Common Bleeding Disorder Research Articles

Evaluating the effectiveness of Let’s Talk Period’s educational outreach for high school students

Von Willebrand Disease, the most common bleeding disorder, is inherited equally by men and women, though bleeding symptoms are usually more evident in females due to their menstrual cycles and childbirth. The goal of developing a youth outreach project was to empower young female high school students with knowledge and resources about abnormal bleeding. The 75-minute presentation was given to five Grade 9 Girls’ Health classes across the Limestone District School Board, and led by a Hemophilia Nurse, supported by a Clinical Research Assistant and a 2nd year undergraduate student, who interacted with students and documented the presentation with photographs. Queen’s REB approved the project, and parental and student permission was obtained for photographs. Using Kahoot, an interactive online quiz program, students participated in short pre- and post-presentation quizzes to evaluate their knowledge and learning. Questions including "True/False: Iron deficiency is normal and expected among young females," were posed within the set of 9 questions on topics of anemia, menstruation, and abnormal bleeding. 84 students participated, aged 14 and 15, and 58 had evaluable quiz results. The results showed an average pre-presentation score of 77%, ranging from 72-83%, with a post-presentation quiz average of 92%, ranging from 83-95%. It was determined that students’ post-presentation scores were significantly higher (p<0.001) than those before the presentation, providing evidence for an increase in student understanding. Testing efficacy of these presentations can help determine their level of utility as a resource for health teachers to implement in their classrooms.

How I investigate for bleeding disorders.

Laboratory investigations for bleeding disorders are warranted when an individual has a personal and/or family history of bleeding, and/or laboratory findings that suggest the possibility of an inherited or acquired bleeding disorder. This review summarizes author's experience with ordering and reporting on diagnostic investigations for common and rare bleeding disorders, with consideration of recent articles on diagnosing bleeding disorders. An updated strategy is presented for investigating common and rare, congenital and acquired bleeding disorders. An investigation of a suspected bleeding disorder requires a practical strategy that considers the clinical problem to be investigated, the pretest probability of true-positive and false-positive findings, the investigations can be performed locally or in a reference laboratory and limit the number of blood samples required to establish a diagnosis. It is often advantageous to simultaneously test for von Willebrand disease and platelet function disorders, and for coagulation defects, including fibrinogen disorders. An investigation for rarer bleeding disorders, including those affecting factor XIII, α2 antiplasmin, and plasminogen activator inhibitor-1, is appropriate when faced with a severe congenital or acquired bleeding problem that cannot be explained by the initial diagnostic investigations. An organized strategy for investigating bleeding disorders that consider important issues, confirms abnormal findings, encourages proper interpretation of the results, and provides a helpful framework for assessing both common and rare causes of bleeding.

ENDODONTIC MANAGEMENT OF DENTAL PAIN IN AN INHIBITOR POSITIVE, SEVERE HEMOPHILIA A PATIENT: A BRIEF REVIEW AND REPORT OF A CASE

Dental health care providers often have to deal with patients requiring special care during treatment planning, and certain precautions while carrying out the procedures, and patients with bleeding disorders are one of them. Hemophilia, an X-linked blood dyscrasia, is the most common bleeding disorder. While hemophilia-A is a deficiency of factor VIII, hemophilia-B (Christmas disease) is a deficiency of factor IX. The present paper presents a case discussing endodontic management of mandibular molars with irreversible pulpits in an inhibitor positive severe hemophilia-A patient. As such patients may require administration of inferior alveolar nerve blocks, so adequate factor levels should be ensured before initiation of local anesthetics. Furthermore, the authors have tried to highlight the barriers to oral health care suffered by such patients and the larger role played by the physicians and oral health care providers in the prevention, early detection, and timely intervention in these cases.

Influence of ABO blood group on von Willebrand factor tests in healthy Saudi blood donors.

: Von Willebrand disease is a common bleeding disorder. The wide variation in von Willebrand factor (VWF) levels between and within normal individuals highlights the clinical challenge of defining its cutoff value. Although studies on the influence of ethnicity on ABO phenotypes and the levels of VWF have been carried out on different ethnicities, there is a lack of such data among Arab population. We aimed to evaluate the correlation of ABO phenotypes with all the parameters of the minimal test panel of VWF including VWF antigen, VWF activity using the ristocetin cofactor and the collagen binding activity assays, and factor VIII coagulant activity (VWF:Ag, VWF:RCo, VWF:CB and FVIII:C) tested in a normal Arab population, and to estimate ABO-specific normal reference range. Blood samples were collected from 87 healthy donors in Riyadh to determine levels of factor VIII and VWF panel between the various ABO phenotypes. The highest mean values of factor VIII : C (128 U/dl), VWF : Ag (125 U/dl), VWF : RCo (109 U/dl) and VWF : CB (91 U/dl) were observed with type AB and the lowest mean values of factor VIII : C (81 U/dl), VWF : Ag (85 U/dl), VWF : RCo (73 U/dl) and VWF : CB (70 U/dl) corresponded to type O. ABO phenotypes significantly influence plasma levels of VWF parameters in Arab nations as seen with other ethnicity. Hence, ABO-specific normal ranges of the minimal test panel of VWF and factor VIII : C are essential for the appropriate prediction of mild von Willebrand disease. Further study including a larger categorized sample size is required to generalize the test panel on the Arab population.

Diagnosis and management of von Willebrand disease in Slovakia

Background: Von Willebrand disease (VWD) is a common bleeding disorder with prevalence in the Slovak Republic of 11.2 cases per 100,000 people. Methods: We conducted a retrospective audit of 610 VWD patients in Slovakia. Results: Care of local patients with VWD primarily occurs through our comprehensive treatment centre, although some patients are managed solely by their primary care physician or community haematologist. Type 1 VWD is the most common subtype, with more females carrying this diagnosis than males. Diagnosis and treatment in general follows guidelines outlined by the European Group on VWD, British Committee for Standards in Haematology and Slovak Society on Haemostasis and Thrombosis. An ongoing study “Genetic Background and Haemostatic Changes in the Patients with VWD” is currently enrolling patients with all VWD subtypes across Slovakia in order to better delineate the extent of VWD and correlate bleeding symptoms with laboratory findings and von Willebrand factor (VWF) sequence variations. Conclusions: VWD diagnosis and management is best performed through hematology specialists familiar with the complexities of this condition, such as those in the hemophilia treatment centres.

Is gingival bleeding a symptom of type 2 and 3 von Willebrand disease?

BackgroundVon Willebrand disease (VWD) is the most common inherent bleeding disorder. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also a leading symptom of plaque-induced gingivitis and untreated periodontal disease. In type 1 VWD gingival bleeding was not increased compared to controls. Thus, this study evaluated whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm.MethodsTwenty-four cases and 24 controls matched for age, sex, periodontal diagnosis, number of teeth and smoking were examined hematologically (VWF antigen, VWF activity, factor VIII activity) and periodontally (Gingival Bleeding Index [GBI]), bleeding on probing [BOP], Plaque Control Record [PCR], periodontal inflamed surface area [PISA], vertical probing attachment level).ResultsBOP (VWD: 14.5±10.1%; controls: 12.3±5.3%; p = 0.542) and GBI (VWD: 10.5±9.9%; controls: 8.8±4.8%; p = 0.852) were similar for VWD and controls. Multiple regressions identified female sex, HbA1c, PCR and PISA to be associated with BOP. HbA1c and PCR were associated with GBI. Number of remaining teeth was negatively correlated with BOP and GBI.ConclusionType 2 and 3 VWD are not associated with a more pronounced inflammatory response to the oral biofilm in terms of BOP and GBI.

Von Willebrand disease—the Nordic perspective

Von Willebrand disease (VWD) is the most common bleeding disorder, showing a broad variation in prevalence of 0.2 to 4 cases per 100,000 inhabitants in type 2 and 0.2 to 1 in type 3 among the Nordic countries. Diagnosis and treatment of VWD in these countries primarily occur through comprehensive treatment centers by following guidelines outlined by the Nordic Haemophilia Council. Accordingly, assignment of VWD is based on comprehensive evaluation, including standardized bleeding score, traditional laboratory analysis and adoptive platelet function studies. The correct classification of VWD types is crucial in determining both the bleeding risk and clinical management, although clinical severity is not always related to biological activity of VWF. There are several developments in both diagnosis and clinical management of VWD. This review focuses on the novel aspects of VWD care in the Nordic countries, involving pure von Willebrand factor (VWF) concentrates as treatment options, as well as laboratory assay development, including the new VWF activity assays and comprehensive whole blood platelet function and global coagulation aspects.

Prevalence of von willebrand disease among university students in Riyadh, Saudi Arabia

BACKGROUND: von Willebrand disease (vWD) is the most common hereditary bleeding disorder, affecting up to 1% of the general population. OBJECTIVES: Estimating the prevalence of vWD among adolescents. DESIGN: This study was conducted between February 2014 and January 2016 on Saudi students in Riyadh. SETTINGS: We conducted an epidemiological survey on university students, using the standardized questionnaire based on molecular and clinical markers for the diagnosis and management of type 1 VWD. MATERIALS AND METHODS: All blood samples were tested for complete blood count, prothrombin time, partial thromboplastin time (PTT), and platelet function analyzer (PFA-100). MAIN OUTCOME MEASURES: Samples had an abnormal result of PTT and/or PFA-100 were tested for von Willebrand factor (vWF) antigen and factor VIII (FVIII) activity. SAMPLE SIZE: 2000 university students aged between 17 and 22 years were included. RESULTS: Of these students, 730 (36.5%) had reported bleeding symptoms, 326 (44.6%) had agreed to give blood samples, 116 (35.5%) samples had prolonged PTT (>41 s), 48 (14.7%) had prolonged PFA-100 adenosine diphosphate, 39 (11.9%) had prolonged PFA-100 epinephrine, and 72 (22.0%) had abnormal results in both PTT and PFA-100. Out of 275 samples tested for vWF (Ag and activity) and FVIII, 13 (3.9%) had reduced levels or nonfunction of vWF and 5 (1.6%) had reduced FVIII levels. After correlation with ABO blood group, only 5 (1.6%) cases were confirmed for vWD. The prevalence of vWD among Saudi adolescents in the selected student population was 1.5%. CONCLUSION: In this study, we report for the first time epidemiological survey of bleeding disorders in Arab ethnicity. LIMITATIONS: As this is a prevalence study, we have no limitations to discuss.

Von Willebrand Disease Screening in Women Undergoing Hysterectomy for Heavy Menstrual Bleeding

BackgroundBleeding disorders in women are under-recognized and under-treated. Women are equally as likely as men to have bleeding disorders other than hemophilia and are disproportionately affected by these diseases due to the bleeding challenges of menstruation and childbirth. The most common bleeding disorder identified in women is von Willebrand disease (VWD). Heavy menstrual bleeding (HMB) is the most common symptom in women with VWD, occurring in up to 93% of patients. Among women with HMB, the reported prevalence of VWD ranges from 5─20%. Women with VWD are also more likely to be diagnosed with hemorrhagic ovarian cysts due to ovulation-associated bleeding and endometriosis due to increased retrograde menstruation. As a result, women with bleeding disorders are more likely to undergo hysterectomy and also undergo hysterectomy at an earlier age than women without bleeding disorders. In 2001, the American College of Obstetrics and Gynecology (ACOG) recommended VWD screening prior to hysterectomy in women with HMB. The actual frequency of VWD screening in clinical practice is unknown.ObjectivesIn this study, we assess patterns of VWD screening in a nationally representative sample of women undergoing hysterectomies for HMB.MethodsWe used the Truven Health MarketScan® Research Databases which include the medical prescription claims of over 109 million covered lives as well as Medicaid data on 8.6 million patients from 14 states. The MarketScan Databases contain patient demographics, physician and facility claims and pharmacy claims. Procedure codes were used to identify women ages 10-44 years undergoing hysterectomy or hysterectomy alternative (HA) from 2011-2013. Subjects were required to have 12 months of continuous enrollment prior to surgery date. We utilized ICD-9 codes to categorize hysterectomy indications and only included women with a diagnosis of excessive bleeding as the indication for surgery. Women with fibroids, genital tract malignancy, and previously diagnosed bleeding disorders were excluded. We defined VWD screening as a laboratory claim for either VWF:Antigen and/or VWF:Activity within the 12 months preceding hysterectomy. To determine if patient and facility level characteristics impacted access to specialty hematology care and/or screening for VWD, we collected the following information: 1) known bleeding disorder diagnosis and/or endometriosis prior to surgery; 2) age; 3) whether patient was living in metropolitan statistical area (MSA; used as a surrogate marker for urban vs rural inhabitance); 4) number of miles and approximate travel time to nearest Hemophilia Treatment Center (HTC). We used ArcMAP® software to calculate distance between the MSA and nearest HTC. MSA data was only available for commercially-insured patients. (Figure 1) Logistic regression was used to assess factors related to the occurrence of VWD screening.ResultsWe identified 13,790 women who underwent hysterectomy/HA for HMB. We excluded 138 with known bleeding disorders leaving 13,652 women in our final analysis (Table 1). Of these, 74 (0.5%) were screened for VWD within 12 months preceding surgery. There were 2,000 women (15%) who underwent other coagulation tests, most commonly prothrombin time and partial thromboplastin time. We had MSA data on 11,557 commercially-insured women, of whom 72.4% lived within a MSA. Women living in a MSA were screened more often than those outside of a MSA (p=0.013). For those living within a MSA, the odds of being screened for VWD was lower in women with endometriosis (OR=0.54, 95% CI 0.31, 0.97; p=0.038) and women living >100 miles from the nearest HTC (OR=0.29, 95% CI 0.11, 0.81; p=0.017).DiscussionThis study demonstrated that despite ACOG expert recommendations, the frequency of VWD screening in a nationally-representative population of publically and commercially-insured women undergoing hysterectomy for HMB was very low. Greater distance from a HTC or a prior diagnosis of endometriosis further reduced the likelihood of VWD screening. It is important to increase awareness that a diagnosis of endometriosis does not rule out the presence of a bleeding disorder. This study brings to light the need for the hematology community to improve education and awareness among women's health providers in order to identify women with bleeding disorders and allow for optimal medical management of HMB prior to surgical consideration. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Factor VIII mutation spectrum in haemophilia A patients in the population of Henan, China.

: Defects in the coagulation factor VIII gene cause haemophilia A, which is the most common X-linked recessive bleeding disorder. In total, 45 affected families were investigated to elucidate the factor VIII gene mutation spectrum. The families were subjected to clinical, biochemical, and molecular analyses. Inverse-shifting PCR was first applied to severe haemophilia A patients to identify inversions in introns 22 and 1. Then, next-generation sequencing was performed to detect mutations in inversion-negative patients with severe haemophilia A and moderate-mild haemophilia A patients. Finally, multiplex ligation-dependent probe amplification was utilized to identify rare cases with large fragment duplications or deletions in the factor VIII gene. In total, 41 mutations were identified, 19 of which (c.24C>A, c.49T>C, c.170_171delTT, c.533T>C, c.1126delG, c.1495delA, c.1660A>C, c.1736A>G, c.2711-2712insAATCT, c.3077C>G, c.3846delA, c.4238C>G, c.4349delG, c.4828G>C, c.5821A>C, c.6190C>T, c.6656T>C, c.6902T>G, and c.1904-2A>T) were novel and 80% (44/55) of the pathogenic mutations fell into the categories of missense (43.6%), nonsense (16.36%), frameshift (14.55%), and splice (5.45%) mutations. Additionally, 10 (18.18%) patients displayed inversions in intron 22 or 1 and one case (1.82%) exhibited a 3059-bp large fragment deletion in factor VIII. This study aimed to provide insight contributing to the genetic diagnosis of haemophilia A and to fill gaps in the factor VIII mutation spectrum in northern China.

Factor VII Deficiency Diagnosed During Severe Ulcerative Colitis Flare

Ulcerative colitis is a recurring inflammatory disease that typically begins in the rectum and affects the colon in a continuous fashion. Although bleeding and anemia are common in ulcerative colitis, severe bleeding is unusual. Ulcerative colitis combined with a concomitant bleeding disorder represents a rare phenomenon that may exacerbate rectal bleeding. We present a case of severe bleeding during an ulcerative colitis flare that unmasked an underlying Factor VII deficiency. A 22-year-old male with a past medical history including ulcerative colitis and autism presented with a one day history of bloody diarrhea. The patient had been diagnosed with ulcerative colitis five years prior when endoscopic biopsies revealed moderately active chronic colitis from the rectum to the cecum. Initial laboratory investigation revealed white blood cell count of 18.0 (K/MM3), hemoglobin 13.8 (g/dL), platelets 344 (K/MM3), elevated CRP 252 (mg/L), ESR 55 (mm/hr) and prothrombin time 24.2 seconds with INR 2.2. Physical examination revealed a healthy young male with mild bilateral lower quadrant tenderness without rebound or guarding and bright red blood on digital rectal exam. The patient was admitted and started on IV solumedrol and empiric metronidazole for a presumed flare of ulcerative colitis. Over the subsequent three days the patient continued to have severe bloody diarrhea with labs showing hemoglobin 10.6 (g/dL) and INR 2.8 despite the administration of vitamin K. A mixing study was performed and showed no evidence of an inhibitor affecting extrinsic pathway plasma procoagulants. Specific factor activity level testing revealed normal Factor II, V, IX and X activity with markedly reduced Factor VII activity of 4%(normal 55-170%). The diagnosis of factor VII deficiency was confirmed and the patient improved with factor replacement therapy and conservative management. Factor VII deficiency is the most common rare congenital bleeding disorder that effects one per 500,000 individuals and typically manifests with prolonged prothrombin time. Bleeding disorders such as Factor VII deficiency may exacerbate the degree of hemorrhage in inflammatory bowel disease (IBD) flares, making prompt recognition of underlying coagulopathies crucial in IBD patients. It is important for clinicians to be familiar with various factor deficiencies and their treatment options in order to control bleeding.Figure: Colonoscopy. Endoscopic images suggest features of ulcerative colitis with profound inflammation in a continuous and circumferential pattern.Figure: Endoscopic Colon Biopsy Specimen: Pathological analysis reveals microscopic features of ulcerative colitis with crypt shortening and distortion.Figure: Endoscopic Colon Biopsy Specimen: Pathological analysis showing paneth cell metaplasia in the left colon, consistent with the diagnosis of ulcerative colitis.

A Rare Cause of Acquired Von Willebrand Syndrome Resulting in Gastrointestinal Bleeding

Von willebrand disease (vWD) is the most common congenital bleeding disorder but acquired von willebrand syndrome (AVWS) is rare. Pathogenesis of AWVS is complex and not fully understood. We report the case of a patient with chronic gastrointestinal bleeding and AVWS from a myeloproliferative neoplasm. A 59-year-old female with a two year history of gastrointestinal bleeding, angioectasia and recurrent hospitalizations for transfusion-dependent anemia presented with a 3 day history of melena. Two weeks prior to presentation, she had an extended upper endoscopy which revealed angioectasias in the jejunum that were cauterized with gold probe. Medications included omeprazole daily and ferrous sulfate three times daily. On arrival, vital signs were stable. Physical exam was remarkable for heart murmur and melena. Abnormal labs included hemoglobin 6.4g/dL and partial prothrombin time 38 seconds. Deep enteroscopy showed a single actively bleeding angioectasia in the proximal jejunum treated successfully with argon plasma coagulation (Fig 1). Heart murmur prompted a von willebrand factor (vWF) panel and echocardiogram. Echocardiogram was normal but ristocetin cofactor, vWF activity, vWF antigen, and factor 8 levels were low. vWF multimers were barely detectable. Further workup included a bone marrow aspiration that confirmed prefibrotic myelofibrosis myeloproliferative neoplasm, AVWS was diagnosed. She was discharged home in stable condition and has been closely monitored by hematology for her myeloproliferative neoplasm. She has not required any further blood transfusions. AVWS is due to a deficiency in the quality or quantity of vWF. The true incidence is unknown since many patients are asymptomatic and therefore undiagnosed. AVWS is characterized by a negative personal and family history of previous bleeding. It is typically seen in the elderly. Angioectasias have been reported in 2-4% of patients with vWD. Management relies on therapy of the underlying process. This case highlights an interesting presentation of a patient with recurrent gastrointestinal bleeding from AVWS secondary to a myeloproliferative neoplasm. Gastroenterologists should be cognizant of this phenomenon as early diagnosis is crucial for appropriate management.Figure: Actively bleeding angiodysplastic lesion in the proximal jejunum.

Expression of CD markers' in immune thrombocytopenic purpura: prognostic approaches.

Immune Thrombocytopenic Purpura (ITP) is a common autoimmune bleeding disorder characterized by a reduction in peripheral blood platelet counts. In this disease, autoantibodies (Auto-Abs) are produced against platelet GPIIb/GPIIIa by B cells, which require interaction with T cells. In this review, the importance of B and T lymphocytes in ITP prognosis has been studied. Relevant literature was identified by a PubMed search (1990-2016) of English-language papers using the terms B and T lymphocyte, platelet, CD markers and immune thrombocytopenic purpura. T and B lymphocytes are the main immune cells in the body. Defective function causes disrupted balance of different subgroups of lymphocytes, and abnormal expression of surface markers of these cells results in self-tolerance dysfunction, as well as induction of Auto-Abs against platelet glycoproteins (PG). Given the role of B and T cells in production of autoantibodies against PG, it can be stated that the detection of changes in CD markers' expression in these cells can be a good approach for assessing prognosis in ITP patients.

Evaluating the maintenance of disease-associated variation at the blood group-related gene B4galnt2 in house mice

BackgroundB4galnt2 is a blood group-related glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice. The wild type allele, found e.g. in the C57BL/6 J strain, directs intestinal expression of B4galnt2, which is the pattern observed among vertebrates, including humans. An alternative allele class found in the RIIIS/J strain and other mice instead drives expression in blood vessels, which leads to a phenotype similar to type 1 von Willebrand disease (VWD), a common human bleeding disorder. We previously showed that alternative B4galnt2 alleles are subject to long-term balancing selection in mice and that variation in B4galnt2 expression influences host-microbe interactions in the intestine. This suggests that the costs of prolonged bleeding in RIIIS/J allele-bearing mice might be outweighed by benefits associated with resistance against gastrointestinal pathogens. However, the conditions under which such trade-offs could lead to the long-term maintenance of disease-associated variation at B4galnt2 are unclear.ResultsTo explore the persistence of B4galnt2 alleles in wild populations of house mice, we combined B4galnt2 haplotype frequency data together with a mathematical model based on an evolutionary game framework with a modified Wright-Fisher process. In particular, given the potential for a heterozygote advantage as a possible explanation for balancing selection, we focused on heterozygous mice, which express B4galnt2 in both blood vessels and the gastrointestinal tract. We show that B4galnt2 displays an interesting spatial allelic distribution in Western Europe, likely due to the recent action of natural selection. Moreover, we found that the genotype frequencies observed in nature can be produced by pathogen-driven selection when both heterozygotes and RIIIS/J homozygotes are protected against infection and the fitness cost of bleeding is roughly half that of infection.ConclusionBy comparing the results of our models to the patterns of polymorphism at B4galnt2 in natural populations, we are able to recognize the long-term maintenance of the RIIIS/J allele through host-pathogen interactions as a viable hypothesis. Further, our models identify that a putative dominant-, yet unknown protective function of the RIIIS/J allele appears to be more likely than a protective loss of intestinal B4galnt2 expression in RIIIS/J homozygotes.

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC). As development of inhibitors to FVIII continues to be a major problem in the care of HA patients, recent studies showing lower rates of inhibitor development with plasma-derived FVIIII products versus recombinant FVIII products have made choosing among the many options now available even more complex. Although still unproven, extended half-life (EHL) products may provide the hope of decreased immunogenicity but need further testing in previously untreated patients (PUPs). This review highlights some of the differences between FVIII products currently available and hopefully assists the clinician to decide which FVIII product to choose for their patients.

Characterization of Hysterectomy/Uterine Ablation Rates in VWD and Undiagnosed Bleeding Using Claims Data [32G

INTRODUCTION: Heavy menstrual bleeding (HMB) is common in women and adolescents post menarche, in some cases resulting in hysterectomy or uterine ablation. Based on retrospective studies 10-62% of women with HMB may have an underlying bleeding disorder (BD), such as von Willebrand Disease (VWD), the most common bleeding disorder. Despite public awareness campaigns, a diagnosis of a potential bleeding disorder is often missed or significantly delayed. Here we characterize the rates of hysterectomy/uterine ablation in a symptomatic undiagnosed (SUD) vs. symptomatic diagnosed VWD (SVWD) population. METHODS: We utilized the IMS Health Real-World Data Adjudicated Claims, looking at patients continuously enrolled for 2+ years (July 2013 ‒ July 2015) with 1+ severe bleed or 2+ bleed claims. These symptomatic patients were classified based on presence (SVWD; n=837) or absence (SUD; n=2,760) of a VWD diagnosis claim. RESULTS: The incidence of hysterectomies/uterine ablation was similar between the SUD vs. the SVWD patients (5.9% and 7.3% respectively). However, the mean age at the time of hysterectomy was significantly (P < 0.05) younger in SUD (35 years) versus the SVWD patients (42 years). 8% of the procedures performed in the SUD occurred in patients 18-25 years old versus 1% in the SVWD patients. CONCLUSION: Treatment options for HMB require an evaluation of the etiology, which may be, in many cases, an underlying BD. A timely diagnosis of VWD allows patients access to therapies specifically targeting VWD, including antifibrinolytics, DDAVP and factor replacement, potentially avoiding or delaying the need for more terminal therapies such as hysterectomy/uterine ablation.

A case of autoimmune severe acquired von Willebrand syndrome (type 3-like)

Von Willebrand disease (VWD) is the most common congenital bleeding disorder and is due to quantitative or qualitative defects of von Willebrand factor (VWF). Acquired defects of VWF, termed acquired von Willebrand syndrome (AVWS), are due to a host of different mechanisms. Autoantibody-mediated AVWS may be associated with lymphoproliferative or immunological disorders, such as systemic lupus erythematosus (SLE). A large majority of AVWS cases are type 1 or type 2A-like and patients tend to have a mild to moderate bleeding tendency. We report a case of severe autoimmune AVWS in a woman with SLE who presented with clinical and laboratory features of type 3 VWD (undetectable VWF antigen, ristocetin cofactor activity, and VWF multimers). A mixing study demonstrated an inhibitor to VWF (6BU/mL). Her bleeds were managed with antifibrinolytics, recombinant activated factor VII, and activated prothrombin complex concentrate. She was initially treated with steroids and intravenous immunoglobulin therapy. However, her bleeding symptoms continued until she was treated with rituximab, and her VWF parameters normalized. She relapsed two years later due to non-compliance with her immunosuppressive medications and expired another two years later secondary to complications of sepsis and uremic pericarditis. This case emphasizes the importance of aggressive initial therapy of SLE to reduce secondary complications, frequent patient monitoring, and continued treatment of the underlying autoimmune disorder in patients with AVWS.

Controversies in the diagnosis of Type 1 von Willebrand disease.

von Willebrand disease (VWD) is the most common bleeding disorder. Type 1 VWD represents the majority of cases and results from a partial quantitative deficiency of von Willebrand factor (VWF). The diagnosis of Type 1 VWD presents many challenges, despite there being three established diagnostic criteria: a personal history of mucocutaneous bleeding, a family history and low VWF levels. These criteria do not always coexist, and there is great overlap of clinical phenotypes and laboratory parameters between healthy individuals and those with VWD. Mild bleeding symptoms can have any number of causes and bleeding is commonly reported in the general population. VWF levels do not always correlate with bleeding symptoms and can be variable between affected family members. Additionally, VWF levels vary widely as a result of both genetic and non-genetic influences. Perhaps the greatest current controversy in the diagnosis of Type 1 VWD is that there is no consensus laboratory cut-off for the diagnosis, raising concern about both over- and under-diagnosis. Ongoing studies are addressing these issues by clarifying the underlying pathogenesis of the disease, as well as the natural history and the risk of future bleeding in those with the diagnosis.

Italian Registry of Congenital Bleeding Disorders.

In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment Centers, members of the Italian Association of Hemophilia Centres (AICE). The number of people identified with bleeding disorders has increased over the years, with the number rising from approx. 7000 in 2000 to over 11,000 in 2015. The NRCC includes 4020 patients with hemophilia A and 859 patients with hemophilia B. The prevalence of the rare type 3 vWD is 0.20/100,000 inhabitants. Less common congenital bleeding disorders include the following deficiencies: Factor I (fibrinogen), Factor II (prothrombin), Factor V, Factor VII, Factor X, Factor XI and Factor XIII, which affect 1953 patients. Hepatitis C Virus (HCV) infection affects 1561 patients, more than 200 of whom have two infections (HCV + HIV). Estimated hemophilia-related drug consumption in 2015 was approx. 550 million IU of FVIII for hemophilia A patients and approx. 70 million IU of FIX for hemophilia B patients. The NRCC, with its bleeding disorder data set, is a tool that can provide answers to fundamental questions in public health, monitoring care provision and drug treatment, as well as facilitating clinical and epidemiological research.

Orthodontic care for patients with bleeding disorders

Oral care providers must be aware of the impact of bleeding disorders on the management of dental patients. Initial recognition of a bleeding disorder, which may indicate the presence of a systemic pathologic process, may occur in dental practice. Furthermore, prophylactic, restorative and surgical dental care of patients with bleeding disorders is best accomplished by practitioners who are knowledgeable about the pathology, complications and treatment options associated with these conditions. The purpose of this paper is to review common bleeding disorders and their effects on the delivery of oral health care. Keywords: Blood coagulation/physiology; Blood coagulation disorders/complications; Dental care