Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters.

The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of “VWF activity” by this assay and may not reflect a functional defect or true hemorrhagic risk.

G lanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the ITGA2B and ITGB3 genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular studies confirm the diagnosis. Management of bleeding is based on a combination of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complications. In addition, pregnant patients pose unique management challenges. This review highlights clinical and molecular aspects in the approach to patients with GT, with particular emphasis on the significance of multidisciplinary care.

© F e r r a t a S t o r t i F o u n d a t i o ntors include the relatively low incidence compared with that in adults, slow acceptance by some pediatricians of the increasing incidence of HA-VTE, lack of evidence on preventability, and -in particular -the paucity of studies applying appropriate methodologies for establishing independent risk factors and validating risk models derived from them. Challenges regarding how to best/consistently define a risk factor -e.g. immobility-also exist, as they do in adults.Lending further credence to the importance of developing evidence-based HA-VTE prevention guidelines for children, the International Society of Thrombosis and Haemostasis (ISTH) convened a Working Group, via the Pediatric/Neonatal Hemostasis and Thrombosis Subcommittee Scientific and Standardization Committee (SSC), to develop recommendations for standardization and future research regarding pediatric HA-VTE risk factors and risk assessment models. As a prerequisite to the development of guidelines, current evidence must be rigorously analyzed. Accordingly, the purpose of this report is to present findings of a systematic review and metaanalysis of the literature on pediatric HA-VTE risk factors and risk-assessment models. Methods Search strategyWe identified English articles using PubMed (1946-May, 2014 and Embase (1980-May, 2014. The search strategies comprised "venous thromboembolism," "risk" and "children" with multiple subject headings and text-words per concept. Given the large body of VTE literature, we began with a sensitive query and progressively specified subsequent queries using major focus syntax and text-word title field restrictions. Selectively exploding subject headings, with relevant subcategories, permitted ever-increasing specificity. The full search strategy for Pubmed is available as Online Supplementary Table S1. Study selectionWe excluded studies of patients older than 21 years based on the definition of pediatric age from the National Institute of Child Health and Human Development. 9 For studies that included pediatric and adult patients, we excluded those without clear subanalyses for patients under 21 years. Similarly, we excluded studies on arterial thromboembolism unless cases of VTE were included and clearly delineated in sub-analyses. Studies were categorized as narrative reviews, commentaries, single case reports, retrospective case series, cross-sectional studies, case-control studies, cohort studies (retrospective and prospective), registry studies, or clinical trials, the first three of which were excluded. Cases series were retained if they included at least 40 cases. Conflicting opinions regarding study design, where insufficiently or inconsistently described, were resolved through group consensus. Data extractionThe following data were initially extracted by a pair of reviewers (BB, AM) and independently confirmed by a second pair (LR, CHvO): study design; number of patients/hospital unit; summary statistics on patients' age, gender; VTE location; time from VT...

BackgroundStudies evaluating risk factors for in-hospital venous thromboembolism in children are limited by quality assurance of case definition and/or lack of controlled comparison. The objective of this study is to determine risk factors for the development of in-hospital venous thromboembolism in children. Design and MethodsIn a case-control study at The Children's Hospital, Colorado, from 1 st January 2003 to 31 st December 2009 we employed diagnostic validation methods to determine pediatric in-hospital venous thromboembolism risk factors. Clinical data on putative risk factors were retrospectively collected from medical records of children with International Classification of Diseases, 9th edition codes of venous thromboembolism at discharge, in whom radiological reports confirmed venous thromboembolism and no signs/symptoms of venous thromboembolism were noted on admission. ResultsWe verified 78 cases of in-hospital venous thromboembolism, yielding an average incidence of 5 per 10,000 hospitalized children per year. Logistical regression analyses revealed that mechanical ventilation, systemic infection, and hospitalization duration of five days or over were statistically significant, independent risk factors for in-hospital venous thromboembolism (OR=3. ConclusionsThese data indicate that risk of in-hospital venous thromboembolism in children with this risk factor combination may exceed that of hospitalized adults in whom prophylactic anticoagulation is indicated. Substantiation of these findings via multicenter studies could provide the basis for future risk-stratified randomized control trials of pediatric venous thromboembolism prevention.

PURPOSE Young individuals with occlusive, proximal limb DVT who have acutely elevated plasma levels of factor VIII and D-dimer are at high risk for post-thrombotic syndrome (PTS) when treated with conventional anticoagulation alone. We sought to evaluate our experience with adjunctive percutaneous mechanical/pharmacomechanical thrombolysis (PMT/PPMT) in such patients. PATIENTS AND METHODS Among 95 children 11 to 21 years of age enrolled in a prospective cohort of venous thromboembolism between March 1, 2006 and November 1, 2009, 16 met eligibility criteria and underwent PMT/PPMT, typically with adjunctive catheter-directed thrombolytic infusion (CDTI) of tissue-type plasminogen activator given post-procedure. RESULTS Median age was 16 years (range: 11–19 years). Thirteen cases (81%) involved lower limbs. Underlying stenotic lesions were disclosed in 53%, with endovascular stents deployed in all cases of May-Thurner. There were no peri-procedural major bleeding events and one symptomatic pulmonary embolism. Technical success rate was 94%. Early (<30 days) locally recurrent DVT developed in 40%, of which 83% were successfully re-lysed. Late recurrent DVT rate (median follow-up duration: 14 months [range: 1–42 months]) was 27%. Cumulative incidence of physically and functionally significant PTS at 1–2 years was 13%. CONCLUSION This experience provides prospective evidence that PMT/PPMT with adjunctive CDTI can be used safely and effectively in adolescents with DVT at high risk for PTS.

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