Significant Bleeding Symptoms Research Articles

The impact of concurrent X chromosome anomalies on diagnosis and bleeding phenotype in children with hemophilia: A single-institution case series.

Hemophilia is an inherited X-linked bleeding disorder characterized by deficiencies of factors VIII or IX. Concomitant X chromosome disorders can impact bleeding phenotype, complicating timely diagnosis and disease management. Herein, we describe three cases of female and male pediatric patients with hemophilia A or B diagnosed between 6days and 4years old in the setting of skewed X chromosome inactivation, Turner syndrome, or Klinefelter syndrome. All of these cases had significant bleeding symptoms, and two patients required initiation of factor replacement therapy. One female patient developed a factor VIII inhibitor similar to that described in males with hemophilia A.

Trends in utilization of first-line palliative treatments for anal squamous cell carcinoma.

Anal squamous cell carcinoma patients often present with significant symptoms, including pain, bleeding, and obstructive symptoms. This requires palliation-directed therapy as a first-line treatment to alleviate symptoms. The proportion of patients receiving first-line palliative treatments is unknown. We aimed to study the factors associated with the use of first-line palliative treatments in stage II-IV anal squamous cell carcinoma patients. We used the National Cancer Database to identify adult patients diagnosed with stage II-IV anal squamous cell carcinoma between 2004 and 2016. We performed univariable and multivariable logistic regression analysis to determine the clinical and sociodemographic variables associated with the utilization of palliative treatment in the first-line setting, including palliative radiotherapy, chemotherapy, surgery, and pain management. Among 16,944 patients diagnosed with stage II-IV anal squamous cell carcinoma, only a small proportion of 492 (2.9%) required first-line palliative treatments to control symptoms. The majority of these patients received palliative radiotherapy (32%), followed by palliative surgery (25%), palliative chemotherapy (19%), combination therapies (14%), and pain management (10%). On multivariable analysis, higher stage disease, lower income, Medicare and Medicaid insurance, and life expectancy <6 months were associated with higher odds of use of first-line palliative therapy. First-line use of palliative treatments to control symptoms is needed in a small proportion of anal squamous cell cancer patients. It was utilized in all stages, but it was most frequently observed in patients with stage IV disease and patients with <6 months life expectancy. First-line palliative therapy was also more frequent in lower-income patients and patients with Medicare and Medicaid insurance which highlights the disparities in anal cancer management.

Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

▪IntroductionImmune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission.MethodsThis open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080).ResultsTotal 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups.ConclusionsLow-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:It includes information or discussion of off-label drug use of tacrilimus.

Ibrutinib effect in acquired von Willebrand syndrome secondary to Waldenström macroglobulinemia

The pathological increase of clonal IgM in Waldenström macroglobulinemia can be associated with acquired von Willebrand syndrome and can be a major risk of bleeding symptoms in this subgroup of patients with Waldenström macroglobulinemia. The Bruton tyrosine kinase inhibitor ibrutinib is one of the approved treatments for symptomatic Waldenström macroglobulinemia. However, some controversy exists regarding the use of ibrutinib in these patients with high risk of bleeding because of its antiaggregant effect that could increase the risk of bleeding. Here, we present the case of a patient with Waldenström macroglobulinemia with associated acquired von Willebrand syndrome and progressively significant bleeding symptoms, who experienced a rapid increase in von Willebrand factor with ibrutinib treatment, despite only reaching a partial response in IgM levels similar to those reached with other previous treatments. We suggest that the control over the monoclonal protein is not the only mechanism that explains the good response, improvement in the bleeding symptoms and von Willebrand factor levels. This fact could be explained by the reduced glycoprotein Ib receptor expression induced by ibrutinib and the consequent von Willebrand factor increase in peripheral blood.

Combination of ATRA and High-Dose Dexamethasone As First-Line Treatment in Adult Immune Thrombocytopenia:a Randomized, Phase 2, Open-Label Trial

Introductions Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by immune-mediated platelet destruction and impaired platelet production. As the immunosuppressive therapy, high-dose dexamethasone (HD-DXM) has been recommended as the standard first-line treatment. Nevertheless, approximately half of ITP patients relapse within 6 months and require further therapies. All-trans retinoic acid (ATRA) is a derivative of vitamin A that has an immunomodulatory effect on hemopoiesis. Our previous study demonstrated that ATRA could induce a more rapid and long-lasting response in patients with corticosteroid-resistant or relapsed ITP (Lancet haematology, 2017). In addition, we found that ATRA corrected impaired platelet production by regulating the complement-IL-1β loop and TNFAIP3/NF-κB/SMAD7 signaling pathway in ITP (Br J Haematol, 2018; Haematologica, 2019). These findings suggested that the addition of ATRA to HD-DXM in treatment-naive patients could improve sustained response rate based on the synergetic function. Here, we present the results of the first prospective, multicenter, randomized, controlled trial with the largest cohort to date comparing the efficacy and safety of HD-DXM plus ATRA vs HD-DXM as first-line therapy in newly diagnosed adult primary ITP patients. Methods In this open-label, randomized, phase 2 trial, we enrolled adult ITP patients from 6 different tertiary medical centers in China. Eligible subjects had confirmed newly-diagnosed, treatment-naive ITP; platelet counts &amp;lt;30×109/L or platelet counts &amp;lt; 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above).Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral ATRA (10 mg twice daily) plus HD-DXM or HD-DXM monotherapy for 12 weeks. DXM was administered orally at 40 mg daily for 4 consecutive days to both arms. The 4-day course of dexamethasone was repeated on days 11 to 14 in the case of lack of response by day 10(Figure 1). The primary endpoint was 6-month sustained response (SR) defined as platelet counts maintained &amp;gt; 50×109/L without any additional ITP-modifying therapy at the 6-month follow up. Key secondary endpoints were initial response by day 14 (OR: platelet count ≥30×109/L and at least 2-fold increase of the baseline platelet count and absence of bleeding; CR: platelet count ≥100×109/L), duration of response (DOR), bleeding scores, and adverse events (AEs). Results Between June 2015, and July 2018, 300 patients were randomly allocated into either ATRA plus HD-DXM (n=150) or HD-DXM monotherapy (n=150). At the 6-month follow-up, the proportion of patients with SR was significantly higher in the ATRA plus HD-DXM group than in the HD-DXM monotherapy group (61% vs 37%, p= 0.009). So far, the increase of almost one quarter is very encouraging. The combination of ATRA and HD-DXM resulted in a higher incidence of early OR at day 14 compared with HD-DXM monotherapy (83% vs 67%, P=0.031), and the CR rate was 60.0% (ATRA+HD-DXM) vs 40.6% (HD-DXM) (P=0.015). Throughout the follow-up period, overall DOR was greater in the combination group, estimated by the Kaplan-Meier analysis. Fewer patients in the combination group than in the monotherapy group relapsed during follow-up (p&amp;lt; 0.001), and the median time to relapse was 75 days (ATRA+HD-DXM) vs 48 days (HD-DXM). Bleeding was more effectively controlled in the ATRA plus HD-DXM arm, with fewer bleeding events and lower bleeding scores. There was no difference between the 2 groups in terms of rescue treatments. All subjects tolerated the treatment well, and no grade 4 adverse events or treatment-related death were reported. No statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. Conclusions ATRA plus HD-DXM is an effective and safe treatment for ITP as a first-line therapy that can provide a sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. Disclosures No relevant conflicts of interest to declare.

Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders.

Inherited dysfibrinogenemia is a rare disorder, for which clinical studies related to the risk of bleeding or thrombosis and the type of causative mutation are scanty. We analyzed the laboratory, clinical, and genotypic features of 50 patients with inherited dysfibrinogenemia belonging to 19 unrelated families. In all the index cases, fibrinogen activity by Clauss method was below the normal range, while it was observed in 57.9% only by PT-derived method. In three families, hypodysfibrinogenemia was evident, associated with three novel mutations (Ter492Gln in FGB, Cys365Asp, and Leu370Phe in FGG). Three additional novel mutations were also identified (Arg114Lys in FGA, Ile131Thr and Trp234Arg in FGG). Bleeding symptoms assessed by ISTH-BAT scored at least 1 in 30% of patients and, significant bleeding symptoms were mainly present in female patients, especially associated with pregnancy. Two patients with FGB Arg44Cys suffered from venous thromboembolism, and two with FGA Arg35His had ischemic stroke at older age. This study confirms the heterogeneity of clinical features in inherited dysfibrinogenemia, due to the wide spectrum of the causative mutations. Larger multicenter studies are needed to assess the definitive correlation of some mutations with bleeding or thrombosis.

Eltrombopag Plus Pulsed Dexamethasone As First Line Therapy for Subjects with Immune Thrombocytopenic Purpura (ITP)

▪Background: Eltrombopag is an oral thrombopoietin receptor agonist that has been licensed for use as second line therapy in ITP patients. For most subjects, platelet counts usually return to baseline within 2 weeks of eltrombopag discontinuation, however, up to 15% of subjects may maintain a prolonged response after discontinuation (BJH Volume 165(6) 2014 865-869). Therefore, we conducted a pilot study to evaluate whether a 12-week course of eltrombopag plus pulsed dexamethasone as first line therapy can increase the proportion of patients with prolonged response.Methods: This multicenter, single arm, open-label pilot study was performed on subjects with newly diagnosed ITP. Eligible subjects had confirmed ITP and platelet counts <30×109/L or platelet counts < 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above). Patients must have no prior ITP treatment except platelet transfusions. All patients provided written informed consent before enrolment. This study was conducted in accordance with the Declaration of Helsinki.Eligibility criteria included isolated thrombocytopenia with exclusions of secondary immune or drug-induced thrombocytopenia, cancer and pregnancy related thrombocytopenia and virus induced thrombocytopenia. Bone marrow examination is not mandatory but must be consistent with peripheral platelet consumptions with no features of dysplasia, extensive fibrosis, aplasia, marrow infiltration if performed.Treatment consisted of eltrombopag 25-75mg daily according to platelet response for 12 weeks plus pulsed dexamethasone, 40mg daily for 4 consecutive days every 4 weeks for 1-3 courses. The primary endpoint was prolonged response defined as platelet counts > 50×109/L for more than 6 months without any ITP therapy after completion of 12-week therapy.The reported prolonged response rate of dexamethasone alone is around 25%, a sample size of 60 subjects will be required to detect a doubling of the prolonged response rate at a significant level of 0.05 with power of 0.9. Differences between prolonged responder and relapsed subject groups were analyzed by the Student's t-test. P values <0.05 were considered significant.Results:46 subjects were enrolled from February 2015 to July 2018. The median age was 40 years, range 18 to 81; 29 were female and 17 were male. Median platelet counts at baseline were 18×109/L, range 1 to 44×109/L. One subject withdrew consent before starting treatment. One was withdrawn because of protocol violations. Three subjects did not have significant increase in platelet counts during the entire 12 weeks treatment despite a maximum of eltrombopag 75mg daily and 3 courses of pulsed dexamethasone. One of them subsequently turned out to be amegakaryocytic thrombocytopenia. These 5 subjects were still included in the final analysis.Twenty-nine subjects had good initial response to treatment and completed at least 6 months follow-up (Fig 1), 19 of them had achieved the primary end point of platelet counts count> 50×109/L for more than 6 months after discontinuation of eltrombopag. The median platelet counts at 6 months were 150×109/L (range 53 to 371×109/L), Average eltrombopag dose was 36.8mg daily and average pulsed dexamethasone was 2.2 courses. Eleven subjects maintained prolonged response for 12 months or more.Four subjects are still receiving treatment and 8 subjects are still on the 6 months off-therapy observation period (median follow up is 12 weeks, range 4 to 21 weeks).Ten subjects relapsed after discontinuation of eltrombopag(Table 1). The median time to relapse was 47.8 days, range 15 to 148 days. Average daily eltrombopag was 45mg and average pulsed dexamethasone was 2.5 courses.So far, the prolonged response rate of 56 % (19/34) among 34 evaluable subjects is very encouraging. According to statistical analysis, seven more prolonged responders among the remaining 26 subjects (14 yet enrolled and 12 pending final evaluation) would suggest that 12-week of eltrombopag plus pulsed dexamethasone as first line therapy may significantly improve prolonged response rate in ITP patients. All subjects tolerated the treatment well and no Grade 3 or above adverse effects were reported.Conclusions: Eltrombopag plus pulsed dexamethasone is an effective and safe treatment for ITP as a first line therapy that can provide sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. DisclosuresCheng:Novartis: Research Funding; BMS: Honoraria, Speakers Bureau; Astrazeneca: Honoraria, Speakers Bureau.

A Rare Case of Refractory Hematemesis Caused by a Gastric Lipoma

Lipomas in the stomach are a rare finding representing less than 1% of all stomach tumors. These are usually asymptomatic and rarely cause significant bleeding or obstructive symptoms. We report an unusual case of a gastric lipoma presenting as massive refractory hematemesis. A 76 year old female taking NSAIDs for a recent hip fracture repair presented with multiple episodes of large volume hematemesis leading to weakness and fatigue. She was initially unstable with hypotension and tachycardia. Her abdominal examination was benign. The patient was intubated for airway protection and resuscitated with blood and intravenous fluids. She had no prior history of gastrointestinal bleeding. The patient underwent an EGD which showed a 3 cm polypoid mass in the posterior gastric body that was actively bleeding. This was cauterized and injected with epinephrine but the patient became hypotensive requiring the case to be stopped. Another EGD was attempted after the patient was transferred to the ICU for stabilization. Endoscopy again showed active bleeding at the mass site and several endoclips were applied and ethanolamine injected for hemostasis. However, bleeding continued with a drop in her hemoglobin and hematocrit to a nadir of 5.9/16.9. Interventional radiology was consulted for embolization. Angiography indicated the bleeding was localized to a branch of the left gastric artery but the vessel could not be accessed due to its tortuosity. The patient was subsequently taken to the operating room given her continued hematemesis. She underwent an open partial gastrectomy removing the stomach body and antrum with retrocolic gastrojejunostomy. Post-surgery, the patient was stable with cessation of bleeding. Anatomical specimens collected from the partial gastrectomy showed a submucosal lipoma measuring 4.5 cm in its greatest dimension with fat necrosis extending into the submucosa and muscularis propria layers. Gastric lipomas are benign tumors of adipose tissue arising from the submucosal layer and rarely present with bleeding or obstructive symptoms. In cases with bleeding the blood loss is usually slow and chronic. Only a few cases of massive bleeding have previously been reported. Endoscopic techniques such as submucosal dissection or unroofing have been employed successfully for treatment of smaller lipomas or those with relatively mild symptoms. However, in the case of larger tumors and those with large volume bleeding surgical resection is usually required.Figure: Initial EGD showing an approximately 3 cm polypoid mass in the posterior gastric body.Figure: The mass seen with EGD shows evidence of active bleeding and an ulcerated tip.Figure: Endoscopic measures failed to achieve hemostasis at the lipoma site.

Can Immature Platelet Fraction (IPF) be Used to Assess Bleeding Risk in Pediatric Immune Thrombocytopenia (ITP) and to Differentiate ITP from Bone Marrow Failure/Aplastic Anemia? A Retrospective Analysis

Immune Thrombocytopenia (ITP) usually presents with isolated, severe thrombocytopenia with very low platelet count (generally less than <30 x 109/L) in the absence of other hematologic abnormalities. However, ITP is a diagnosis of exclusion without any definite diagnostic test that can confirm the diagnosis at the time of presentation and clinicians occasionally worry at the time of presentation about other bone marrow processes that may present with thrombocytopenia, which would require considerably different therapy. In light of current guidelines suggesting that observation is likely to be safe in pediatric patients with low platelet counts without significant bleeding, identifying patients at risk for severe hemorrhage is even more important to help guide therapy. In addition, appropriately differentiating ITP from other diagnoses may also prevent inappropriate administration of ineffective therapies. The immature platelet fraction (IPF) is a measure of platelet turnover measuring RNA containing, large platelets by fluorescently labeling the platelets and utilizing flow cytometric gates programmed into the Sysmex XN-3000 hematology analyzer. We examined the medical laboratory records of 134 patients who had an IPF performed over the past 4 months for correlation between IPF and bleeding manifestations. In ITP patients who presented with significant bleeding symptoms (defined as epistaxis which was more than brief, oral bleeding more than palatal petechiae or GI or intracranial hemorrhage), the IPF was significantly lower than in those who presented with no bleeding or cutaneous bleeding only (bruising and petechiae): IPF=4.3%±1.6 SEM in bleeding patients versus 21.8%±1.8 SEM in not bleeding patients; p<0.0001. In two patients with life threatening hemorrhage and ITP (GI bleeding with drop in hemoglobin requiring both PRBC transfusion and treatment to raise the platelet count; ICH resulting in mortality), the IPF was low at the time of initial hemorrhage, but increased after ITP therapy (GI Bleed: plt 1K, IPF 5.3% increased to 20.3% after IVIG; ICH plt 6K, IPF 1.8% increased to 12.8% after IVIG and prednisone). We also examined first platelet count and IPF in 127 patients with ITP and 21 patients with BMF/AA who presented to our institution since October 2013. In this cohort of patients, the IPF in patients with ITP was significantly higher than in the BMF/AA patients and an IPF of >5.3 was associated with a negative predictive value of 80% for BMF/AA (IPF 16.6%±1.2 SEM in ITP vs. 2.9%±1.4 SEM in BMF/AA). In summary, we demonstrate that the IPF is a useful and simple adjunct in diagnosis of ITP which can help differentiate the patients most likely to have ITP from those who may need further diagnostic evaluation and require treatment to prevent bleeding complications. Further studies will focus on the ability of the IPF to prospectively predict the bleeding risk of patients and categorize patients. DisclosuresLambert:GSK: Consultancy; NovoNordisk: Honoraria; Hardin Kundla McKeon & Poletto: Consultancy.

Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations

We report the molecular characterisation of two novel cases of inherited hypofibrinogenemia. After sequencing all coding regions and intron-exon boundaries of the three fibrinogen genes (FGA, FGB, and FGG), two different novel mutations were found, one homozygous and one heterozygous. The first patient, with a mild bleeding history and mild discrepancy between functional and immunological fibrinogen, showed a novel homozygous nonsense mutation in exon 5 of FGA (p.Trp373*, p.Trp354* according to the mature protein) caused by a G>A transition at nucleotide position 1,119. The resulting truncation in the Aα chain is likely to reduce the efficiency of fibrinogen assembly and secretion. The second patient, referred after ischemic stroke (functional fibrinogen 77mg/dL), had a novel heterozygous splicing mutation in intron 5 of FGB (IVS5+2T>A or c.832+2T>A), which we demonstrated to cause either exon 5 skipping or the inclusion of 75bp belonging to intron 5. Neither splicing defect alters the reading frame: one results in a 38-residue deletion and the other in a 25-residue insertion in the D domain of fibrinogen Bβ chain. This report confirms that genetically determined partial deficiencies of fibrinogen with levels greater than 50mg/dL are rarely associated with significant bleeding symptoms and that homozygous null mutations removing a significant portion of the Aα chain may be associated with mild fibrinogen deficiency.

Cyclophosphamide Efficacy and Toxicities in the First Line Treatment of Acquired Hemophilia

Background: Acquired hemophilia is a rare bleeding disorder caused by antibodies against factor VIII. Patients without a personal or family history of coagulopathy may present with significant bleeding symptoms, often later in life. Acquired hemophilia has been associated with pregnancy, malignancy, and autoimmune disorders, but in approximately 50% of cases no clear etiology is identified. The two goals of treatment include control of bleeding and eradication of the antibody. Current recommendations based on data from large registries suggest that cyclophosphamide and high-dose steroids should be the first-line treatment of acquired hemophilia.The objective of our study was to describe our experience with cyclophosphamide and steroids for the initial treatment of acquired hemophilia.Methods: We conducted a retrospective chart review of patients with acquired hemophilia presenting to an urban tertiary referral center over 12 months. Data included gender, age, comorbidities, symptoms, factor VIII activity, and Bethesda Unit inhibitor titers (BU) at presentation. We documented the type of agents administered to control bleeding. We recorded type, dosing, duration and complications of immunosuppressive treatments. Complete blood counts, factor VIII activity, and inhibitor titers were checked weekly at clinic visits. Goals of immunosuppression treatment were the resolution of bleeding symptoms, factor VIII activity >50%, and a BU titer < 1.Results: We identified six patients with acquired hemophilia (2 males, 4 females). The median age was 78.5 years, range 51-94. Four patients presented with muscular hematomas of the extremities, one with diffuse bruising, and one with a lower intestinal bleed. One patient had HIV and was on anti-retroviral therapy, one patient had advanced breast cancer, and four patients had no significant co-morbidities. Five of 6 patients had undetectable factor VIII activity by one-stage chromogenic activity assay (<1%), one patient presented with Factor VIII activity of 18%. The median BU titer was 57.5 (range 3.1-691). One of five patients had a low titer BU < 5.Five out of 6 patients received FEIBA for control of acute bleeding at diagnosis, one patient did not require hemostatic agents because bleeding was judged to be minor. Five of six patients were treated with daily oral cyclophosphamide at a median dose of 1.94 mg/kg (range 1.4-2.6 mg/kg) and prednisone at 1mg/kg. One patient received six doses of rituximab followed by cyclophosphamide. Compliance and side effects from oral cyclophosphamide and steroid treatments were assessed at weekly visits. Steroids were tapered based on clinician judgment. The median time to a factor VIII > 50% and to a BU titer <1 were 38.5 days (range 19-87) and 51.5 days (range 19-92) respectively. Four of six patients required dose reduction or interruption of cyclophosphamide for neutropenia (ANC < 1000; n=3) or lymphopenia (CD4 count <100; n=1). The median time to cytopenias requiring dose reduction was 48.5 days (range 43-50 ). Two patients with neutropenia presented to the ED with fevers and required GCSF for neutropenia.Conclusions: Weight-based oral cyclophosphamide with steroids resulted in remission of acquired hemophilia in 4 of 6 patients. Factor VIII recovery occurred within two weeks, inhibitor eradication took twice as long and usually disappeared around the time of the development of febrile neutropenia. Our case series underscores the need for caution with cyclophosphamide in older patients. Given the risk of infection and sepsis from immunosuppression in this older population, regular clinical monitoring including weekly CBCs and cyclophosphamide dose reduction may be required. Additional first-line therapies should be explored in this older population in well-designed multicenter clinical trials. DisclosuresChapin:Novo-Nordisk: Honoraria; Alexion: Honoraria. De Sancho:Novo-disk: Honoraria.

Influence Of Updated ASH Guidelines On Practice Patterns In Management Of Newly Diagnosed Childhood ITP, 2007-2012

▪ BackgroundTreatment recommendations for childhood Immune Thrombocytopenia (ITP) in the United States have been a subject of much debate. In early 2011, the American Society of Hematology (ASH) updated their guidelines, recommending that children with ITP be managed with observation alone when there is mild or no bleeding symptoms regardless of platelet count, reserving hospitalization and pharmacologic treatment for those with significant bleeding. The objective of this study was to better understand the impact these recommendations have had on practice patterns at a large, urban, pediatric tertiary care hospital in the United States. MethodsWe examined data from patients aged 0-17 with newly diagnosed ITP seen in inpatient and outpatient locations at the Children's Hospital of Philadelphia (CHOP) between January 1, 2007 and December 31, 2012. A cohort was developed by querying the hospital data system for all patients treated 2007-2012 using the ICD-9 code for ITP (287.31). Chart review was used to exclude patients with alternative diagnosis for thrombocytopenia, diagnosis prior to the time of interest, and initial treatment elsewhere. We compared management strategies at diagnosis and retreatment rates in the first 6 months after the initial diagnosis. The primary outcome, management at diagnosis, was analyzed by logistic regression and chi square analysis. Results502 unique patients were identified. After chart review, an evaluable cohort of 313 patients with newly diagnosed ITP remained. The most common reasons for elimination were an alternative diagnosis (n=41), diagnosis in a previous year (n=68), and initial treatment at another hospital (n=69). Of those with an alternative diagnosis, Evan's syndrome (n=8) and ALPS (n=5) were the most common reasons for elimination. New diagnoses per year ranged from 34-51 in 2007-2009 and 60-63 in 2010-2012. The mean platelet count and age at diagnosis were 16.9 x10^9/l and 6.22 years old, respectively. Distribution was skewed toward lower platelet count and younger age. Overall, 19.5% of patients were noted to have bleeding symptoms beyond bruising or petechiae. The most common bleeding symptoms at presentation were epistaxis (n=25), wet purpura (n=20), gastrointestinal bleeding (n=5), hematuria (n=4), and menstrual bleeding (n=4). Intracranial hemorrhage was rare (n=2, 0.6%). Overall, 55% of patients were managed with pharmacologic treatment at diagnosis. Of those treated, 98% were treated with IVIG. Additionally, the proportion of patients observed at diagnosis rose significantly during this time period from 34% of patients in 2007-2010 to 49.2% in 2011 (p<.02) and 72% in 2012 (p<0.001). Via logistic regression, younger age, lower platelet count, and year of diagnosis were significantly associated with increased odds of pharmacologic treatment. During 2010-2012, 21% of patients were also treated within 0.25-6 months after diagnosis, with no significant difference by year or initial management (p>0.5). The majority treated after diagnosis were due to “low platelet counts” (n=14), bruising/wet purpura (n=6), or parental anxiety/activity level (n=3). One child, initially treated with IVIG, presented with ICH secondary to trauma 1.5 months after diagnosis.ConclusionsOver time, a significantly increased proportion of patients were observed at diagnosis. Though we cannot prove causation, this change demonstrates a strong association between timing of ASH recommendations and increase in observation rates. As we increased the proportion of children being observed at diagnosis we did not see an increase in the proportion of children receiving treatment or those with significant bleeding symptoms in the following 6 months. Additionally, we found that 37% of patients originally identified via ICD-9 code did not meet our criteria for evaluation of ‘newly diagnosed ITP'. As there is a greater shift to observing patients, along with the development of outpatient infusion services, inpatient databases could become skewed in regard to ITP. Because of this, caution should be utilized in using ICD-9 code alone to identify new diagnoses, especially when chart review is not accessible. Future studies will be able to identify the changing national trend in admission and management and whether adoption of ASH guidelines is widespread. Disclosures:Lambert:Amgen: Research Funding; Nestle: Consultancy; GSK: Research Funding.▪ [Display omitted]

Cross Sectional Study to Evaluate the Utility of Screening Tools to Identify Low Von Willebrand Factor Levels In Women with Menorrhagia (ZPMCB-VWD).

AbstractAbstract 3839Menorrhagia is a common symptom of haemostatic disorders and often triggers an evaluation for a bleeding disorder. Clinical screening tools, to identify women with menorrhagia who have an underlying bleeding disorder, are very desirable. Scoring systems to quantify menstrual blood loss in women, the Pictorial Blood Loss Assessment Chart, (PBAC), and to assess the severity of bleeding symptoms in individuals diagnosed with von Willebrand disease (VWD), European Union Bleeding Score (EU-BS) (MCMDM-1VWD), were evaluated for their ability to predict the presence of low von Willebrand factor (VWF) level in a cohort of 150 women recruited from an outpatient gynecology clinic. One of us (SG or ML) completed a PBAC and an EU Bleeding questionnaire with the participant. Menorrhagia cases were defined by a PBAC ≥185 and controls by a PBAC<185 (n=75 in each group). Complete blood count (CBC), ABO blood group, VWF activity (VWF:RCo) and VWF antigen (VWF:Ag) were measured in all subjects. Due to the variability in the laboratory testing of VWF: RCo and to capture all women with low levels, low VWF level was defined as VWF:RCo or VWF:Ag'60 IU/dl in our study. PBAC score correlated with the presence of menorrhagia defined by the menorrhagia score of MCMDM-1VWD (Spearman's Rank correlation coefficient, r=0.51, p<0.0001). PBAC of ≥185 had a sensitivity and specificity of 86% and 64% for predicting a menorrhagia score≥1 (AUC=0.80, p<0.0001). When women were evaluated for bleeding symptoms using the EU questionnaire, the most common bleeding symptom in the entire cohort was bruising in 42% followed by menorrhagia in 35%. Compared to women without menorrhagia, women with menorrhagia had an increased frequency of other bleeding symptoms including bleeding with invasive procedures (bleeding with tooth extraction 11% vs. 1% and bleeding with surgery 12% vs. 4%), post partum hemorrhage 15% vs. 8% and epistaxis 11% vs. 4%. Of the 150 women, 20 had an overall EU score of ≥4, mean 7.5 (range 4–22) indicating significant bleeding symptoms including menorrhagia and bruising in 85%, bleeding after surgical procedures in 45% followed by post partum hemorrhage and epistaxis in 35 %. Comparing menorrhagia cases to controls, the statistically significant difference between the two groups was in the median overall EU-BS (1 vs. 0, p=0.007) and poor wound healing with frequent scarring (24% vs. 9.3%, p=0.027).We found that 21.3% women with menorrhagia had low VWF level (VWF:RCo or VWF:Ag ≤ 60 IU/dl) compared to 14.6% women without menorrhagia (p =0.28). Comparing the 27 subjects with low VWF level with the 123 subjects with normal VWF level, the median VWF:RCo was 47 vs. 101IU/dl (p<0.0001), median PBAC was 234 vs. 176 (p=0.34), median EU-BS was 0 in both groups. There was no predictive correlation between the PBAC score and VWF:RCo (Spearman's Rank correlation coefficient r=0.05, p=0.54) and between the EU-BS and VWF: RCo level (Spearman's Rank correlation coefficient, r=0.07, p=0.37). The only predictor of low VWF: RCo was blood group O (OR: 8.9, 95% CI 2.9–27.6). The majority (87%) of blood group O subjects with low VWF level did not have a bleeding phenotype (EU-BS ≤3).In our cohort, the predictor of post partum hemorrhage was menorrhagia (OR: 4.1, 95% CI-1.4-11.8, p=0.009) and the only predictor of surgical bleeding and bleeding with tooth extraction was bleeding from minor wounds (OR: 11,95% CI-2.5-47, p=0.001; OR: 34,95% CI-6.9-166, p<0.0001 respectively). We conclude that PBAC is an easy and quick method for assessing the severity of menorrhagia in an outpatient setting. A score of ≥185 can be reliably used to diagnose clinical menorrhagia and as a threshold score to screen for other bleeding symptoms using the EU questionnaire. Women with menorrhagia are more likely to have bleeding with other invasive procedures, post partum bleeding and epistaxis. Menorrhagia could be a surrogate marker for an underlying bleeding disorder or a connective tissue disorder as reflected by the higher EU-BS and symptoms of poor wound healing in women with increased menstrual blood loss. We could not determine a PBAC score or EU-BS that could be used to identify women with low VWF. Low VWF level correlated best with blood group O, however a majority of these women did not have a bleeding phenotype (EU-BS≤3). Studies in a large cohort of women to identify reliable predictors of clinical bleeding are warranted. Disclosures:Gill:CSL Behring: Research Funding.

The impact of bleeding history, von Willebrand factor and PFA–100® on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM‐1VWD

The relationships between the Platelet Function Analyzer (PFA)-100 and von Willebrand factor (VWF) levels and bleeding score (BS) were evaluated within a multicentre project on Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand disease (MCMDM-1VWD). PFA-100 closure time, either with epinephrine (EPI) or adenosine diphosphate (ADP)-cartridges, was measured in 107 index cases, 105 affected and 71 unaffected family members, and 79 healthy controls. By regression analysis VWF levels were strongly related to both closure times, with a non-linear progression. In a multiple stepwise regression model, age- and sex-adjusted PFA-100 ADP and VWF ristocetin cofactor activity (VWF:RCo) were independently associated with BS. Most of the variation of BS was predicted by PFA-100 ADP and VWF:RCo alone. In the subgroup of patients with subtle abnormalities of the multimeric pattern, VWF was invariably reduced and closure time prolonged in almost all of them. Neither PFA-100 ADP nor EPI closure times appeared to significantly improve the diagnostic capability of VWF antigen (VWF:Ag) measurement. Thus, in an unselected population a normal PFA-100 would be useful to exclude VWD, but whether it could replace the more specific VWF assay in patients with significant mucocutaneous bleeding symptoms remains to be investigated prospectively.

Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire.

Excessive bruising and mucocutaneous bleeding are frequent presenting symptoms in childhood. A detailed bleeding history can distinguish children who may have an inherited bleeding disorder from those who are normal. There is a lack of standardization of such history taking in pediatric practise. To assess the performance of a Pediatric Bleeding Questionnaire (PBQ), an adaptation of a standardized adult bleeding questionnaire and score that includes pediatric-specific bleeding symptoms, in a cohort of children with von Willebrand disease (VWD). Bleeding scores were determined by interview, for children with a previous diagnosis of VWD and a control group of unaffected siblings. Bleeding scores were obtained for 100 children with VWD, median age 10.9 years (range, 0.8-17.8 years), and 21 unaffected siblings. Median bleeding score in children with VWD was 7.0 (range, 0-29) and in the control group was 0 (range, -1-2). Bleeding score varied within and between each VWD type: definite type 1, n = 40, median, 9.0 (range, 2-18); possible type 1, n = 38, median, 2.0 (0-15); type 2, n = 6, median, 14.0 (3-17); and type 3, n = 16, median, 12.0 (4-29). Bleeding scores in affected children correlated with age (Spearman's correlation coefficient, 0.35; P = 0.0004). The most frequent clinically significant bleeding symptoms were surgical bleeding, bleeding after tooth extraction and menorrhagia. Post-circumcision bleeding, cephalohematoma, macroscopic hematuria and umbilical stump bleeding were clinically significant in 32% (of circumcised males), 4%, 4% and 3% of children, respectively. The PBQ provides a standardized quantitation of bleeding severity in children with VWD.

Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor

AbstractInvestigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease.

Eltrombopag Is Efficacious in Patients with Refractory Chronic Idiopathic Thrombocytopenic Purpura (ITP) - Data from the EXTEND Study

INTRODUCTION: Refractory ITP patients have an unmet medical need for new treatment options. It is unknown how novel therapeutic agents such as eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline), the first oral, small-molecule, non-peptide thrombopoietin receptor agonist, may help ITP patients refractory to standard therapies. Eltrombopag was shown to substantially increase platelet counts during 2 placebo-controlled trials including >200 previously treated chronic ITP patients. EXTEND is an ongoing, open-label study designed to assess the long-term safety and clinical benefit of eltrombopag in patients with chronic ITP.METHODS: A post hoc analysis of EXTEND data assessed the efficacy of eltrombopag treatment in 165 chronic ITP patients, by refractoriness to prior therapy. Patients included had to have been on study ≥6 weeks. Refractory patients were defined as those with no response to a prior therapy (corticosteroids, IVIg, anti-D, or rituximab), and non-refractory patients were those previously treated patients who had either relapsed or become intolerant to their prior therapy. Specifically, corticosteroid-refractory patients had to have either no prior response to corticosteroids, or if there had been at least 1 documented response, there was subsequently nonresponse to all corticosteroids attempted. To determine whether outcome of prior therapy impacts a patient's response to eltrombopag, refractory ITP patients were compared to non-refractory ITP patients with regard to 3 measures of clinical benefit: 1) the proportion of patients who achieved platelet counts ≥50,000/μL and 2X baseline, 2) median weekly platelet counts on therapy through 39 weeks (9 mo.), and 3) the proportion of patients with clinically significant bleeding symptoms (WHO Grades 2–4) at each week on therapy through 39 weeks (9 mo.). Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: Grade 0 = no bleeding, Grade 1 = mild bleeding, Grade 2 = moderate bleeding, Grade 3 = gross bleeding, and Grade 4 = debilitating blood loss.RESULTS: Of the 165 patients included, 68 were refractory to at least 1 of the following medications: corticosteroids (no response, n = 36; no response following prior response, n = 7), IVIg (n = 20), anti-D (n = 12), or rituximab (n = 23). The median baseline platelet count was 17,000/μL in both the refractory and non-refractory patients. Overall, 75% (n = 51/68) of refractory patients achieved platelet counts ≥50,000/μL and 2X baseline, compared to 84% (n = 81/97) of non-refractory patients. A logistic regression model, adjusted for baseline splenectomy status, ITP medication use, and baseline platelet count showed no significant difference in this response between refractory and non-refractory patients (p = 0.1425). In addition, weekly median platelet counts in both refractory and non-refractory patients generally remained at or above 50,000/μL from week 1 through week 39 (9 mo.). While refractory patients had more clinically significant bleeding at baseline than non-refractory patients: 32% (n = 22/68) and 14% (n = 14/97), respectively, the proportion of patients with clinically significant bleeding in both groups was lower than baseline at any point from weeks 1 to 39. The proportion of patients with clinically significant bleeding in both groups was generally reduced 50% from baseline throughout this period.CONCLUSION: Eltrombopag induces long lasting platelet count increases and reduces clinically significant bleeding symptoms in refractory and non-refractory chronic ITP patients. We hypothesize that eltrombopag's novel mechanism of action, stimulation of platelet production, underlies its ability to successfully treat patients refractory to treatments which impede platelet destruction.

Management of menorrhagia in women with inherited bleeding disorders: general principles and use of desmopressin

The haemostatic system has a central role in controlling the amount and the duration of menstrual bleeding, thus abnormally prolonged or profuse bleeding does occur in most women affected by inherited bleeding disorders. Whereas irregular, premenarchal or postmenopausal uterine bleeding is unusual in inherited or acquired heamorrhagic disorders, severe acute bleeding and menorrhagia at menarche and chronic menorrhagia during the entire reproductive life are common manifestations. Prevalence and morbidity of menorrhagia in inherited bleeding disorders have been poorly investigated. It can be estimated that 40% to 60% of currently menstruating women with type 1 or 2 and more than 60% of women with type 3 VWD complain of menorrhagia with a significant impact on their quality of life. Menorrhagia may be particularly distressing in adolescents because of their delicate emotional equilibrium. Similar epidermiology has been described in other inherited disorders like factor XI deficiency, platelet functional defects and in carriers of haemophilia A and B. Women presenting with ''isolated'' menorrhagia, that is without significant additional bleeding symptoms, a situation reported by up to 15% of healthy women, do not demand investigation to exclude an occult bleeding disorder. A multidisciplinary approach is required for diagnosis and treatment. Gynaecological supervision is always required to exclude organic causes unmasked by the bleeding disorder. Treatment options are similar to those for menorrhagia in general with the addition of desmopressin and replacement therapy and the exclusion of non-steroidal anti-inflammatory drugs. The therapeutic plan should take into consideration the patient's preferences, age and severity of bleeding. Iron supplementation is of paramount importance. Remedies used in clinical practice for menorrhagia in general (tranexamic acid, combined oral contraceptives [COC], levonorgestrel intrauterine system [LNG-IUS]) are first tried. In case of failure or contraindication (COC and LNG-IUS are best avoided in adolescents), before considering surgical options, treatment with desmopressin becomes the preferred choice in patients known to be responsive. The availability of desmopressin preparations for self-administration makes home treatment feasible in well selected cases. The treatment is efficacious and safe provided that patients are instructed to self-administer the agent only during the first two or three more heavy days of menstrual period, for a maximum of three to four doses and no more than two consecutive administrations at a 12-h interval.

Evaluation of Children with Suspected Bleeding Disorder Applying the Impact-R [Cone and Plate(let) Analyzer

Background: von Willebrand's disease (VWD) is the most common bleeding disorder, affecting between 1–10% of the general population. There is a need for a simple test to screen patients with bleeding symptoms before more labor-intensive diagnostic steps are taken. The Impact-R [Cone and Plate(let) Analyzer (CPA)] (DiaMed Switzerland), was designed in an attempt to test platelet function under close to physiological conditions. Citrated whole blood is applied on polystyrene surface, under controlled shear conditions using a cone and plate device, followed by a quantitative analysis of platelet deposition to immobilized plasma von Willebrand's factor (VWF) and fibrinogen. Results of the test are presented for adhesion as % surface coverage (SC) and for aggregation as average size (μm2, AS). In this study we report the use of CPA test in evaluation of children with suspected bleeding disorder.Methods: Fifty-four consecutive children with bleeding symptoms and normal platelet count and coagulation tests were evaluated between August 1st, 2006 and July 31, 2007. In addition to the CPA test, all children were tested for VWF: antigen plasma level, VWF: ristocetin activity, factor VIII: C plasma level, platelet aggregation test using turbidometric aggregometer (Helena, USA) and blood type. The study was approved by the local Helsinki committee. Statistical analysis was done by SPSS.Results: Of 54 children, 10 (18.9%) were diagnosed with VWD and 6 (11.1%) children were diagnosed with platelet function defect according to bleeding history, family history, aggregation and factor VIII/VWF tests. To test the validity of the CPA as a screening test for diagnosis of VWD and platelet function defects a ROC curve was formulated for both SC and AS measurements. The best cutting point for a positive test was equal or less then 6.5% for SC measurement (sensitivity 60%, specificity 65%), and equal or lest then 26.5μm2 for AS measurement (sensitivity 67%, specificity 81.6%). The predictive value of a normal CPA test (negative predictive value), i.e. SC > 6.5% and AS > 26.5μm2, was 92%. Of the 26 normal CPA tests, one child was diagnosed with mild type I VWD and one child was diagnosed with mild platelet defect in response to epinephrine (40%). The predictive value of an abnormal CPA test (positive predictive value) was 50%. Of the 28 abnormal CPA test, 9 children were diagnosed with VWD, 4 children with platelet defect in response to epinephrine (<30%) and one child with platelet defect in response to collagen (10%). Significant bleeding symptoms (bleeding score 3 or more) were reported in 4 of 14 children with abnormal CPA test but with normal VWF, normal factor VIII and normal platelet aggregation.Conclusions: The CPA test was found to be a useful tool for excluding VWD and platelet function defect in children suspected for bleeding disorder. Yet, in case of an abnormal CPA test, further testing are needed. Interestingly, abnormal CPA test was the only finding in some children with a significant bleeding history, suggesting other underlying adhesion defects yet to be described.

Development of a Screening Tool in Women Presenting with Unexplained Menorrhagia.

Menorrhagia is a common clinical problem among reproductive age women and 5% of women in the US seek medical attention annually for menorrhagia. Recent studies suggest that underlying bleeding disorders, particularly Von Willebrand disease and platelet dysfunction, are prevalent in women presenting with menorrhagia. However referral for comprehensive hemostatic evaluation of the substantial numbers of women with otherwise unexplained menorrhagia is problematic given the complexity, availability, and cost of hemostatic testing and the lack of effective point of care screening tests for this population. In the present study, we evaluated 146 women (ages 13–55 yrs) with unexplained menorrhagia in order to develop a simple screening tool for stratifying women for referral for comprehensive hemostatic evaluation and testing. Women with a physician diagnosis of menorrhagia were studied on days 3–9 of their menstrual cycle. ASA, NSAIDS, herbals and other potentially platelet function impairing medications were discontinued at least 14 days prior to study and estrogen based treatment was discontinued for at least 1 menstrual cycle. Women underwent comprehensive hemostatic testing including VWF, platelet aggregation and ATP release, and factor assays. A 12 page questionnaire was developed based on significant bleeding symptoms in a CDC study of women with known VWD (Drews CD, Dilley AB, Lally C, Beckman MG, Evatt B. J Am Med Womens Assoc 2002; 57:217–218) and was administered to study subjects. A combination of 8 questions in 4 categories, including history of duration/extent of menorrhagia, anemia treatment, excessive bleeding with hemostatic challenges, and family diagnosis, resulted in a sensitivity of 81% (95% CI 74–89) and positive predictive value 71% (95% CI 63–71) for hemostatic abnormalities. Adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 93% (95% CI 89–98). The data suggest that a simple 8 question screening tool with implementation of a pictorial blood assessment chart may be useful for physicians evaluating women presenting with menorrhagia to help determine which women to refer for comprehensive hemostastic testing and evaluation.