Mosunetuzumab in combination with CHOP in previously untreated DLBCL: safety and efficacy results from a phase 2 study.

Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to or relapse after first-line therapy, highlighting the need for better treatments. Mosunetuzumab is a CD20 × CD3 bispecific antibody that engages and redirects T cells to eliminate malignant B cells. In this phase 2, open-label study (NCT03677141), 40 patients (52.5% with international prognostic index ≥3) with previously untreated DLBCL initiated 6 cycles of IV mosunetuzumab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Mosunetuzumab was administered in cycle 1 as step-up doses to mitigate cytokine release syndrome [CRS], and a dose of 30 mg was given on day 1 of cycles 2-6. Efficacy end points included objective and complete response rates, as determined by the investigator, via positron emission tomography-computed tomography, using Lugano 2014 criteria (87.5% and 85.0%, respectively). At a median follow-up of 32.0 months, the estimated 2-year progression-free survival and event-free survival rates were 65.4% (95% confidence interval [CI], 49.5-81.4) and 60.4% (95% CI, 44.7-76.1), respectively. CRS occurred in 60.0% of patients; all events were grade 1 (45.0%) or grade 2 (15.0%) and occurred primarily in cycle 1. Mosunetuzumab-related grade ≥3 neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%). Grade 5 AEs were reported in 2 patients. Neutropenia occurred in 70.0% of patients, mostly during cycle 1 and was of short duration. These findings demonstrate promising activity and a manageable safety profile for mosunetuzumab-CHOP and warrant further investigation of mosunetuzumab in first-line combination regimens for DLBCL.

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development.

A Critical Evaluation of Enoxaparin Dose Adjustment Guidelines in Children.

OBJECTIVES: The purposes of this study are to perform a large-scale evaluation of the standardized dosage adjustment nomogram recommended by the American College of Chest Physicians (CHEST) for the management of enoxaparin in hospitalized pediatric patients and to determine the necessity of routine and repeated anti-factor Xa (anti-Xa) levels. METHODS: A retrospective cohort study was designed, and charts were reviewed in a single tertiary care institution for all patients who received enoxaparin between October 1, 2010, through September 30, 2016. Patients were included if they were receiving treatment doses of enoxaparin according to the pediatric CHEST guidelines, had a subtherapeutic or supratherapeutic anti-Xa level drawn at 3.5 to 6 hours after a dose, had a dose changed in an attempt to attain a therapeutic anti-Xa level, and had a second anti-Xa level drawn 3.5 to 6 hours after the dose change. Descriptive statistical methods were used to characterize the ability of dose adjustment via a nomogram to attain an anti-Xa of 0.5 to 1 unit/mL. RESULTS: A total of 467 patients were identified who received the appropriate initial dose and dosage adjustment and whose levels were drawn according to the CHEST guidelines. In patients who had an initial anti-Xa level of <0.35 units/mL and received the nomogram recommended dose increase of 25% ± 5%, 28 out of 96 patients (29.2%) reached therapeutic levels. Of 197 patients who had an initial anti-Xa level between 0.35 and 0.49 units/mL and who received the nomogram recommended dose increase of 10% ± 5%, 116 (58.9%) reached therapeutic levels. Of 50 patients with an initial anti-Xa level between 1.1 and 1.5 units/mL and who received the nomogram dose decrease of 20% ± 5%, 31 (62%) reached therapeutic levels. CONCLUSIONS: The current dosage adjustment nomogram recommended by the CHEST guidelines does not reliably lead to therapeutic anti-Xa levels when used to adjust enoxaparin doses in pediatric patients.

PREVAPIX-ALL: Apixaban Compared to Standard of Care for Prevention of Venous Thrombosis in Paediatric Acute Lymphoblastic Leukaemia (ALL)-Rationale and Design.

Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.

Warfarin-Rifampin Drug Interaction in a Pediatric Patient.

Rifampin has been documented to significantly attenuate the effect of warfarin in adult patients. No data have been presented on the use of rifampin and warfarin in a pediatric patient. We report an extreme case of increased warfarin metabolism in a pediatric patient who was concomitantly receiving rifampin, despite receiving other medications that significantly decrease warfarin metabolism. The inhibitory effect of rifampin on warfarin therapy may be amplified in pediatric patients.

Enoxaparin Population Pharmacokinetics in the First Year of Life.

AIMS: Enoxaparin dosing requirements in the first year of life can be highly variable. Characterization of pharmacokinetics in this patient population can assist in dosing. METHODS: Patients less than 1 year postnatal age who received enoxaparin and had an anti-factor Xa activity level drawn as inpatients were identified through the pharmacy database over a 5-year period. Patients on renal replacement therapy or with hyperbilirubinemia were excluded. Data collection included demographic variables, indication for enoxaparin, enoxaparin doses, anti-factor Xa activity levels, serum creatinine, hemoglobin, hematocrit, platelet count, and urine output over the previous 24 hours. Population pharmacokinetic analysis was performed with NONMEM. RESULTS: A total of 182 patients [male 50%, median 100 days postnatal age (range: 4-353 days)] met the study criteria. Patients received median 22 doses (range: 1-526) at a mean starting dose of 1.38 ± 0.43 mg/kg with median 5 (range: 1-56) anti-factor Xa activity levels measured. A 1-compartment proportional and additive error model best fits the data. Allometrically scaled weight significantly decreased the objective function value, as did serum creatinine on clearance, and postmenstrual age (PMA) on volume of distribution. When evaluated graphically, dosing based on PMA appeared to have less variability as compared to postnatal age-based dosing. CONCLUSIONS: Dosing of enoxaparin in infants younger than 1 year should incorporate PMA.

Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A.

Turoctocog alfa pegol (N8-GP, Novo Nordisk, Bagsværd, Denmark), an extended half-life glycoPEGylated recombinant factor VIII (rFVIII), is being developed for prophylaxis and treatment of bleeds in haemophilia A patients. pathfinder™5 is a multinational, open-label, single-arm trial to assess safety, efficacy and pharmacokinetics of N8-GP in paediatric (<12 years), previously treated patients. Boys with severe haemophilia A (<1 % FVIII), no history of inhibitors and previously treated with FVIII products (>50 exposure days [ED] for patients aged 0-5 years [younger cohort]; >150 ED for patients aged 6-11 years [older cohort]) were included. For prophylaxis, N8-GP was dosed at 50-75 IU/kg twice weekly; bleeds were treated with 20-75 IU/kg. Half-life was estimated for the patients' previous FVIII product and for N8-GP. Sixty-eight patients received N8-GP; none developed inhibitors and no other concerns were identified. Median annualised bleeding rate was 1.95 (1.94 and 1.97 in the younger and older cohorts, respectively). Twenty-nine patients (42.6 %; 15 younger and 14 older children, respectively) did not report any bleeding while on N8-GP prophylaxis; 39 patients (57.4 %; 19 younger and 20 older children, respectively) reported 70 bleeds (all mild/moderate). N8-GP treatment was successful for 78.6 % of bleeds in all patients, 80.0 % in younger and 77.5 % in older patients. Most bleeds (80.0 %) were treated with ≤2 injections. Half-life ratio between N8-GP and the patients' previous FVIII product was 1.85. N8-GP was well tolerated and provided effective prophylaxis and treatment of bleeds in paediatric patients with severe haemophilia A.

Population pharmacokinetics of human antithrombin concentrate in paediatric patients.

AIMS: Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic profile of human (plasma-derived) antithrombin concentrate in paediatric patients. METHODS: A 5-year retrospective review was performed of patients <19 years of age admitted to our institution who received antithrombin concentrate, were not on mechanical circulatory support and had baseline (predose) and postdose plasma antithrombin activity levels available for analysis. Demographic and laboratory variables, antithrombin dosing information and data on the use of continuous infusion unfractionated heparin were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. The model developed was tested against a validation dataset from a cohort of similar patients, and a predictive value was calculated. RESULTS: A total 184 patients met the study criteria {46.7% male, median age [years] 0.35 [interquartile range (IQR) 0.07-3.9]}. A median of two antithrombin doses (IQR 1-4) were given to patients (at a dose of 46.3 ± 13.6 units kg-1 ), with median of three (IQR 2-7) postdose levels per patient. Continuous infusion unfractionated heparin was administered in 87.5% of patients, at a mean dose of 34.1 ± 22.7 units kg-1 h-1 . A one-compartment exponential error model best fit the data, and significant covariates included allometrically scaled weight on clearance and volume of distribution, unfractionated heparin dose on clearance, and baseline antithrombin activity level on volume of distribution. The model resulted in a median -1.75% prediction error (IQR -11.75% to 6.5%) when applied to the validation dataset (n = 30). CONCLUSIONS: Antithrombin pharmacokinetics are significantly influenced by the concurrent use of unfractionated heparin and baseline antithrombin activity.

Association of outcomes and anti-Xa levels in the treatment of pediatric venous thromboembolism.

BACKGROUND: There are few data in the pediatric population evaluating the relationship between measured anti-Xa levels during enoxaparin therapy and thrombotic outcomes. OBJECTIVE: To determine whether there is a difference in outcomes in children who receive enoxaparin with mean anti-Xa levels between 0.45 and 0.79 unit/ml (low therapeutic range) versus between 0.80 and 1.05 unit/ml (high therapeutic range) throughout their course of their treatment. METHODS: We retrospectively identified subjects with uncomplicated venous thromboembolism treated with enoxaparin. RESULTS: Of 69 patients with any response to therapy, 48 (70%) had mean anti-Xa levels in the low therapeutic range and 21 (30%) had mean anti-Xa levels in the high therapeutic range. Of 20 patients with no documented response to therapy, 13 (65%) had mean anti-Xa levels in the low therapeutic range and 7 (35%) had mean anti-Xa levels in the high therapeutic range. Forty-eight (79%) of the 61 patients with low-range mean anti-Xa level had any response to therapy. Twenty-one (75%) of the 28 patients with high-range mean anti-Xa level had any response to therapy. Chi-square test (P = 0.080) and logistic regression (OR = 1.23, P = 0.70) demonstrated no significant association between mean anti-Xa range (lower vs. upper) and therapy response. CONCLUSIONS: There was no statistically significant difference between low-range versus high-range mean anti-Xa levels and thrombus resolution. Empiric clinical practices of targeting anti-Xa levels in the higher therapeutic range to achieve better outcomes may not be warranted.

Recognition and management of platelet-refractory bleeding in patients with Glanzmann's thrombasthenia and other severe platelet function disorders.

Patients with rare qualitative platelet disorders or platelet function disorders (PFDs) may present to the hospital physician with severe bleeding episodes or excessive surgical bleeding. Although standard treatment consists of platelet transfusions, repeated transfusions may result in the development of antiplatelet antibodies (APA) or clinical refractoriness, rendering further platelet therapy ineffective. In such settings, an approved treatment option for patients with Glanzmann's thrombasthenia (GT), one of the well-known rare PFDs, is recombinant activated coagulation factor VII (rFVIIa). Data regarding the efficacy of rFVIIa in patients with GT and platelet refractoriness are available from a large patient registry, an international survey, and multiple case reports and demonstrate efficacy in patients with and without refractoriness or APA. This article reviews the rFVIIa clinical data in patients with GT and platelet refractoriness and discusses clinical implications relevant to the hospital-based physician. Because uncontrolled bleeding can be life-threatening, hospital physicians should be alert to the signs of platelet refractoriness, be able to recognize continued internal or external bleeding, and know how to adapt treatment regimens for the effective management of bleeding. The management of patients who receive rFVIIa should occur in consultation with a hematologist with experience in PFDs, and patients with suspected platelet refractoriness should be referred to such a hematologist as early as possible. A critical unmet need is the development of a definition of an adequate response to platelet transfusion, which would facilitate early recognition of platelet refractoriness in patients with PFDs who exhibit a normal platelet count.

Pediatric Acquired von Willebrand Syndrome in Cardiopulmonary Disorders: Do Laboratory Abnormalities Predict Bleeding Risk?

There are conflicting reports on whether or not laboratory abnormalities in pediatric acquired von Willebrand syndrome (AVWS) predict bleeding manifestations in patients with cardiopulmonary disorders (CPD). We retrospectively reviewed charts of patients with AVWS and CPD (n=16) seen at Texas Children's Hospital from 2003 to 2012. The most common CPD were valve stenoses, ventricular septal defects, and pulmonary hypertension. All patients had loss of high molecular weight multimers. Fifteen (94%) patients presented with bleeding symptoms, with menorrhagia and epistaxis being the most common. Von Willebrand ristocetin cofactor activity (VWF:RCo), as well as the use of anticoagulant or antiplatelet medication, did not predict bleeding manifestations (P=0.70 and 0.84, respectively). VWF:RCo/VWF antigen (Ag) ratio of <0.7 was significantly associated with presence of bleeding symptoms. All patients who had complete repair of their cardiac defect experienced normalization of VWF multimers and VWF:RCo/Ag ratio, as well as bleeding symptom resolution. We conclude that increased bleeding risk is associated with low VWF:RCo/Ag ratio in pediatric AVWS due to CPD. However, other laboratory abnormalities such as VWF:RCo level and qualitative multimer analysis, do not appear to predict bleeding. Future studies exploring quantification of multimer loss may be helpful in further assessing bleeding risk associations.

Assessment of an Electronic Intervention in Young Women with Heavy Menstrual Bleeding.

STUDY OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Bleeding disorders (BD) occur in up to 50% of adolescents with heavy menstrual bleeding (HMB). This presents unique challenges to health care providers because of the complexity of treating the condition and such complexity can result in difficulty with patients understanding basic information about their condition, limit communication with medical providers, and patient compliance. The aim of the study was to use an electronic approach to enhance patient compliance with medications used to treat their HMB, and to provide educational access to adolescents with BD. This was a prospective cohort study involving patients in a Young Women's Bleeding Disorder Clinic at a single children's hospital. Subjects were given an iPod Touch (Apple Inc, Cupertino, CA) device (ITD), preloaded with the iPeriod (Winkpass Creations) application. Participants recorded information about their BD that they learned about on BD Web sites, and menses, and medications. Electronic and charted data were collected to monitor compliance with prescribed treatment regimens. All ITD allowed Wi-Fi access to allow teens to explore BD Web sites and knowledge was assessed. RESULTS: Twenty-three of 45 subjects completed the study. The mean age was 14.1 ± 1.9 years. Subjects who were compliant with the ITD (group 1), charted on baseline symptoms, menstrual flow (83.3%), cramps (100%, 23/23), breakthrough bleeding (95.6%, 22/23), mood (95.6%, 22/23), and medication use (91.7%) for a mean of 9.3 ± 3.1 months. Subjects who were nonusers (group 2) did not report on symptoms, their condition, or medication use in the device (n = 22). More than 75% (17/23) of subjects in group 1 used hormones alone or hormones with antifibrinolytic agents to control HMB. No subjects stopped or missed medications who were in group 1 intentionally, and also there were 9 enrollees within this same group who missed a medication related to awaiting the prescription to be filled from pharmacy. In group 2, 17 enrollees missed medications, resulting in 19% (4/22) of these enrollees being admitted to hospital for 1-2 days. In addition, enrollees in group 2 missed more medications on average compared with group 1. No subjects in group 1 required admission for HMB treatment failure during the study period, compared with those in group 2 (P = .006). All subjects in group 1 reported accessing Web sites using their ITD to learn about their BD. Groups 1 and 2 did not differ in the number of medications that were prescribed during the time frame (P = .77) or the number of follow-up clinic visits (P = .49). Furthermore, those in group 1 reported fewer breakthrough bleeding episodes than those in group 2 according to clinic notes (P = .03). Users of the ITD were given a set of knowledge questions. Group 2 subjects were not consistent users of the ITD use and did not complete the knowledge questions. Group 1 and 2 could not be compared with regard to knowledge as a result. CONCLUSION: ITD is an excellent tool for adolescents with HMB and BD to allow self-monitoring, provider monitoring, and improve educational access through engaging technology; compliance with device use was associated with several parameters suggestive of improved clinical outcomes.

Validation Study of the Composite Score to Identify Von Willebrand Disease in Children.

BACKGROUND: The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD. PROCEDURE: Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined. RESULTS: A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%. CONCLUSIONS: The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.

Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities.

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the mainstay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials.

Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis.

OBJECTIVE: To characterize features of antithrombin concentrate (ATC) use in children receiving unfractionated heparin (UFH) therapy for acute thrombosis. STUDY DESIGN: All pediatric patients at Texas Children's Hospital who received ATC in the context of UFH therapy for acute thrombosis during February 2011 to May 2013 were analyzed. RESULTS: Fifty-one children received ATC during UFH therapy for acute thrombosis. Median age was 3 months (IQR 1 to 18 months). Clinical indications included venous (53%), arterial (37%), venous and arterial (6%), and intracardiac (4%) thrombosis. Median baseline antithrombin (AT) level was 61% and UFH dose was 26 U/kg/h. The median dose of ATC was 49.9 IU/kg (IQR 32.6 to 50.0 IU/kg). Although most patients (86%) did not undergo a change in UFH dose, there was a significant increase in both AT and anti-factor Xa level after the first dose of ATC (P < .001 for both). There was no correlation between ATC dose or increment in AT level above baseline and the achievement of targeted anticoagulation by anti-factor X activity level. Adverse bleeding events occurred in 10% of patients. CONCLUSIONS: There was a significant change in AT and anti-factor Xa activity level after a single dose of ATC despite little to no change in dose of UFH. ATC appears to facilitate anticoagulation with UFH in some children with acute thrombosis but the degree of response is variable and dependent on factors identified in this study. Bleeding and other theoretical risks must be carefully considered.

Oral Tranexamic Acid versus Combined Oral Contraceptives for Adolescent Heavy Menstrual Bleeding: A Pilot Study.

STUDY OBJECTIVE: To compare the efficacy of oral tranexamic acid (TA) with combined oral contraceptives (COC) in reducing menstrual blood loss (MBL) and improving quality of life in adolescent heavy menstrual bleeding (HMB). DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized crossover trial with 17 postmenarchal girls aged 21 years and younger with HMB who were seen at our institution. INTERVENTIONS: Patients were randomized to group A (TA arm) or group B (COC arm), each for 3 cycles, with crossover to the second arm after 1-month washout. MAIN OUTCOME MEASURES: The primary end points were difference in improvement in MBL and QOL, from baseline to end of each therapy. RESULTS: Seventeen patients were enrolled (mean age 14.2 years, range 11.7 to 16.8 years). Nine patients completed both arms; 8 patients withdrew from the study due to adverse events or noncompliance. Compared with baseline, significant improvement (P < .05) was demonstrated by TA and COC in MBL (mean Pictorial Blood Assessment Chart score decrease: TA, 536.4; COC, 430.6) and quality of life (mean Pediatric Quality of Life Inventory(TM) version 4.0 Generic Scales score increase: TA, 15.6; COC, 16.75), but no significant difference was noted between TA and COC (P > .05). There was statistically significant reduction in the length of menstrual cycle for COC only (mean reduction 5.3 days; P = .04) and not for TA (P = .18). Ten patients (58%) experienced adverse events that were possibly drug related (TA: n = 3, 30%; COCP: n = 7, 64%). CONCLUSION: In this pilot study, oral TA appeared as efficacious as COC in the management of adolescent HMB by reducing MBL and improving quality of life.

Hemostatic abnormalities in young females with heavy menstrual bleeding.

OBJECTIVE: To study the prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young females referred to a multidisciplinary clinic for evaluation of heavy menstrual bleeding (HMB). METHODS: Retrospective chart review was undertaken for 131 post-menarchal girls with HMB, 7 to 17 years of age, enrolled in the institutional 'Menorrhagia Data Registry' protocol. The diagnostic approach included: (1) complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, von Willebrand panel (2) platelet aggregometry, specific clotting factor assay, fibrinolytic pathway analysis, and factor XIII level as needed. The prevalence of hemostatic abnormalities and the prognostic significance of clinical variables associated with hemostatic abnormalities in young girls with HMB were evaluated. RESULTS: A hemostatic abnormality was identified in 69 (53%) young girls with HMB. Of these, 27 (21%) had an underlying bleeding disorder and 42 (32%) had a risk factor for bleeding, namely low von Willebrand factor activity. A larger number of girls with underlying bleeding disorder had personal history of other bleeding symptoms (48% vs 31%) and bleeding after surgical or dental procedure (25% vs 8%) when compared to females without hemostatic abnormality. Furthermore, girls with risk factor for bleeding (low vWF activity) were more likely to have bleeding after surgical or dental procedure (15% vs 8%) and family history of bleeding (79% vs 60%) than patients without hemostatic abnormality. CONCLUSIONS: There is high prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young girls with HMB. These findings support comprehensive and systematic hemostatic evaluation in this group of patients.

Age-related differences in urinary 11-dehydroxythromboxane B2 between infants, children, and adolescents: another example of developmental hemostasis?

Our study was developed to ascertain reference ranges of 11-dehydrothromboxane B2 (11-dhTXB2) in the urine of healthy pediatric subjects. Urine samples were analyzed using the AspirinWorks™ assay that measures levels of 11-dehydrothromboxane B2. 128 individuals (2 months to 18 years) were identified as healthy and not receiving aspirin. When adjusted as picograms/milligrams urine creatinine, there was a negative correlation between age and level of 11-dehydrothromboxane B2 (P = 0.0001). This study confirms a negative correlation between age and level of urinary 11-dehydrothromboxane B2 and provides a set of age-specific reference ranges.