Direct oral anticoagulant therapy in adolescent venous thromboembolism: A systematic review.

Adolescent venous thromboembolism (VTE) has unique challenges in management, complications, and compliance to anticoagulants. Direct oral anticoagulants (DOACs) have been approved for pediatric VTE management, with an increasing use especially in adolescents. Primary objective is to evaluate the safety and efficacy of DOAC therapy in adolescent VTE. Secondary objectives include adverse events, bleeding events, and overall mortality. A SR protocol was registered in PROSPERO 2022 (CRD42022363928). Databases were searched from inception to September 22, 2022. Studies with children aged 10-18 years, VTE diagnosis, DOAC therapy, randomized control trials (RCTs), cohort, and relevant study types were included. Studies including prophylaxis, non-DOAC therapy, arterial thrombosis, age outliers, non-relevant study types were excluded. Findings are reported in accordance to PRISMA 2020. Nine reports from five studies, published between 2016 and 2022, were included. Rivaroxaban was the most common DOAC. VTE recurrence was 0.02% in the rivaroxaban phase III trial and one patient in the dabigatran phase IIb/III trial. Complete/partial thrombus resolution (CR/PR) was 76.6% in the rivaroxaban phase III trial, and 83.9% in the dabigatran phase IIb/III trial. CR/PR was found to be 68.4% in Dhaliwal et al. study and 83.3% in Hassan et al. study. Major bleeding occurred in one patient. Headache and gastrointestinal symptoms were commonly seen. All-cause mortality occurred in a patient due to cancer progression. DOAC therapy in adolescent VTE had CR/PR in two-thirds of the patients, with low incidence of VTE recurrence and major bleeding. As there are only two randomized controlled trial (RCTs), future adolescents' studies are required to validate our results.

Thromboembolism in children with multisystem inflammatory syndrome: a literature review.

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory response observed in children several weeks to months after acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). On review of all published cases of thromboembolism (TE) as a complication of MIS-C, 33 cases of TE were found with incidence ranging from 1.4 to 6.5%. TE occurred mostly in children aged 12 years and above. One-third of the cases were cerebral infarcts and the remaining cases included intracardiac and radial arterial thromboses, upper and lower extremity deep vein thrombosis, pulmonary embolism, and splenic infarcts. Five were asymptomatic cases and 3/33 (9%) patients (all three with cerebral infarcts) died. To conclude, TE appears to be a significant complication of MIS-C caused by SARS-CoV-2 infection, associated with morbidity and/or mortality. Patients ≥12 years are affected more often, and TE occurs despite thromboprophylaxis in some patients. Thromboprophylaxis should be considered in all cases after reviewing the concomitant bleeding risk. Prospective studies are needed to confirm the role of standard-dose thromboprophylaxis and to explore whether higher-dose thromboprophylaxis is required in certain high-risk patients with MIS-C. IMPACT: Compiles all cases of thromboembolism associated with COVID-19-related MIS-C, a report that has not been published to date.

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.

Perioperative Hemostatic Management in Ehlers-Danlos Syndrome: A Report of 2 Cases and Literature Review.

Ehlers-Danlos syndrome (EDS) is associated with easy bruising and bleeding complications in the majority. Although bleeding complications are frequently observed during surgery in these patients, the perioperative hemostatic prophylaxis of patients with EDS is not standardized. We present 2 cases of effective perioperative hemostatic management of patients with EDS and review the literature to raise awareness of hemostatic issues during surgery and discuss medical options to consider for perioperative hemostatic management based on our clinical experience and literature review.

Oral pyogenic granuloma in hemophilia: a report of 2 cases.

Pyogenic granulomas (PGs) are benign vascular lesions occurring in skin and mucous membranes, often secondary to trauma or chronic inflammation. Oral PGs have never been described previously in hemophilia. We describe 2 pediatric patients with hemophilia A, who developed PGs with inadequate factor therapy for bleeding. PG pathophysiology suggests an association with hemophilia given chronic vascular damage and low-grade inflammation at sites of bleeding in hemophilia patients. Knowledge about the occurrence of PGs in hemophilia patients is essential for prompt diagnosis and early institution of factor therapy, which in turn allows more rapid cessation of bleeding and lesion involution.

Hormonal therapies in females with blood disorders: thrombophilia, thrombosis, hemoglobinopathies, and anemias.

There is widespread use of gonadal steroid hormone therapy for a variety of indications throughout the reproductive and postreproductive lifespan. These therapies may have particular benefits and specific risk among those with blood disorders, including inherited or acquired bleeding disorders, thrombophilia, thrombosis, or anemia. This clinical review is intended to provide a guidance for counseling and management of adolescent and adult biologic females with thrombophilic risk factors and/or thrombosis who require hormonal therapy. In general, synthetic estrogens present in contraceptive products should be avoided in those with a personal or strong family history of thrombosis or thrombophilias. In contrast, natural estrogens present in formulations for climacteric symptom management do not need to be avoided, and vaginal or transdermal formulations are preferred. Likewise, transdermal estradiol is preferred for gender-affirming hormone therapy and requires individualized assessment in those at high risk of thrombosis. Progestogens (either synthetic progestins or naturally occurring progesterone) can be used safely in nearly all patients. There is minimal safety evidence among anticoagulated patients at risk for thrombosis, which requires a patient-specific approach when discussing hormone therapies.

Gynecologic Bleeding Complications in Postmenarchal Female Adolescents Receiving Antithrombotic Medications.

STUDY OBJECTIVE: The prevalence, clinical features, and management of gynecologic bleeding complications and health care provider awareness of these in postmenarchal adolescents receiving antithrombotic medications has rarely been addressed in the literature. We sought to address these issues in a review of our experience in a pediatric tertiary care center. DESIGN, SETTING, AND PARTICIPANTS: A retrospective chart review was conducted with institutional review board approval from 2004 to 2014, on eligible postmenarchal adolescents receiving antithrombotic medications. Descriptive statistics were used. RESULTS: Sixty-eight adolescents received antithrombotic medications (thromboembolism in 67 of 68; 99%; cardiac causes in 4 of 68; 6%), which included enoxaparin, warfarin, unfractionated heparin, alteplase, fondaparinux, and aspirin. Heavy menstrual bleeding (HMB) screening questions were documented by treating hematologists in 52 of 68 patients (76%; 95% confidence interval, 65%-86%). Adolescent gynecology consult was requested for 25 of 68 patients (37%). After antithrombotic medications were started, 13 of 68 (19%) developed HMB. Anemia was found in 43% of patients tested (18 of 42); 50% (9 of 18) and 78% patients (14 of 18) received packed red blood cell transfusion and iron therapy, respectively. Five patients (5 of 68; 7%) developed hemorrhagic ovarian cysts, 40% (2 of 5) were treated with surgery, 16% (1 of 5) received transfusions, and 100% (5 of 5) received or continued progesterone-only therapy with no recurrence. CONCLUSION: Adolescents receiving antithrombotic medications are at risk of developing gynecologic bleeding complications, which can result in anemia, hospitalization, transfusions, or surgery. Provider awareness/screening of HMB as a bleeding complication of antithrombotic medications is less than optimal. Future prospective studies in adolescents receiving antithrombotic medications are needed to better evaluate provider awareness and the prevalence of gynecologic bleeding complications, which can lead to effective management.

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.

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.