Undiagnosed Bleeding Disorders Research Articles

Closing the Gap: A Multidisciplinary Quality Improvement Project Improving Diagnosis and Care for Women with Undiagnosed Bleeding Disorders

Background: Research has shown that irrespective of the hemostatic challenges women face during their lives, they are less likely to be referred to a hematologist than their male counterparts and are managed primarily from a symptomatic standpoint. Women face many barriers to diagnosis including lack of provider awareness of bleeding disorders and the work-up required to make a diagnosis. Unique to menstruating women, there is overlap between many gynecologic diagnoses that can mimic a bleeding disorder; hence, leading to misdiagnosis and treatment targeted towards symptomatology as opposed to establishing a diagnosis. There also remains a major barrier for many women in the United States for diagnosis due to lack of access to care and health literacy. In Eastern North Carolina, compared to United States averages, we have high rates of uninsured, higher rates of poverty, higher patient to primary care physician ratios, and a higher rate of minority patients. Methods: We report on an ongoing, prospective quality improvement project funded by the Foundation for Women and Girls Bleeding disorders that aims to improve the identification of concurrent bleeding disorders in women presenting to the gynecology clinic with excessive vaginal bleeding. During routine gynecology patient encounters, patients are consented and screened utilizing the WHO Bleeding Assessment Tool (BAT). Women who score more than 6 on th e BAT are referred to our Bleeding Disorders Clinic for further diagnostics and evaluation by a hematologist. During the Bleeding disorders evaluation, the BAT score is repeated and specific testing to define a bleeding disorder is obtained. If patients are identified with a bleeding disorder such as Von Willebrand's disease or congenital platelet disorders, additional therapy to correct these are instituted to improve bleeding. In addition, patients who are severely iron deficient from menorrhagia are offered IV iron replacement. Results: In the first three months of this project, we have consented and screened over 70 patients in OB/GYN clinic. Twelve patients (17%) that have screened positive with a score of 6 or more. All twelve patients are being evaluated for congenital bleeding disorders. During our project, the Gynecology physicians have become more aware of patients who might be at risk and have increased their self-referral for hematology evaluation. Demographically, most of our patients came from five counties. Each of these counties has a higher rate of uninsured patients with an average of 16.6%, ranging 15-21% compared with national average of 12%. These counties also have higher rates of patient to primary care ratios than national average, minus Pitt County, a training hospital, with a combined average 1,127:1 ranging from 990:1 to 1,270:1 compared to US average 810:1. Median household Income averaged $46,040 ranging $41,200 to $50,300 with US average of $69,700. Black population made up 34.6% on average and ranging from 23% to 56% compared to national average of 12%. And rurality averaged 47.4% ranging 25.4% to 65.6% compared to national average of 19.3%. Conclusions: This project demonstrates the ability to impact the collaboration between hematology and our gynecology colleagues in identifying undiagnosed bleeding disorders. This study also addresses the disparities faced in medically underserved regions as well as those who have financial and social barriers to care. The rate of positive screening reflects a population of patients who would otherwise not undergo diagnostics at this time potentially missing patients with an untreated bleeding disorder. By better identifying bleeding disorders that complicate gynecologic bleeding, we can develop improved treatment plans to enhance the efficacy of gynecologist control of patient's symptoms. We can also improve the recognition of bleeding disorders by a group of physicians, our OB/Gyn team, who often are the primary providers for many young women in rural Eastern NC.

Implementation of a Bleeding Risk Screening Tool and Hematology Referral Process Prior to Pediatric Endoscopy.

Gastrointestinal (GI) endoscopic procedures are considered low risk with an overall bleeding risk for upper and lower endoscopies of 0.11%. However, a certain population of patients may have a higher risk for bleeding, and there is not a standardized process for screening patients to determine who these patients are. At Children's Wisconsin, our gastroenterology and hematology divisions adapted an abbreviated version of a validated, history-based bleeding risk screening tool and implemented a hematology referral process to identify those at risk for bleeding prior to their first endoscopy. Provider compliance with the bleeding screen, referral to hematology, time to be seen in hematology clinic, new diagnoses of bleeding disorders, and bleeding complications were assessed from 2019 to 2021 across 3 phases. Provider compliance with the bleeding screen improved throughout our study from 48% (120/251) to 75% (189/253). For those who screened positive, compliance with referral to hematology ranged from 38% to 74% across our phases. The overall time to be seen by hematology decreased from 30 days to 7.5 days. Eighteen patients ultimately screened positive and were seen in hematology clinic, of whom 22% (4/18) were diagnosed with a new bleeding disorder. No bleeding complications were seen in our study population. Our quality improvement project provided a standardized screening tool to assess preoperative bleeding risk and reinforced the value of a history-based screening tool. This modified screening tool identified those with an undiagnosed bleeding disorder and preventative measures were undertaken to prevent procedural bleeding complications.

Pattern of Hemorrhagic Disorders in Patient with Bleeding Manifestations

Background: Adults with undiagnosed bleeding disorders present in a variety of ways. While severe bleeding disorders and most congenital bleeding disorders initially present during childhood, conditions associated with heavy bleeding only after a haemostatic challenge (Such as surgery or trauma) often present during adulthood. The evaluation of a patient with a possible bleeding disorder can be one of the most challenging referrals in hematology practice. In the absence of much evidence-based outcomes data, the practitioner’s experimental judgment will be called upon to formulate a working diagnosis and management plan in many instances. The present study is aimed to find out the incidence of diseases presenting with bleeding manifestations and their clinical patterns with age and sex relationship. It is also important to establish the pathological correlation with clinical features. Materials and methods: This observational study was carried out in the Department of Hematology, Armed Forces Institute of Pathology, Dhaka cantonment for a period of one year between 01 January 2018 to 31 December 2018. A total of 57 cases of all ages with bleeding manifestations were studied clinically and appropriate laboratory investigations were carried out to find the causes of bleeding. Statistical analysis was done by using SPSS for windows version 17. c2 test was used as the tests of significance and p value <0.001 was accepted as the level of significance. Results: Out of 57 cases, 21(36.84%) patients were found to have acute leukemia, 15(26.32%) patients were idiopathic thrombocytopenic purpura, 11(19.30%) patients had haemophilia and 10(17.54%) patients were diagnosed as hypoplastic anemia. Among the bleeding manifestations, purpura was found in 42(73.68%) patients, gum bleeding in 24(42.11%) patients, melaena in 13(22.81%) patients, epistaxis in 11(19.30%) patients, menorrhagia in 09(15.79%) and bleeding inside joint cavity in 08(14.04%) patients. In this series, 11 cases of haemophilia, a sex linked bleeding disorders were diagnosed where 05(45.45%) cases had no positive family history. Conclusion: The successful management of bleeding manifestation depends upon the ability to make a quick diagnosis, so that a rapid and adequate therapy can be adopted. IAHS Medical Journal Vol 5(1), June 2022; 74-77

Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors’ Organisation centers for patients with unclassified bleeding disorders

BackgroundBleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. ObjectivesTo examine UK haemophilia centre registration patterns and current practice for UBD patients. MethodsIn a two‐step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. Results/discussionOverall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. ConclusionThis study provides a snapshot of current practice and real‐world data in this area. Future studies need to address the gaps in evidence.

Preoperative bleeding risk assessment with ISTH-BAT and laboratory tests in patients undergoing elective surgery: A prospective cohort study.

Patients with inherited haemorrhagic disorders may bleed during surgery. No questionnaire on bleeding diathesis has been yet validated for the preoperative period and current guidelines provide conflicting recommendations. We aimed to assess if preoperative assessment with ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assesment Tool) and laboratory screening tests is useful to identify mild previously undiagnosed bleeding disorders (BDs) and to predict bleeding complications in selected patients undergoing elective surgery. Consecutive patients undergoing elective surgery received ISTH-BAT evaluation and laboratory screening for platelet count, Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Subjects with an abnormal ISTH-BAT and/or laboratory results underwent further testing, and they were compared with a 1:1 random gender-, age- and type of surgery- matched control group. Overall, 1502 consecutive surgical patients (1186 adults, 316 children) were enrolled. Of these, 83 (5.5%, 95% confidence interval 4.4-6.8) patients (37 adults and 46 children) had an abnormal ISTH-BAT, and/or prolonged PT and/or prolonged aPTT and/or low platelet count; of them, one subject had low von Willebrand factor level, three Factor XII deficiency and four anticardiolipin and/or antiB2GPI antibodies. No major bleeding was reported in these 83 patients and their controls. ISTH-BAT and laboratory screening tests do not accurately detect mild BDs in selected patients undergoing elective surgery.

High Throughput Sequencing in 3449 Patients with Bleeding and Platelet Disorders: Novel Gene Discovery and Robust Diagnosis

BackgroundBleeding symptoms are common and reported at some point by 25% of the population. Laboratory investigations frequently fail to provide an explanation for the symptoms or to identify those at significant risk of future bleeding. A similar problem is presented by patients with congenital thrombocytopenia which often cannot be distinguished from acquired disorders and making investigation of platelet function impractical. The broad heterogeneity of phenotypes associated with established disorders further complicates diagnosis. For these reasons, we have developed High Throughput Sequencing (HTS) approaches to investigate patients with undiagnosed bleeding and platelet disorders (BPDs) through the ThromboGenomics 79 gene panel HTS (TG) test and by whole genome sequencing (WGS).MethodsBPD cases were recruited in 3 broad categories: Group 1: 1321 cases suspected to have a defect in one of the 79 known BPD genes (ie genes known to harbour variants responsible for a BPD); Group 2: 212 cases being prepared for elective surgery with self-reported bleeding symptoms; and Group 3: 1916 cases with a suspected inherited BPD, not thought to be caused by a variant in one of the 79 known BPD genes. DNA samples from the first two groups were sequenced by the TG test and from the third group by WGS as part of the first 35,000 samples for the 100,000 Genomes Project.In total, 3449 DNA samples from BPD patients have been analysed by HTS. Laboratory and clinical phenotypes were recorded using Human Phenotype Ontology (HPO) terms. Variants were called and prioritised based on minor allele frequency, predicted impact and presence in the Human Gene Mutation Database and those variants present in the 79 known BPD genes were reviewed by a multi-disciplinary team (MDT) where pathogenicity was assigned to variants using ACGS criteria (Clearly pathogenic [CPV], Likely pathogenic [LPV] and Variant of unknown significance [VUS]).ResultsA mean of 6.6 variants were assessed at MDT for each case. In Group 1 pathogenic variants were observed in 713 of 1321 (54%) of cases and >40% were novel and labelled as LPV; ~20% of variants discussed were designated VUS. In sharp contrast, pathogenic variants were only identified in 6 of 212 (2.8%) Group 2 cases. In Group 3, pathogenic variants were identified in 106 of 1916 (12%) cases. In >300 cases with non-syndromic thrombocytopenia, CPV or LPV were identified in ~30%. In contrast, in 131 cases with a significant bleeding disorder but no identified laboratory platelet or coagulation abnormality causal variants were observed in only 5 cases.ConclusionThese results demonstrate the success of HTS approaches in providing a genetic diagnosis for patients with well-defined inherited platelet or coagulation defects. In addition, 23 novel BPD genes were identified by analysis of the WGS data from Group 3 cases, including NBEAL2, RBM8A, SRC, DIAPH1, TPM4, ABCC4 and KDSR. Furthermore extensive replication was demonstrated in nearly 100 Group 3 cases for recent BPD gene discoveries by other groups (C6ORF25, CYCS, RNU4ATAC, STIM1, RASGRP2, ETV6, ACTN1). All MDT-reviewed variants and appended HPO terms are shared in ClinVar, supporting the international effort to improve reference catalogues, aligned to ASH's Precision Medicine initiative.DiscussionHTS has been particularly successful for thrombocytopenia, but the yield for bleeding disorders without numerical platelet or coagulation defects is low. Our results, and the observations by others are compatible with the notion that the genetic architecture of unresolved BPD cases is extremely diverse. Continuing efforts such as the 100,000 Genomes Project with sharing and transparency of data across projects will enable better interpretation of variants and the discovery of novel genes. Finally, we are annotating the non-coding space with data from recently identified GWAS variants for blood cell traits, BLUEPRINT and ROADMAP epigenome marks, and eQTLs for blood cell traits to interpret the regulatory regions of the genome and identify non-coding variants causing BPD and other unresolved rare diseases of the blood. DisclosuresNo relevant conflicts of interest to declare.

Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

Thromboxane A2 receptor deficiency is a qualitative platelet disorder that partially impedes adequate platelet signaling and aggregation. Generally, these patients have mild hemorrhagic manifestations in basal conditions, but may show severe bleeding when faced with a hemostatic challenge. We present the case of a 30-year-old female patient that arrives at the Hematology service with an undiagnosed bleeding disorder. She presented hemorrhagic complications during an augmentation mammoplasty and during an exodontia procedure, yet, during a C-section she presented none. At the first consultation she had normal coagulation factor levels by coagulometry, and normal platelet aggregation test for ADP, ristocetin, collagen and epinephrine. A platelet aggregation test for arachidonic acid confirmed thromboxane A2 deficit disorder. Thromboxane A2 deficit disorder is a rare qualitative platelet disorder that requires an extensive knowledge of coagulation and platelet function and tests, and a high level of clinical suspicion. These tests are especially difficult to interpret during pregnancy due to normal modifications to bodily function during this process.

Post-Tonsillectomy Hemorrhage and the Diagnosis of Occult Pediatric Coagulopathies.

The primary objective of this investigation was to determine rates of abnormal coagulation panels and diagnoses of coagulopathies in children with post-tonsillectomy hemorrhage (PTH). Secondary objectives identified patient demographics and hemorrhage event characteristics that correlated with a coagulopathy diagnosis. Case series with chart review. Patients requiring operative control of PTH at a tertiary children's hospital between 2015 and 2019 were included. Details of tonsillectomy procedures and hemorrhage events were reviewed along with screening labs for coagulopathy, referrals to hematology and bleeding disorder diagnoses. There were 250 children included. Mean age was 8.8 years (95% CI: 8.2-9.4) and 53.6% were males. PTH events occurred at a median of postoperative day six (mean: 5.9, 95% CI: 5.4-6.3), and 14.8% occurred within 24 hours of surgery. In this series, 23 patients (9.2%) had a second PTH, and three (1.2%) had a third PTH. Single and multiple PTH patients were similar with respect to age, gender, postoperative day, and technique (P > .05). Screening coagulation panels were obtained on presentation in 67.8% of children with one PTH and abnormally elevated in 38.3%. All children with multiple PTHs had labs drawn with 34.8% having elevated levels. No child with a single PTH was diagnosed with a bleeding disorder. Conversely, 87.0% of children with multiple PTHs saw hematology and three (13.0%) were diagnosed with a bleeding disorder (P < .001). Obtaining coagulation panels in pediatric patients presenting with PTH is rarely useful and diagnosing a coagulopathy is uncommon. However, among children with a second PTH, referral to hematology is reasonable as this group has a significantly higher, albeit small, incidence of undiagnosed bleeding disorders. 4 Laryngoscope, 131:E2069-E2073, 2021.

Prospective evaluation of ISTH‐BAT as a predictor of bleeding disorder in adolescents presenting with heavy menstrual bleeding in a multidisciplinary hematology clinic

BackgroundHeavy menstrual bleeding (HMB) can be the first manifestation of an undiagnosed bleeding disorder (BD). Identifying a BD can be challenging in the adolescent age group. The utility of bleeding assessment tools (BAT) remains elusive in this population. AimWe evaluated the ability of the International Society on Thrombosis and Haemostasis‐BAT (ISTH‐BAT) in predicting a BD in adolescents referred for HMB to a multidisciplinary hematology clinic. MethodsTwo hundred adolescents with HMB underwent a standardized evaluation for BD. The clinical characteristics, laboratory data, and bleeding scores (BS) assessed using ISTH‐BAT were prospectively collected. Comparisons were made between patients based on the diagnosis of BD receiver operating characteristic (ROC) curve analyses of ISTH‐BAT were performed to assess its value for predicting BD. ResultsOverall, 33% (n = 67) of adolescents were diagnosed with a BD. The mean ISTH‐BAT BS was higher in BD as compared to those without (4.1 versus 3.1, P < .0001), but the mean menorrhagia‐specific scores did not differ (2.9 in both groups). The ISTH‐BAT demonstrated a modest discriminative ability as a screening tool to identify BD in girls with HMB with an area under the curve (AUC) of 0.71. The ROC analysis demonstrated that with increasing BS, the sensitivity decreased, but the specificity increased. At BS = 3, sensitivity was 88%, specificity 31%, and accuracy 50%; at BS = 5, sensitivity was 37%, specificity 94%, and accuracy was 75%. There was no change thereafter. ConclusionIn adolescents with HMB, an ISTH‐BAT BS of >4 instead of the established cut‐off of >2 in children is highly specific in predicting a BD.

Screening for undiagnosed bleeding disorders in post-tonsillectomy bleed patients: Retrospective review and systematic review of the literature

ObjectivesThere is currently no standard for screening children with post-tonsillectomy bleeds (PTB) for coagulopathy disorders. This study aims to identify children with occult coagulopathy diagnosed at PTB and to identify factors associated with diagnosis. A systematic review of the literature further identified trends in this topic. MethodsA retrospective chart review of patients returning to the operating room for PTB at a tertiary children's hospital was undertaken from 2012 to 2016. A systematic review using Medline OVID was subsequently performed. ResultsOf 12,503 tonsillectomies, 311 children (52% male, mean age 8 years) required surgery for PTB (2.5% rate). Twenty-one patients (7%) had multiple episodes. Only two patients (0.6%) (both with known coagulopathy) underwent pre-tonsillectomy labs and 260 (84%) had labs at PTB. Six patients (2%) were diagnosed with a new coagulopathy, most commonly von Willebrand's Disease (vWD) in five (2%). Three patients (1%) were diagnosed at first PTB and three (1%) at second PTB. Of the three diagnosed at second PTB, two had normal partial thromboplastin time (PTT). In systematic review, 1243 manuscripts were reviewed and 8 papers discussing this topic are presented. ConclusionOccult coagulopathy was rarely diagnosed at PTB, but this may be limited by inconsistent screening. PT and PTT are not sensitive tests for vWD, and normal coagulation labs may lead to delayed diagnosis. The literature reveals occult coagulopathy is rare but often diagnosed after severe or recurrent hemorrhage. In order to provide efficient care and medical management, a standardized algorithm and sensitive labs for screening PTB patients are needed.

Let's Talk Period! Preliminary results of an online bleeding awareness knowledge translation project and bleeding assessment tool promoted on social media.

Undiagnosed bleeding disorders are common and can pose significant health risks, especially for women. Recently, a self-administered bleeding assessment tool (Self-BAT) was validated in von Willebrand disease. To increase awareness of undiagnosed bleeding disorders through the use of an informational website (http://letstalkperiod.ca) targeted at women in their reproductive years. The Let's Talk Period website was built in consultation with a medical communications company and focus groups of women, with the aim of clearly presenting key messages around menstrual bleeding. The website was promoted through social media and local and national interviews. Upon completion of the online Self-BAT available at http://letstalkperiod.ca, the result is displayed to the user along with a recommendation to seek medical attention if the score is abnormal. During the initial 3-month period, there were 5158 page views from 64 countries. A total of 489 individuals, 95% female, completed the online Self-BAT. The mean Self-BAT score was 6, range 0-44. Abnormal Self-BAT scores were reported in 45% of the respondents, of whom 96% were female. The most commonly reported bleeding symptoms were menorrhagia (98%) and postpartum haemorrhage (82%). Bleeding symptoms were similar across different geographical areas. An online screening tool is an effective method of identifying individuals concerned with abnormal bleeding. A significant portion of the general population report experiencing symptoms of abnormal bleeding. In women, the most frequently reported bleeding symptoms were menorrhagia and postpartum haemorrhage.

Let's Talk Period: Preliminary Results of an Online Bleeding Awareness Knowledge Translation Project and Bleeding Assessment Tool Promoted on Social Media

Background: Undiagnosed bleeding disorders can pose significant health risks, especially for women. As many as 1 in 1000 individuals have a bleeding disorder, many of whom are undiagnosed. Lack of understanding about the difference between normal and abnormal bleeding, particularly menstrual bleeding, is a barrier to diagnosis. Recently, a self-administered bleeding assessment tool (Self-BAT) was validated as a screening tool for von Willebrand disease (VWD).Objective: Our objective was to increase awareness of undiagnosed bleeding disorders through the use of an informational website (http://letstalkperiod.ca) targeted at women in their reproductive years. Here we report the results from the first 10 weeks of this knowledge translation project.Methods:The Let’s Talk Period website was built in consultation with a medical communications company, with the aim of clearly presenting key messages around menstrual bleeding. Focus groups with young women were held to determine optimal communication strategies and an iterative process of expert review was undertaken prior to launch. Upon completion of the integrated Self-BAT application, the result of whether the bleeding score is normal or abnormal is displayed to the user, along with a recommendation to seek medical attention if the score is positive/abnormal (≥6 for adult females,≥4 for adult males, ≥3 for individuals < 18 years). Queen’s University Legal Department provided advice regarding website disclaimers. Research Ethics Board approval was sought but deemed unnecessary, given that no identifiable information is collected. Website users must electronically indicate that they have read and understood a disclaimer about the use of the Self-BAT application before being granted access, and must enter their age and gender.The website was promoted through an interview with the senior author that aired on Canadian national television in the context of a segment on VWD. Additional promotion occurred using social media such as Facebook and Twitter, as well as during local interviews at Queen's University and Kingston General Hospital. The social media networks of the Canadian Hemophilia Society, the World Federation of Hemophilia, the Foundation for Women and Girls with Blood Disorders were also engaged to promote the website.Results: For the 10-week period beginning May 14, 2016 there were 4,907 page views and 3,001 sessions initiated by 2,597 individual users from 62 countries. The average session length was 1 minute and 12 seconds; 15 were longer than 30 minutes. The majority of sessions (60%) were initiated in Canada. Table 1 outlines the countries with the highest volume of website visits.A total of 460 individuals, 438 (95%) of whom were female, completed the online Self-BAT. Individuals ranged in age from 12 to 71 years (mean 36 years). Individuals aged 35 to 44 years represented the largest proportion of users who completed the Self-BAT (31%), followed by those aged 25 to 34 years (28%). The mean Self-BAT score was 6 and scores ranged from 0 to 44. Abnormal age and gender specific Self-BAT scores were reported in 45% of the respondents (n=209), of which 98% were female. Of the individuals with abnormal Self-BAT scores the most commonly reported symptoms (Table 2) were menorrhagia (99%), post-partum hemorrhage (84%), bleeding from the oral cavity (78%), cutaneous bleeding (74%) and epistaxis (56%). Frequency of specific symptoms of menorrhagia are outlined in Table 3. The most common symptom of post-partum hemorrhage reported was bleeding longer than 6 weeks after delivery (16%). Surgery or ICU admission post-partum was required in 3 women.Conclusion: Initial results from the first 10 weeks of an informational website demonstrated that this platform is capable of reaching users from around the world. We have demonstrated that an online screening tool will be used by individuals concerned about abnormal bleeding. In women, the predominant symptoms of abnormal bleeding reported were menorrhagia and post-partum hemorrhage. In future, we plan to expand the educational content of the Let's Talk Period website, including information directed at medical professionals and a regular blog directed at the public. Additionally, we plan to seek research ethics approval for knowledge translation research tracking the outcomes of abnormal bleeding scores in local website users. [Display omitted] [Display omitted] [Display omitted] DisclosuresJames:Bayer: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Biogen: Consultancy; Basalt: Consultancy.

Laboratory evaluation of patients with undiagnosed bleeding disorders.

The evaluation of patients with a bleeding tendency represents a challenge as the routinely available tests for evaluating bleeding disorders are limited, complicating the laboratory determination of the clinically observed bleeding tendency. As a result, some bleeding disorders remain undiagnosed. The aim of the study was to evaluate whether global coagulation tests would contribute to the laboratory analysis of patients with undiagnosed bleeding disorders. Patients were evaluated for coagulation and fibrinolysis activities by thrombin generation test and euglobulin lysis time. In addition, plasma activity of factor XIII, plasminogen, α-2 antiplasmin, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor was also obtained. Forty-five patients were included. Eight per cent presented a mild bleeding disorder and 20% a moderate bleeding disorder. The thrombin generation test results were similar between patients and controls. Euglobulin lysis time results, however, were lower in patients than in controls, both before (median 175 vs. 250 min, respectively; P = 0.003) and after (median 145 vs. 115 min, respectively; P ≤ 0.001) arm constriction, suggesting that they were experiencing hyperfibrinolysis. Interestingly, patients' median thrombin-activatable fibrinolysis inhibitor activity was higher than in controls (21.2 vs. 19.46 μg/ml; P = 0.016). However, plasminogen, α-2 antiplasmin, plasminogen activator inhibitor-1, and factor XIII activities did not differ between the groups. Global coagulation and fibrinolysis tests proved to be limited in detecting the hemostatic disorders in some patients with a relevant bleeding tendency and may not be adequate to address their bleeding risk. Bleeding scores are currently the available medical approach for the evaluation of these patients.

Heavy Menstrual Bleeding as a Common Presenting Symptom of Rare Platelet Disorders: Illustrative Case Examples

Heavy menstrual bleeding (HMB) is a common symptom in patients who present to the obstetrician-gynecologist or adolescent medicine specialist and might result from an underlying inherited bleeding disorder. Whereas relatively common bleeding disorders such as von Willebrand disease are often included in standard laboratory assessments, rarer platelet function disorders can be challenging to diagnose. Additionally, HMB can be a particularly difficult symptom to manage in adolescents with platelet function disorders, and it is associated with decreased quality of life. We review the diagnostic and management issues of patients with platelet function disorders through the presentation of 2 patient case reports, with a focus on a diagnosis of Glanzmann thrombasthenia, an inherited qualitative disorder that affects platelet function. Whereas the first patient presented to the emergency department before the diagnosis of a bleeding disorder and required a hematologic referral and extensive laboratory assessments, the second patient had been diagnosed with Glanzmann thrombasthenia as a child but experienced severe management challenges at the onset of menarche. In both patients, collaboration between the obstetrician-gynecologist or adolescent medicine specialist and the hematologist was critical for achieving acute management of the bleeding symptoms and for ensuring optimal long-term disease management. Together, these cases highlight the importance of properly identifying females with HMB who might have an undiagnosed bleeding disorder and of consulting with a hematologist to determine an appropriate management plan throughout all life stages.

Improving care and treatment options for women and girls with bleeding disorders.

Women and girls may experience increased bleeding symptoms as carriers of haemophilia. They can also be affected by other hereditary bleeding diatheses such as von Willebrand disease, platelet dysfunction defects or deficiencies of coagulation factors (F) such as FI, FII, FV, FVII, FX, FXI and FXIII. In addition to general bleeding symptoms, such disorders pose unique problems for women due to their impact on reproductive health. Women and adolescent girls with undiagnosed bleeding disorders frequently experience heavy menstrual bleeding (HMB; menorrhagia), leading to impairment of daily activities. Other gynaecological and obstetric manifestations, for example miscarriage, bleeding during pregnancy and postpartum haemorrhage (PPH), can occur. Treatment for HMB should consider patient wishes relating to preservation of fertility, and management options include hormonal measures, desmopressin, antifibrinolytics, platelet concentrate transfusions and clotting factor therapy. During pregnancy, monitoring clotting factor levels informs the need for prophylactic therapy; subsequent haemostatic cover can minimise PPH. Under-recognition of bleeding disorders in females may lead to inappropriate, or lack of, treatment. This may be avoided by increased disease awareness, prompt and accurate diagnosis, and a multidisciplinary approach to patient care. This review considers the range of hereditary bleeding disorders that may affect women and adolescent girls, and their evaluation and management.

Providing young women with credible health information about bleeding disorders.

BackgroundApproximately 1% of U.S. women may have an undiagnosed bleeding disorder, which can diminish quality of life and lead to life-threatening complications during menstruation, childbirth, and surgery.PurposeTo understand young women’s knowledge, attitudes, and perceptions about bleeding disorders and determine the preferred messaging strategy (e.g., gain- versus loss-framed messages) for presenting information.MethodsIn September 2010, a web-assisted personal interview of women aged 18–25 years was conducted. Preliminary analyses were conducted in 2011 with final analyses in 2013. In total, 1,243 women participated. Knowledge of blood disorders was tabulated for these respondents. Menstrual experiences of women at risk for a bleeding disorder were compared with those not at risk using chi-square analyses. Perceived influence of gain- versus loss-framed messages also was compared.ResultsParticipants knew that a bleeding disorder is a condition in which bleeding takes a long time to stop (77%) or blood does not clot (66%). Of the women, 57% incorrectly thought that a bleeding disorder is characterized by thin blood; many were unsure if bleeding disorders involve blood types, not getting a period, or mother and fetus having a different blood type. Women at risk for a bleeding disorder were significantly more likely to report that menstruation interfered with daily activities (36% vs 9%); physical or sports activities (46% vs 21%); social activities (29% vs 7%); and school or work activities (20% vs 9%) than women not at risk. Gain-framed messages were significantly more likely to influence women’s decisions to seek medical care than parallel loss-framed messages. Findings suggest that the most influential messages focus on knowing effective treatment is available (86% gain-framed vs 77% loss-framed); preventing pregnancy complications (79% gain- vs 71% loss-framed); and maintaining typical daily activities during menstrual periods.ConclusionsLack of information about bleeding disorders is a serious public health concern. Health communications focused on gain-framed statements might encourage symptomatic young women to seek diagnosis and treatment. These findings and corresponding recommendations align with Healthy People 2020 and with CDC’s goal of working to promote the health, safety, and quality of life of women at every life stage.

P-072 Recurrent spontaneous abortion in women with bleeding disorders

P-072 Recurrent spontaneous abortion in women with bleeding disorders

Endometrial haemostasis and menstruation

Under normal physiological circumstances menstruation is a highly regulated, complex process that is under strict hormonal control. During normal menstruation, progesterone withdrawal initiates menstruation. The cessation of menstrual bleeding is achieved by endometrial haemostasis via platelet aggregation, fibrin deposition and thrombus formation. Local endocrine, immunological and haemostatic factors interact at a molecular level to control endometrial haemostasis. Tissue factor and thrombin play a key role locally in the cessation of menstrual bleeding through instigation of the coagulation factors. On the other hand, fibrinolysis prevents clot organisation within the uterine cavity while plasminogen activator inhibitors (PAI) and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity. Abnormalities of uterine bleeding can result from imbalance of the haemostatic factors. The most common abnormality of uterine bleeding is heavy menstrual bleeding (HMB). Modern research has shown that an undiagnosed bleeding disorder, in particular von Willebrand disease (VWD) and platelet function disorders, can be an underlying cause of HMB. This has led to a change in the approach to the management of HMB. While full haemostatic assessment is not required for all women presenting with HMB, menstrual score and bleeding score can help to discriminate women who are more likely to have a bleeding disorder and benefit from laboratory haemostatic evaluation. Haemostatic agents (tranexamic acid and DDAVP) enhance systemic and endometrial haemostasis and are effective in reducing menstrual blood loss in women with or without bleeding disorders. Further research is required to enhance our understanding of the complex interactions of haemostatic factors in general, and specifically within the endometrium. This will lead to the development of more targeted interventions for the management of abnormal uterine bleeding in the future.

Barriers to effective diagnosis and management of a bleeding patient with undiagnosed bleeding disorder across multiple specialties: results of a quantitative case-based survey

Background:Bleeding symptoms commonly seen by multiple physician specialties may belie undiagnosed congenital or acquired bleeding disorders. Acquired hemophilia is a potentially life-threatening cause of unexplained acute bleeding manifested by an abnormal activated partial thromboplastin time (aPTT) that does not correct with 1:1 mixing with normal plasma.Methods:Practicing physicians (hematology/oncology, emergency medicine, geriatrics, internal medicine, rheumatology, obstetrics and gynecology, critical care medicine, and general surgery) completed an online survey based on a hypothetical case scenario.Results:Excluding surgeons and obstetrician/gynecologist respondents, 302 physicians (about 50 per specialty) were presented with an older adult woman complaining of recurrent epistaxis. Nearly 90% ordered a complete blood count and coagulation studies (aPTT, prothrombin time [PT]/international normalized ratio [INR]). Despite a prolonged aPTT of 42 seconds, <50% of nonhematologists would repeat the aPTT, and <45% would consult a hematologist; emergency medicine physicians were least likely (10%) and rheumatologists were most likely (43%) to consult. After presentation weeks later with bruising and abdominal/back pain, ≥90% of physicians within each specialty ordered a complete blood count or PT/INR/aPTT. Despite an aPTT of 63 seconds, the majority did not repeat the aPTT. At this point, approximately 75% of internal medicine and geriatric physicians indicated they would consult a hematologist, versus 47% in emergency medicine and 50% in critical care. All participants preferred abdominal computed tomography (80%–84%). After 12 hours of additional observation, 73% to 94% of respondents consulted a hematologist. Complete blood count revealed anemia and an aPTT twice the upper limit of normal; emergency medicine physicians remained least likely to request a consult.Conclusion:Determining the cause of an abnormal coagulation study result should carry equal weight as looking for the site of bleeding and could be facilitated by consultation with a hematologist. Insight from this survey highlights knowledge and practice gaps that could be the target of focused educational initiatives.

Predictors of Bleeding Disorders in Children with Epistaxis: Value of Preoperative Tests and Clinical Screening

Objective: Children with recurrent epistaxis despite medical therapy may be at higher risk of having a bleeding disorder. The objective of this study was to identify the prevalence of previously undiagnosed bleeding disorders in children with severe epistaxis who failed medical therapy requiring intraoperative nasal cautery. Method: Retrospective chart review from October 15, 2006 to December 31, 2010. Inclusion criteria: children (&lt;19 years) with epistaxis referred to otolaryngology, no known bleeding disorder, and failed medical therapy requiring nasal cautery. Data collected: duration and severity of epistaxis, bleeding history, family history of bleeding. Screening CBC, PT and PTT were performed on all of patients. Results: Of 248 subjects referred for epistaxis, 47 met study inclusion criteria (mean age 8.6 ± 3.8 years; male:female ratio 29:18). Coagulation studies revealed 12.8% (6/47) prolonged PT, 8.5% (4 /47) prolonged PTT, 10.6% (5/47) prolonged PT and PTT. Three with borderline levels proceeded to surgery. Twelve were referred to hematology secondary to abnormal coagulation studies. Of these, five patients (5/12, 42%) were diagnosed with a bleeding disorder (3-type 1 von Willebrand’s disease (VWD), 1-platelet aggregation disorder, and 1-factor VII deficiency). Overall, 6.4% (3/47) had VWD in this cohort, which is higher than the reported prevalence of 1%. Conclusion: Knowledge of whether a child has a coagulopathy prior to surgery can limit complications. In this highly selected group of patients with persistent epistaxis, 10.6% (5/47) had a bleeding disorder. It is important to consider hemostatic testing in high risk patients.