patients (80%). Additional measures included antifibrinolytic and uterotonic agents, Rusch balloon insertion, uterine curettage/packing, and vessel embolisation. Eight patients required hysterectomy. All women survived to discharge from hospital. No adverse events, including thrombosis, were recorded. This study provides further support for the safety and efficacy of rFVIIa as adjunct therapy in major obstetric haemorrhage.

The use of elastic compression stockings for post-thrombotic syndrome in a child.

Post‐thrombotic syndrome (PTS) is a potential complication following deep vein thrombosis (DVT) in children. Guidelines for management of PTS in children are non‐existent. The absence of guidelines may limit the use of elastic compression stockings (ECS), offered for prevention and treatment of PTS in adults. We report the case of a 6‐year‐old, who developed PTS following a presumed line‐related lower limb DVT, with dramatic improvement in functional status with ECS use. The presented case highlights the subtle nature of symptoms, potential benefits and limitations of ECS use for PTS, and current lack of evidence in children. Pediatr Blood Cancer 2009;53:462–463.

Comparison of 'time within therapeutic INR range' with 'percentage INR within therapeutic range' for assessing long-term anticoagulation control in children.

Maintenance of anticoagulation response to warfarin within target therapeutic range (TTR) is essential to minimize the risk of either thromboembolism or hemorrhage caused by underor over-dosing, respectively. Anticoagulation control in children receiving chronic warfarin therapy has been reported by many studies to be poor [1–3]. The increasing use of point-of-care testing devices and parent/patient education programmes for anticoagulated children has somewhat improved control but it remains suboptimal when compared with anticoagulated adults [4–7]. Anticoagulant control in children is usually reported as the percentage of International Normalised Ratio (INR) values within TTR (%ITTR) [1–4,6]. However, the advent of pointof-care testing devices has allowed INR testing to occur more frequently during periods of instability, which might render the use of %ITTR an inappropriate form of assessing anticoagulation control. An alternative method described by Rosendaal et al. [8] measures percentage time in therapeutic range (%TIR) using linear interpolation. This method allocates an INR value to each day, including days between INR tests, and is therefore likely to minimize the disproportionate effect of temporary frequent INR testing on the assessment of long-term anticoagulant control. This study compared the %ITTR method with the %TIR method for assessing anticoagulant control in a cohort of children treated with warfarin. Anticoagulant records and hospital notes for children who were anticoagulated with warfarin under the care of paediatric cardiology services at The Freeman Hospital, Newcastle upon Tyne, were examined retrospectively. Data were collected from 3 months after the start of anticoagulant therapy and included demographic details, indication for warfarin therapy, target INR range, INR values, frequency of INR tests and occurrence of thromboembolic and hemorrhagic events. The cohort was divided into subgroups according to target INR range (2.0–3.0 or 2.5–3.5) and indication for anticoagulant therapy (Fontan circulation, other cardiac indication or non-cardiac indication). The patient cohort was divided into four age groups (£ 1, 2–5, 6–12 or 13–17 years) according to age at the time of each INR measurement. Data were inputted into 4S Dawn Clinical Software (4S Information Systems Ltd, Milnthorpe, UK) in order to calculate %TIR using the linear interpolation methodology described previously by Rosendaal et al. [8]. The average %ITTR and %TIR were determined for each patient for the duration of their anticoagulant monitoring. %ITTR was compared to %TIR using a paired t-test and the differences between %ITTR and %TIR were compared between subgroups. Mean number of dose changes per month was compared between subgroups, following logarithmic transformation to achieve approximate normality within groups, using the t-test or one-way analysis of variance (ANOVA). Mean number of INR measurements per month was compared between subgroups using the Mann–Whitney test or Kruskall–Wallis test. Statistical analysis was performed usingMinitab v15.0 (Coventry, UK) andP-values< 0.05were considered significant. Anticoagulation records for 38 consecutive children (21 boys) with a median age of 8.3 years (range, 1.1–17.2 years), anticoagulated with warfarin between January 1996 and April 2009, were reviewed. All children were monitored using a point-of-care testing device (Coaguchek S or Coaguchek XS; Roche Diagnostics Ltd, Burgess Hill, UK) and received advice on warfarin dose by telephone contact with the same two pediatric cardiology nurse specialists. Indications for anticoagulant therapy were: Fontan procedure, 16 patients; prosthetic mitral valve replacement, eight; primary pulmonary hypertension, four; cardiomyopathy, three; coronary aneurysm, one; thrombotic stroke, one; and truncus arteriosus repair, one. Patients were monitored for a median of 29 months (range, 2– 115 months) and data were collected for a total of 112 years of warfarin therapy. Treatment outcome variables are shown in Table 1.P-values correspond to the differences between %ITTR and %TIR for the entire cohort and for each of the subgroups. For the entire cohort, mean %TIR was significantly higher than the mean Correspondence: Tina T. Biss, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK. Tel.: +44 191 2448858; fax: +44 191 2820814. E-mail: t.t.biss@ncl.ac.uk

Emergency warfarin reversal with prothrombin complex concentrates: UK wide study.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2141. 2008.07028.x (This link will take you to the article abstract). Please note: Blackwell Publishing are not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.