Medical decisions in hemophilia care are primarily related to the type of factor replacement and treatment regimen. With the growing number of treatment options for patients with hemophilia, decision making is more complex and requires careful consideration of benefits, risks, and patient goals. Shared decision making and decision-aid tools facilitate patient and healthcare provider communication. In this review, the overall role of shared decision making in medicine is outlined, with special emphasis on models for practical implementation. Examples of shared decision making in hemophilia are outlined, and application to new therapeutics is discussed through a case-based approach.
Superior vena cava syndrome (SVCS) results in vascular, respiratory, and neurologic compromise. A systematic search was conducted to determine the prevalence of pediatric SVCS subtypes and identify clinical characteristics/treatment strategies that may influence overall outcomes. Data from 101 case reports/case series (142 patients) were analyzed. Morbidity (30%), mortality (18%), and acute complications (55%) were assessed as outcomes. Thrombosis was present in 36%, with multi-modal anticoagulation showing improved outcome by >50% (P = 0.004). Infant age (P = 0.04), lack of collaterals (P = 0.007), acute complications (P = 0.005), and clinical presentation may have prognostic utility that could influence clinical decisions and surveillance practices in pediatric SVCS.
Background: Pediatric venous thromboembolism (VTE) has increased over the past 10 years, with central venous catheters (CVC) being the strongest risk factor. Current tools are not sufficient to predict VTE risk. The utility of biomarkers in predicting CVC-related VTE has been minimally explored. Our objective is to determine the utility of microparticles (MPs), factor VIII (FVIII) activity, and thrombin generation (TG) in prospectively predicting VTE occurrence in hospitalized children with CVCs. Procedure:In this nested case-control pilot study, consecutive hospitalized children needing CVC placement (1 month to 21 years) were enrolled. Venous samples were collected prior to or within 24 h of CVC placement. MPs were measured using factor Xa initiated clot-based assay. FVIII was measured using a one-stage clot-based assay. TG was measured using calibrated automated thrombogram.Results: There were three CVC-related VTE events (7%) in our cohort of 42 subjects. Xa clotting time (XaCT) ratio was lower (0.68 ± 0.07 vs 0.95 ± 0.21, P = .4), while FVIII (461 ± 120 vs 267 ± 130, P = .02), peak thrombin (418 ± 89 vs 211 ± 101, P = .001), endogenous thrombin potential (ETP) (1828 ± 485 vs 1282 ± 394, P = .03), and velocity index (VI) (182 ± 28 vs 75 ± 53, P = .001) were higher in subjects with CVC-related VTE compared to those without CVC-related VTE. Sensitivity/specificity analysis revealed optimal cutoff values for XaCT ratio (0.75), FVIII (370), ETP (1680), peak (315), and VI (130), with receiver operating characteristic area under the curve values >0.9.Conclusion: MPs, FVIII, and TG can potentially predict pediatric CVC-related VTE in a prospective fashion. Stratification according to VTE risk may aid in guiding preventative efforts in future studies.
Background: Pediatric hospital-acquired venous thromboembolism (HA-VTE) has increased over the past ten years (Raffini et al. Pediatrics 2009; 124; 1001-1008), with an associated increase in both VTE-associated complications and treatment-related adverse events. Children with VTE have a four-fold increase in length of admission compared to children without VTE. There are many known clinical risk factors but the presence of central venous lines (CVLs) has been shown to be among the strongest risk factors in children (Mahajerin et al. Haematologica 2015 Aug; 100(8): 1045-50). Current tools, including clinical risk-prediction scoring systems as well as genetic risk factors, are not sufficient to predict VTE risk at this time. Identification of dependable, rapid and cost-effective biomarkers for the prediction of VTE in children with CVLs is essential in guiding anti-coagulation prophylaxis, thus reducing VTE occurrence among hospitalized children with CVLs. Objectives: Determine the ability of thrombin generation (TG) and microparticle-based phospholipid-dependent procoagulant potential (MP-PPL) to predict VTE occurrence in hospitalized children with CVLs. Methods: Plasma sample were collected from 34 hospitalized acutely ill children between the age of 1 month and 21 years, who are at risk for VTE due to multiple known clinical risk factors, including a newly placed non-tunneled CVL. Children that had undergone a recent cardiac catheterization or on dialysis, plasmapheresis or ECMO were excluded. Samples from 16 age matched healthy controls were also collected. Venous samples were collected prior to CVL placement. Platelet poor plasma (PPP) was obtained according to a strict protocol to minimize pre-analytical variable. All pertinent clinical and laboratory information was extracted, including CVL-related variables and details of VTE in affected subjects. TG was measured by means of the calibrated automated thrombogram (CAT). MP-PPL was measured using two methods: 1) Functional assay that detects the ability of circulating MPs to indirectly facilitate thrombin generation (Zymuphen MP-Activity kit, Hyphen BioMed, France), 2) Clot-based assay that measures phospholipid-dependent, factor Xa initiated clotting time in relation to normal controls (STA-Procoag-PPL, Diagnostica Stago). Results: The median age of our cohort was 10 yrs (IQR 12, range 0 - 19), with a slight male predominance (53%) and increased representation of adolescents (41%). CVLs were placed in an intensive care setting in 38% of subjects and 39% of subjects had an underlying condition associated with chronic inflammation. The median duration of CVL placement from admission was 2 days (IQR 5, range 1 - 19) and the median total duration of CVLs were 14 days (IQR 20, range 5 - 84). Line-associated VTE occurred in 9% (3/34) of children with CVL and one subject had a VTE unrelated to CVL. There was no observed significant difference between children with or without line-related VTE in terms of age, gender, lag of CVL placement from admission, duration of CVLs, caliber of initial vessel of insertion, number of lumens, size of CVL and internal length of the CVL. However, all subjects with line-associated VTE were admitted for acute infection to an intensive care setting, with the majority of VTE occurring within 48 hours from line placement (2/3). Correlation analysis of the two MP-PPL assays was significant (r = -0.659). Even though the MP-PPL functional assay did not show a significant difference between subjects with and without line-associated VTE (p-value 0.189), the MP-PPL clot-based assay showed measurable difference between the two groups, both as an absolute value and as a ratio (p-value: 0.04 and 0.038 respectively, Table 1). Peak thrombin generation (p-value 0.001), estimated thrombin potential (ETP) - (p-value 0.02) and velocity index (p-value 0.001) were significantly higher in subjects with line-associated VTE (see Figure 1). Subject recruitment and sample analyses, involving these assays and other potential biomarker candidates, are ongoing. Conclusion: Given the rising incidence of pediatric VTE, the ability to use biomarkers to stratify patients according to their VTE risk will provide a vital tool to guide preventative efforts, and minimizing unnecessary expense and toxicities. TGA and MP-PPL have shown great potential for differentiating children with CVLs that may develop a line-related VTE as a HA-VTE. Disclosures No relevant conflicts of interest to declare.
: Thromboelastography (TEG) is a global assay used for evaluating features of clot formation in vitro. Dabigatran is a reversible direct inhibitor of thrombin that has not been studied in neonates using a sophisticated global assay, such as TEG. Neonatal hemostasis differs from adult hemostasis in both quantitative and qualitative characteristics. Our aim was to compare the TEG clotting profile of neonatal and adult platelet-poor plasma when exposed to different concentrations of dabigatran. We used commercially collected adult pooled plasma and neonatal cord blood collected from placentas of healthy full term newborns. Platelet-poor plasma was isolated, pooled, and frozen. Prior to experiment, plasma was thawed and filtered. A reaction mixture of CaCl2, corn trypsin inhibitor, tissue factor, and dabigatran in imidazole buffer was mixed with plasma in a TEG cup. Time to clot initiation (R-time), speed of clot strengthening (α-angle), and maximum clot strength (maximal amplitude) were measured. Scanning electron microscopy was performed to evaluate fibrin clot structure. Without dabigatran, there was no significant difference in TEG measurements between neonatal and adult samples. However, neonatal plasma clotting with dabigatran had slower onset, slower speed, and weaker clots that were more porous with thicker fibers, compared with adult plasma clotting. Thus, neonatal plasma may be more sensitive to dabigatran as assessed by our in-vitro TEG study.
Background: Non-severe hemophilia A and B account for 50% of patients with hemophilia, in which factor level does not consistently correlate with bleeding phenotype. Clinical decision-making in regards to timely prophylaxis initiation and tailored surgical management could be informed by a biomarker that is more predictive of bleeding phenotype. We hypothesized that a global method to assess clotting potential, such as thrombin generation (TG), is more predictive of bleeding phenotype than factor level. Objectives: Determine the ability of TG, as compared to standard baseline factor activity, to differentiate bleeding phenotype severity in patients with non-severe hemophilia. Methods: Subjects were recruited from two hemophilia treatment centers (HTCs): Rady Children's Hospital San Diego (RCHSD) and Center for Inherited Blood Disorders (CIBD). Subjects were eligible for enrollment if they were at least one year of age and had a diagnosis of non-severe congenital hemophilia A or B, or were genetically confirmed or suspected female carriers. All enrolled patients or their parents completed the standardized, self-administered pediatric bleeding questionnaire (Self-PBQ) or bleeding assessment tool (Self-BAT). Clinical and laboratory information were extracted from the medical chart, including age at diagnosis, bleeding event history, past surgical history, treatment history and factor VIII or IX gene analysis. Validation of self-reported bleeding symptoms was performed using chart-derived data. Bleeding phenotype was assessed using standard calculation of the bleeding score, as defined by the respective validated self-reported tools. For the purpose of this analysis, we defined a high bleeding score as 13 or more, while a low bleeding score was defined as 12 or less. After a washout period of 5x the standard half-life of the administered factor product, blood samples were collected at time of enrollment. Platelet poor plasma was obtained according to a strict protocol to minimize pre-analytical variables. TG was measured by means of the calibrated automated thrombogram, with three different reagents: low (1 pM of tissue factor [TF]), regular (5 pM of TF) and High (20 pM of TF). The following TG parameters were evaluated: Peak TG (Peak), estimated thrombin potential (ETP) and velocity index (VI). Results: Eighty-one subjects were enrolled. The median age of our cohort was 15.6 years (IQR 21.2, range 4.9 - 59.8), with a slight female predominance (51%) due to inclusion of female carriers. The median follow-up period at the HTC was 5.3 years (IQR 7.5 years), with the majority having follow-up for at least three years. Enrolled patients had the following diagnoses: mild hemophilia A (70%), mild hemophilia B (3%), moderate hemophilia A (13%), moderate hemophilia B (3%), hemophilia A carriers with normal factor VIII levels (10%) and hemophilia B carriers with normal factor IX levels (1%). Median age at diagnosis was 8 years (IQR 26.3, range 0.1 - 56.1), which strongly correlated lower baseline factor activity (r=0.573, p-value < 0.0001). The median baseline factor activity was 21% (IQR 26, range 2 - 249). Factor exposure occurred in 46% of patients (n=37), of which 5 patients were on prophylaxis at time of enrollment. Chronic arthropathy was present in 2 patients (one with mild hemophilia A and one with moderate hemophilia A) and none of the patients had a history of an inhibitor. The majority of patients had a low bleeding score (74% vs. 26%). Baseline factor level and TG values obtained with regular reagent (5 pM of TF) showed significant correlation with bleeding score (r = -0.229 to -0.237, p-value < 0.05), while values obtained with other reagents did not show a significant correlation. Sensitivity/specificity analysis revealed the following optimal cutoff values for differentiating between bleeding severities, as obtained from TG with regular reagent: ETP (<1240 nM min), Peak (<130 nM) and VI (<23 nM/min), with analysis results as shown in Table 1. Conclusion: Even though both TG and baseline factor level had comparable correlation with bleeding severity, all TG values with 5 pM TF showed a much higher sensitivity outcome and greater ability to differentiate between bleeding severities in this population. This approach shows potential for predicting bleeding severity in patients with non-severe hemophilia and should be validated in long-term prospective studies. Disclosures Nossair: Novo Nordisk: Other: Conference - Haemophilia Acadamy; Novo Nordisk: Research Funding. Hwang:BPI: Consultancy; Bayer: Consultancy; Hema Biologics: Consultancy; Shire: Consultancy; Bioverativ: Other: PI in clinical research study. Thornburg:ATHN: Research Funding; Bayer Pharmaceuticals: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Bioverativ: Consultancy; Genentech: Speakers Bureau; Octapharma: Research Funding; NovoNordisk: Research Funding; Shire: Research Funding; Johns Hopkins All Children's Hospital: Research Funding; Bluebird Bio: Consultancy.
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