Riten Kumar

Changing Paradigm of Hemophilia Management: Extended Half-Life Factor Concentrates and Gene Therapy.

Management of hemophilia has evolved significantly in the last century-from recognition of the causative mechanism in the 1950s to commercially available clotting factor concentrates in the 1960s. Availability of lyophilized concentrates in the 1970s set the stage for home-based therapy, followed by introduction of virally attenuated plasma-derived, and then recombinant factor concentrates in the 1980s and 1990s, respectively. The subsequent years saw a paradigm shift in treatment goals from on-demand therapy to prophylactic factor replacement starting at an early age, to prevent hemarthrosis becoming the standard of care for patients with severe hemophilia. In the developed world, the increasing use of home-based prophylactic regimens has significantly improved the quality of life, and life expectancy of patients with severe hemophilia. Seminal developments in the past 5 years, including the commercial availability of extended half-life factor concentrates and the publication of successful results of gene therapy for patients with hemophilia B, promise to further revolutionize hemophilia care over the next few decades. In this review, we summarize the evolution of management for hemophilia, with a focus on extended half-life factor concentrates and gene therapy.

Prevalence and risk factors for post thrombotic syndrome after deep vein thrombosis in children: A cohort study

BACKGROUND While post thrombotic syndrome (PTS) is increasingly recognized as a frequent and potentially serious complication of deep vein thrombosis (DVT) in children, limited information is available regarding predictors of PTS. METHODS Using the Mayo Clinic Master Diagnostic Index, all pediatric patients (age 0 to 18 years) with a potential DVT based on ICD-8 codes over the 15-year period, 1995 to 2009 were identified. A validated PTS survey instrument was mailed to eligible patients followed by a second mailing and three reminder phone calls for non-responders. Baseline clinical and radiographic characteristics were abstracted from patient medical records and tested as potential predictors of PTS using logistic regression. Associations were summarized by calculating odds ratios (OR) and corresponding 95% confidence intervals. RESULTS Ninety patients agreed to participate. The mean age (±SD) at DVT diagnosis and survey completion were 12.8 (±6.1) and 19.3 (±7.7) years, respectively. Fifty three respondents (59%) reported mild PTS whereas 12 (13%) reported moderate-to-severe PTS. Pain (34%) and dilated blood vessels (40%) were the most frequent PTS symptom and sign, respectively. On multivariate analysis, predictors of PTS included duration between incident DVT and survey completion (OR 1.75; 95% CI: 1.08-2.84) and number of thrombosed vein segments (OR 1.40; 95% CI: 1.05-1.86). CONCLUSION Over 70% of children with DVT report subsequent symptoms or signs of PTS, though only 13% report clinically significant, moderate-to-severe PTS. Number of thrombosed vein segments at diagnosis and time duration between incident DVT and survey completion were independent predictors of PTS.

Clinical presentation and molecular basis of congenital antithrombin deficiency in children: a cohort study

In this study we report the largest descriptive cohort of congenital antithrombin (AT) deficiency in children, its clinical presentation, molecular basis and genotype‐phenotype correlation. Paediatric patients diagnosed with AT deficiency at two tertiary care childrens hospitals over a 10‐year period were retrospectively reviewed. SERPINC1 gene sequencing was offered to subjects who did not already have the test performed. Molecular modelling and stability simulations were performed for the novel mutations identified. Twenty‐nine subjects from 18 pedigrees were identified. Mean age (± standard deviation) at diagnosis and mean duration of follow‐up were 8·4 (± 6·6) years and 6·6 (± 5·7) years respectively. Most recent mean AT activity and AT antigen levels (n = 20) were 0·53 (± 0·09) iu/ml and 0·60 (± 0·17) iu/ml respectively. Ten subjects were diagnosed secondary to low AT activity measured following venous thrombo‐embolism (VTE). All 10 subjects had additional risk factors at the time of VTE. None of the 19 subjects diagnosed with AT deficiency in the setting of positive family history have had VTE with 7·4 (± 5·8) years follow‐up. Mutation analysis has been completed on 19 subjects from 16 pedigrees. Nine unique mutations, including 4 novel mutations were identified.

Prevalence and risk factors for venous thromboembolism in children with sickle cell disease: an administrative database study

A hypercoagulable state resulting in increased venous thromboembolism (VTE) has been described in adults with sickle cell disease (SCD), but similar data for children are lacking. The objective of this retrospective cohort study was to describe the rate of VTE and risk factors associated with VTE in children with SCD across tertiary-care childrens hospitals in the United States between the years 2009 and 2015. We used the Pediatric Health Information System database to investigate all pediatric patients with SCD admitted to 1 of 48 participating institutions between 1 January 2009 and 30 September 2015. International Classification of Disease, Ninth Edition, Clinical Modification codes were used to identify index thromboembolic events and chronic medical conditions known to be associated with VTE. Billing codes were used to identify central venous line (CVL) placement and pharmaceutical billing codes to identify estrogen containing oral-contraceptive use. Logistic regression analysis was used to study the association among unique patient characteristics, VTE, and death. 10 454 eligible subjects with SCD were identified. Median age (±interquartile range) of study cohort was 10 (±11) years. 181 subjects (1.7%) developed an index venous thromboembolic event during the study period. Median age at VTE diagnosis was 15.9 (±7.4) years. On multivariable logistic regression analysis, CVL placement, chronic renal disease, history of stroke, female sex, length of hospitalization, intensive care unit utilization, and older age were associated with VTE. After adjusting for other variables, VTE was independently associated with death. In summary, VTE can occur in pediatric patients with SCD. CVL placement is a modifiable risk factor for VTE development.

Molecular structural analysis of a novel and de-novo mutation in the SERPINC1 gene associated with type 1 antithrombin deficiency

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Thrombocytopenia Pitfalls: Misdiagnosing Type 2B von Willebrand Disease as Ethylenediaminetetraacetic Acid-Dependent Pseudothrombocytopenia.

A 9-month-old boy was referred to our emergency department for extensive bruising. Medical history was relevant for increased bleeding postcircumcision and vaccination. Baseline coagulation laboratory values were normal, and a complete blood count revealed severe thrombocytopenia (Table; available at www.jpeds.com). Review of peripheral smear revealed platelet clumps, presumed to be ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia (PTCP) (Figure). The severity of bruising raised suspicion for nonaccidental trauma, prompting the involvement of child protection services. The hemostasis-thrombosis team was consulted and additional coagulation laboratory values revealed low von Willebrand factor (vWF) antigen (32%) and ristocetin cofactor activity (<8%). vWF multimer analysis showed loss of high-molecular-weight multimers, suggesting a diagnosis of type 2B von Willebrand disease (vWD). Findings of nonaccidental trauma testing (skeletal survey, computed tomography brain scan, and ophthalmology examination) were negative. vWF exon 28 gene sequencing confirmed a sequence variant in the A1 domain, c.3940G>C, p.V1314L, which is associated with type 2B vWD.

Risk Factors for Neonatal Venous and Arterial Thromboembolism in the Neonatal Intensive Care Unit-A Case Control Study

Objective To identify risk factors associated with venous and arterial thrombosis in sick neonates admitted to the neonatal intensive care unit. Study design A case‐control study was conducted at 2 centers between January 2010 and March 2014 using the Childrens Hospital Neonatal Database dataset. Cases were neonates diagnosed with either arterial or venous thrombosis during their neonatal intensive care unit stay; controls were matched in a 1:4 ratio by gestational age and presence or absence of central access devices. Bivariable and conditional logistic regression analyses for venous and arterial thrombosis were performed separately. Results The overall incidence of neonatal thrombosis was 15.0 per 1000 admissions. A higher proportion of neonates with thrombosis had presence of central vascular access devices (75% vs 49%; P < .01) were of extremely preterm gestational age (22–27 weeks; 26% vs 15.0%; P < .05) and stayed ≥31 days in the neonatal intensive care unit (53% vs 32.9%; P < .01), when compared with neonates without thrombosis. A final group of 64 eligible patients with thrombosis and 4623 controls were analyzed. In a conditional multivariable logistic regression model, venous thrombosis was significantly associated with male sex (AOR, 2.12; 95% CI, 1.03–4.35; P = .04) and blood stream infection (AOR, 3.47; 95% CI, 1.30–9.24; P = .01). Conclusions The incidence of thrombosis was higher in our neonatal population than in previous reports. After matching for central vascular access device and gestational age, male sex and blood stream infection represent independent risk factors of neonatal venous thrombosis. A larger cohort gleaned from multicenter data should be used to confirm the study results and to develop thrombosis prevention strategies.

Mesoaortic compression of a left-sided inferior vena-cava presenting as recurrent pulmonary embolism in a child-a novel anatomic thrombophilia?

To the editor: Venous thromboembolism (VTE) is uncommon in children, with an estimated incidence of 1–2 cases/100,000 children.1 While provokedVTE is being increasingly recognized in childrenadmitted to tertiary-care hospitals, unprovoked VTE remains rare.2 A 13-year-old previously-healthy male presented to our hospital with syncope, substernal chest pain, and dyspnea. Upon evaluation, he was found to be tachycardic, tachypneic, and hypoxic. Computed tomography pulmonary angiogram (CTPA) demonstrated bilateral emboli in the main pulmonary arteries with evidence of right heart strain. Doppler ultrasounds of his lower and upper extremities were negative for deep vein thrombosis. There was no history of surgery, immobilization, trauma, smoking, or use of recreational drugs. Serum troponin-I was elevated at 1.98 ng/ml (reference range< 0.029 ng/ml). Patient was diagnosed to have submassive pulmonary embolism (PE) and was treated with catheter-directed thrombolysis, followed by therapeutic anticoagulation with enoxaparin for 6 months.3 Thrombophilia testing was completed at the 3-month appointment and was negative (Supplementary Table S1). Patient underwent a repeat CTPA and echocardiogram at the 6-month follow-up appointment which showed radiological resolution of the PE and no evidence of right ventricular dysfunction.4 Within 3 days of stopping anticoagulation, patient re-presented to the emergency department with chest discomfort and palpitation. CTPA confirmed recurrent bilateral submassive PE. Laboratory evaluation was concerning for an elevated troponin at 0.443 ng/ml. He was again treated with catheter-directed thrombolysis and subsequently started on therapeutic anticoagulation with enoxaparin. A contrastenhanced CT of his abdomen and pelvis was performed which demonstrated an enlarged left-sided inferior vena cava (IVC, megacava), marked dilation and ectasia of the iliac veins, and residual thrombus within the dilated left internal iliac vein (Figure 1A). A conventional venogram with pullback pressures obtained from the right atrium to the iliac system showed hemodynamically significant compression of the left-sided IVC as it passed from left to right between the aorta and superior mesenteric artery with stasis and turbulent flow within the IVC and dilated pelvic veins (Figure 1B). The patient is currently on long-term anticoagulation. Congenital anomalies of the IVC including left-sided IVC, duplicated IVC, and IVC atresia have been described in children.5 Most IVC anomalies are clinically silent and only diagnosed incidentally on abdominal imaging done for other indications. A singular left-sided IVC is rare with an estimated prevalence of 0.2–0.5%.5–7 This anomaly results from persistence of the left supracardinal vein instead of the right supracardinal vein.7 The left-sided IVC usually passes in front of the aorta at the mesoaortic angle to join the left renal vein.5–7 F IGURE 1 Contrast enhanced CT images of the abdomen (panel A) showed markedly dilated IVC positioned left of midline. Digitally subtracted venogram (panelB) confirmed thepresenceof a dilated left IVC with meso-aortic compression of the vein and a well-developed network of lumbar and epidural veins providing collateral drainage of the pelvis and lower extremities

Inferior vena cava atresia predisposing to acute lower extremity deep vein thrombosis in children: A descriptive dual‐center study

Thrombosis in the healthy pediatric population is a rare occurrence. Little is known about the optimal treatment or outcomes of children with unprovoked acute lower extremity (LE) deep vein thrombosis (DVT) associated with atresia of the inferior vena cava (IVC).