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.

Oxygen saturation thresholds in managing sickle cell disease at US children's hospitals.

BACKGROUND: Adequate oxygen saturation (SpO2 ) is crucial for managing sickle cell disease (SCD). Children with SCD are at increased risk for occult hypoxemia; therefore, understanding SpO2 threshold practices would help identify barriers to oxygen optimization in a population sensitive to oxyhemoglobin imbalances. We investigated SpO2 cutoff levels used in clinical algorithms for management of acute SCD events at children's hospitals across the United States, and determined their consistency with recommended national guidelines (SpO2  > 95%). METHODS: Clinical pathways and algorithms used for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in SCD were obtained and reviewed from large children's hospitals in the United States. RESULTS: Responses were obtained from 94% (140/149) of eligible children's hospitals. Of these, 63 (45%) had available clinical algorithms to manage VOC and ACS. SpO2 cutoff was provided in 71.4% (45/63) of clinical algorithms. Substantial variation in SpO2 cutoff levels was noted, ranging from ≥90% to more than 95%. Only seven hospitals (5% of total hospitals and 15.6% of hospitals with clinical algorithms available) specified oxygen cutoffs that were consistent with national guidelines. Hospitals geographically located in the South (46.8%; n = 29/62) and Midwest (54.8%; n = 17/31) were more likely to have VOC and ACS clinical algorithms, compared to the Northeast (26.5%; n = 9/34) and West (36.4%; n = 8/22). CONCLUSION: There is inconsistency in the use of clinical algorithms and oxygen thresholds for VOC and ACS across US children's hospitals. Children with SCD could be at risk for insufficient oxygen therapy during adverse acute events.

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.

Once-daily Compared With Twice-daily Enoxaparin Maintenance Therapy Appears Safe and Efficacious in Pediatric Venous Thromboembolism.

INTRODUCTION: Once-daily enoxaparin (ODE), considered standard of care for venous thromboembolism (VTE) treatment in adults, has been infrequently assessed in children. To contribute available data to a limited field, we reviewed our center's experience with ODE in treating pediatric VTE compared with twice-daily enoxaparin (TDE). MATERIALS AND METHODS: A retrospective analysis of children and adolescents 18 years of age or below diagnosed with VTE and treated at our institution with ODE or TDE maintenance therapy between April 2015 and December 2020 was performed. Patient demographics, clinical and laboratory data pertaining to VTE diagnosis, and management were gathered from electronic medical records and compared between the 2 cohorts. RESULTS: Seventy-one children met the eligibility criteria. All patients were initially treated with TDE for 2 weeks before transitioning to ODE maintenance therapy (n=39; 55%) or continuing with TDE dosing (n=32; 45%).Extremity VTE was more common in ODE ( P =0.051) versus pulmonary/intracardiac sites in TDE ( P =0.002) when compared with other sites. Median enoxaparin dosing was 1.5 and 1.1 mg/kg/dose in ODE and TDE cohorts, respectively. Bleeding episodes were rare without any difference between the cohorts. Two patients (6%) were lost to follow up in TDE cohort. All evaluable patients in both cohorts had either complete/partial response (ODE n=35 [90%]; TDE n=24 [75%] or stable thrombus ODE n=4 [10%]; TDE n=6 [19%]). CONCLUSIONS: Our results indicate that ODE, used after the initial TDE treatment period, is as safe and efficacious as TDE maintenance for the treatment of pediatric VTE. The difference in VTE sites may have contributed to the equal efficacy of both the cohorts. Future prospective studies in pediatric VTE are needed to validate these results.

Adolescent acquired thrombotic thrombocytopenic purpura: An analysis of the Pediatric Health Information System database.

The outcomes and characteristics of acquired thrombotic thrombocytopenic purpura (TTP) in adolescents is poorly understood due to an absence of studies focused on this population. To better understand the life-threatening disorder in this age, we performed an analysis of adolescent patients (ages 10-21) with TTP in the Pediatric Health Information Systems database from 2009 to 2020. The primary outcomes evaluated were in-hospital mortality and rate of TTP relapse. Secondary outcomes included rates of hemorrhagic and thrombotic complications during hospitalizations for TTP. Patients were included if they had a thrombotic microangiopathy diagnostic code, ADAMTS13 lab obtained, and received therapeutic plasmapheresis. Patients that received treatment for other non-TTP microangiopathies were excluded. A total of 99 patients with 123 hospitalizations for TTP treatment were identified. In-patient mortality occurred in 6 % (n = 6) and TTP relapse in 20 % (n = 20) of the cohort. Median time from initial admission to relapse was 33 days (IQR 15, 92). A hemorrhagic complication was identified in 29 % (n = 36) and thrombotic complication in 15 % (n = 19) of the cohort. The presence of underlying comorbidities was not associated with TTP relapse and only a diagnosis of cancer was associated with increased mortality. The rate of mortality and relapse in adolescent TTP is lower than that seen in adult registries. Long term prospective studies are needed to understand the long-term consequences of adolescent onset acquired TTP.

Cerebral sinus venous thrombosis in children with inherited bleeding disorders: A case series.

In patients with inherited bleeding disorders, thrombus development poses a challenge in balancing the management of thrombosis and bleeding. Pediatric antithrombotic therapy guidelines do not address the treatment of a thrombus in the setting of a bleeding disorder. We present a case series of four children with inherited bleeding disorders presenting with cerebral sinus venous thrombosis and bleeding, in order to summarize the different therapeutic approaches and outcomes of these patients.

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.

Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations.

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar "pathogenic" variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar "pathogenic" variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10-6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Low von Willebrand Factor in Children and Adolescents: A Review.

Importance: Recent studies have documented increased bleeding symptoms and related complications in patients with low von Willebrand factor (VWF), highlighting the clinical significance of this entity. Because children and adolescents with VWF deficiencies often present to primary care physicians with bleeding symptoms, physicians need to be aware of this condition for early detection. Observations: Studies have found that children and adolescents with low VWF (VWF levels of 30-50 IU/dL) can present with clinically significant bleeding, including mucosal, menstrual, postsurgical, and posttraumatic bleeding, leading to complications such as anemia, iron deficiency, transfusion, hospitalization, and poor quality of life. Detecting and promptly managing low VWF in children and adolescents with bleeding are essential because failure to do so can lead to significant morbidity in adulthood, especially among female patients, including continued heavy menstrual bleeding; postpartum hemorrhage; related gynecologic complications, such as hemorrhagic ovarian cysts; and surgical interventions for heavy menstrual bleeding, including hysterectomy. This narrative review summarizes the observations of several studies that have shed light on the pathophysiologic mechanisms of low VWF and bleeding in these patients and the available diagnostic modalities and treatment options. Conclusions and Relevance: Studies in children and adolescents have provided important insights into the clinical phenotype, complications, pathophysiologic mechanisms, evaluation, and management of low VWF, now recognized as an important clinicopathologic entity, as presented in this review. As gatekeepers, primary care physicians play an important role in guiding patients with this recently recognized clinicopathologic entity toward appropriate specialty care and providing continued comanagement to prevent future complications as the patients enter adulthood.

Immune thrombocytopenia following multisystem inflammatory syndrome in children (MIS-C) - a case series.

Patients with coronavirus disease 2019 (COVID-19) from novel coronavirus (SARS-CoV-2) infection may present with immune thrombocytopenia (ITP). Multisystem inflammatory syndrome in children (MIS-C) is a serious complication of SARS-CoV-2 causing systemic organ dysfunction. This case series presents the first reported cases of patients who developed ITP following MIS-C, while completing corticosteroid tapers. These patients responded to standard of care therapies for ITP and had appropriate platelet count recovery. We emphasize the importance of careful monitoring of those recovering from COVID-19 or MIS-C, to proactively identify clinical and laboratory abnormalities, in addition to long-term cardiovascular sequelae.

Management of anticoagulation associated reproductive tract bleeding in adolescent and young adult females - Results of a multinational survey.

INTRODUCTION: Reproductive tract bleeding (RTB) is an important outcome in menstruating females on anticoagulant therapy (AC). The diagnosis and management of AC-RTB in adolescent and young adult (AYA) females is unknown. AIMS: The aim of this study was to survey the contemporary patterns of diagnosis and management of AC-RTB in AYA females. METHODS: SurveyMonkey® questions were sent to members of 1) Pediatric and Neonatal Thrombosis Hemostasis Subcommittee and Women's Health Subcommittee of the International Society on Thrombosis and Haemostasis and 2) Hemostasis and Thrombosis Research Society. Results are reported using descriptive statistics. RESULTS: Response rate was 33% (251 out of 753). AC-RTB was infrequently reported. Menstrual history was not routinely reviewed prior to initiation of AC. Respondents indicated a differential risk of AC-RTB, most frequently with Rivaroxaban. Respondents continued hormonal therapy (HT) if an AYA female was on it at the start of AC. When AC-RTB occurred, management strategies were variable with initiation of HT or antifibrinolytic therapy being the most frequent. The timing of AC-RTB after the thrombotic event influenced the respondents' choice of therapy. Differences were seen in the management strategies between US and non-US participants, with more US respondents initiating HT while more non-US respondents modifying the AC regimen. Respondents uniformly reported complications with AC-RTB and with its treatment. CONCLUSION: This survey highlights the need to review menstrual history at the start of and during AC and for future research into choosing the optimal AC in AYA females. The results can inform the design of future studies.

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

Diagnosis, Clinical Characteristics, and Treatment Modalities of Adolescent May-Thurner Syndrome-associated Deep Venous Thrombosis.

May-Thurner syndrome (MTS) predisposes individuals to develop lower extremity deep venous thrombosis (DVT) because of compression of the left common iliac vein. Diagnosis of the anatomic obstruction is critical for effective therapy, as treatment by interventional radiology is often required in addition to anticoagulation to prevent thrombus progression and recurrence. The authors performed a retrospective review of adolescent patients who presented with MTS-associated DVT at a pediatric tertiary care center from 2009 to 2018 to assess for delays in MTS diagnosis after the presentation. Fourteen patients (median age 16.5 y, range, 13.8 to 17.9 y) were included, no DVTs were provoked by a central venous catheter. The median time from DVT to MTS diagnosis was 0.65 months (range, 0 to 21.5 mo). The initial imaging modalities used for DVT diagnosis were not able to diagnosis MTS. All patients were treated with anticoagulation and 13 underwent interventional therapy. Four patients had thrombus progression or recurrence, whereas 6 had complete thrombus resolution on follow-up imaging. Three patients who had a delayed MTS diagnosis had clinical worsening despite therapeutic anticoagulation requiring rehospitalization. Adolescent patients with "unprovoked" left lower extremity DVT should undergo appropriate imaging to diagnose MTS to allow for adequate medical and interventional therapy.

The spectrum and severity of bleeding in adolescents with low von Willebrand factor-associated heavy menstrual bleeding.

Low von Willebrand factor (VWF) in adults is associated with significant bleeding, most notably heavy menstrual bleeding (HMB) and postpartum hemorrhage, although this has not been characterized in adolescents. The objectives of this analysis of a multicenter single arm observational cohort study in adolescents with low VWF-associated HMB were to describe the bleeding phenotype, HMB severity, and related complications. Eligibility criteria included postmenarchal females <21 years of age with HMB (Pictorial Blood Assessment Chart [PBAC] score >100) and low VWF (2 values of VWF activity ≥30 and ≤50 IU/dL). Patients diagnosed with other bleeding disorders were ineligible. Clinical phenotype data, including PBAC and Bleeding Assessment Tool (BAT) scores, laboratory data, and HMB management/outcome details, were extracted. Patient demographics and clinical characteristics were summarized as medians with minimum/maximum values or frequencies with percentages. Groups were compared using a Wilcoxon rank-sum test or Fisher's exact test. A total of 113 patients met inclusion criteria, and 2 were excluded. Ninety four percent had a significant bleeding phenotype (BAT score >2), with predominantly mucocutaneous bleeding (32%-44%), postprocedural/surgical bleeding (15%), and severe HMB (BAT HMB domain score ≥2; 90%). Bleeding complications included iron deficiency (60%), anemia (21%), transfusion (12%), and hospitalization (10%). Desmopressin challenge response in subjects tested was good and sustained. Several (48%) required combined therapy for HMB (hormonal/hemostatic), and one third did not show improvement despite therapy. Our results suggest that adolescent females with low VWF have a significant bleeding phenotype and resultant complications warranting a focus on prompt diagnosis, appropriate therapy, and prevention of complications.

Megaloblastic Anemia Progressing to Severe Thrombotic Microangiopathy in Patients with Disordered Vitamin B12 Metabolism: Case Reports and Literature Review.

We describe 2 children with cobalamin G disease, a disorder of vitamin B12 metabolism with normal serum B12 levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.

Hematologic Considerations and Management of Adolescent Girls with Heavy Menstrual Bleeding and Anemia in US Children's Hospitals.

STUDY OBJECTIVE: To assess the frequency, severity, and inpatient management of girls admitted with heavy menstrual bleeding and iron deficiency anemia at US children's hospitals, with a focus on hematologic considerations. DESIGN: Retrospective multicenter cohort study from October 2012 through September 2015. SETTING: Children's hospitals submitting data to the Pediatric Health Information System. PARTICIPANTS: Female patients, age 8-18 years, admitted with heavy menstrual bleeding and anemia as either a primary or secondary diagnosis. Patients with cancer, immune thrombocytopenic purpura, aplastic anemia, and pregnancy were excluded. INTERVENTIONS AND MAIN OUTCOME MEASURES: Hemostatic evaluation; provision of iron therapy. RESULTS: We identified 1183 admissions (1134 unique patients). Patients' median (interquartile range) age was 14 (11-17) years. Forty-one percent were Caucasian (n = 480), 31% African American (n = 371), and 26% Hispanic ethnicity (n = 310). Intensive care use occurred in 5% of admissions (n = 56). Hemostatic assessment was inconsistent; 15% (n = 182) had no such evaluation. Two-thirds (n = 797; 67%) involved transfusions, 37% (n = 433) received no inpatient iron therapy, and 17% (n = 197) received no hormonal or antifibrinolytic therapy. Hemostatic evaluation was associated with intensive care use: odds ratio (OR), 4.80 (95% confidence interval [CI], 1.16-19.86; P = .03); emergency department visit: OR, 2.60 (95% CI, 1.86-3.65; P < .01); private insurance: OR, 1.62 (95% CI, 1.12-2.35; P = .01); and younger age: OR, 0.84 (95% CI, 0.77-0.92; P < .01). CONCLUSION: Hundreds of girls with heavy menstrual bleeding and anemia are hospitalized at US children's hospitals each year with variable inpatient hematologic evaluation and management. Future guidelines should emphasize early identification of at-risk patients and promote effective implementation strategies to reduce the burden of this preventable complication.

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.

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.