Differences in bleeding phenotype and provider interventions in postmenarchal adolescents when compared to adult women with bleeding disorders and heavy menstrual bleeding.

INTRODUCTION: Due to lack of patient/health care provider awareness causing delayed diagnosis, the bleeding phenotype and provider interventions in adolescents with heavy menstrual bleeding (HMB) and bleeding disorders (BD) may be different when compared to adults. AIM: The aim of this study was to compare/characterize bleeding phenotype and provider interventions in postmenarchal adolescents < 18 years and premenopausal adults ≥ 18 years with HMB and BD. METHODS: Patient demographics, BD, and provider interventions/therapy details for HMB were compared between both age groups enrolled in the Centers for Disease Control and Prevention (CDC) Female Universal Data Collection (UDC) surveillance project in United States hemophilia treatment centres. Cross-sectional descriptive analyses including frequency distributions, summary statistics, bivariate and logistic regression analyses were performed. RESULTS: Of 269 females (79 adolescents; median age 16 years, interquartile range (IQR) = 2; 190 adults; median age 27 years, IQR = 13) evaluated, BD distribution was similar in both groups. Compared to adolescents, adults more often had family history of bleeding (Adjusted odds ratios [AOR] = 2.6, 1.3-5.6), delay in diagnosis (AOR = 2.5, 1.2-4.9), bleeding with dental procedures (AOR = 2.0, 1.0-4.0), gastrointestinal bleeding (AOR = 4.6, 1.0-21.9), anaemia (AOR = 2.7, 1.4-5.2), utilized desmopressin less often (AOR = 0.4, 0.2-0.8) and underwent gynaecologic procedure/surgery more frequently (AOR = 5.9, 1.3-27.3). CONCLUSION: Bleeding phenotypes of adolescents and adults with HMB and BD were different with more frequent bleeding complications, anaemia, gynaecologic procedures/surgeries, less desmopressin use and more delay in diagnosing BD in adults. Longitudinal studies are needed to determine whether improved patient/provider awareness and education will translate to early diagnosis and timely management of BD/HMB in adolescents that may prevent/reduce future haematologic/gynaecologic complications.

Von Willebrand factor for menorrhagia: a survey and literature review.

BACKGROUND: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. METHODS: We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. RESULTS: Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. CONCLUSIONS: This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Recombinant von Willebrand factor: a first-of-its-kind product for von Willebrand disease.

von Willebrand disease (VWD) is caused by quantitative or qualitative defects in von Willebrand factor (VWF). The mainstay of therapy is desmopressin, which is, however, not useful in certain forms of VWD notwithstanding adverse events. For these patients, plasma-derived factor VIII (pdFVIII)/VWF concentrates have been available for close to three decades but have a theoretical risk of disease transmission, hypersensitivity/allergic reactions, inhibitors and thrombosis. A recombinant VWF (vonicog alfa, Vonvendi™; manufactured by Baxalta, now part of Shire) was approved by the U.S. Food and Drug Administration (FDA) in December 2015. This review will survey the literature based on a MEDLINE review on the safety, efficacy and pharmacokinetics of Vonvendi. It will also summarize the ongoing studies on Vonvendi available in the public domain. Vonvendi may have an important role in the management of VWD. However, more studies are needed, especially in special populations such as surgical patients, patients with major gastrointestinal bleeding from arteriovenous malformations and pregnant women and children, who are most likely to benefit from it.

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN).

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.

Challenges of rare disease research: limited patients and competing priorities.

Rare disease research is increasingly challenging. For those with haemophilia, this is an exciting time, with the promise of new therapies at the bench and in early phase clinical trials. Yet, it is also a time for critical assessment and planning to assure the success of the clinical research effort. As successes at the bench have enabled transition of novel peptides, longer-acting factor products and gene therapy to clinical trials, clinicians face the challenges of limited number of patients, competing priorities and strained resources. To solve these problems and assure the success of the clinical research effort, it is essential that the research process be enabling and the dialogue be global, involving academia with industry, and physicians with patients. This is a critical juncture in the process, especially with new national initiatives in clinical research at hand. Needs must be assessed and priorities must be set to assure that despite the challenges, exciting new therapies will ultimately translate into safe, effective therapies for patients. Finally, these challenges are by no means restricted only to rare disease research. With the evolution of genetic medicine, it is likely that the general medical disease research of the future will include small clinical trials of new agents for small subsets of patients with certain disease mutations. Thus, the milestones we achieve in this ongoing process will hopefully not only enable clinical trials research in a rare disease, but also in many medical genetic disease of the future.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia.

While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score > 100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA-100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non-VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

Diagnosis and treatment of inherited factor X deficiency.

Factor X is a vitamin K-dependent, liver-produced serine protease that serves a pivotal role in coagulation as the first enzyme in the common pathway to fibrin formation. Inherited factor X deficiency is a rare autosomal recessive bleeding disorder that is estimated to occur in 1:1,000,000 individuals up to 1:500 carriers. Several international registries of FX-deficient patients have greatly expanded the knowledge of clinical phenotype. A proposed classification of severity is based on FX:C activity measurements: an FX:C measurement <1% is severe, an FX:C measurement of 1-5% is moderate and an FX:C measurement of 6-10% is mild. Levels above 20% are infrequently associated with bleeding and heterozygotes are usually asymptomatic. Among patients with FX:C levels <10%, unlike moderate or severe haemophilia A and B, mucocutaneous bleeding symptoms such as epistaxis and menorrhagia occur in the majority. In addition, patients with moderate-severe deficiency may have symptoms similar to that of haemophilia A and B, including haemarthrosis, intracranial haemorrhage, and gastrointestinal bleeding. Genotype characterization may offer important clues about clinical prognosis. More than 80 mutations of the F10 gene have been identified, most of which are missense mutations. There is no specific FX replacement product yet readily available, but fresh frozen plasma and prothrombin complex concentrates can be used for treatment of bleeding symptoms and preparation for surgery.

Menorrhagia associated with laboratory abnormalities of hemostasis: epidemiological, diagnostic and therapeutic aspects.

Historically, the pathogenesis of menorrhagia has focused on anatomic and hormonal etiologies. However, in the past decade, numerous epidemiological studies have confirmed an association of von Willebrand factor (VWF) deficiency and menorrhagia with an incidence of VWF deficiency of 13% (95% CI, 11%, 16%). Such patients have a reduced quality of life and incur a high rate of seemingly unnecessary gynecological interventions. In addition, it appears that platelet function abnormalities are c. 3- to 4-fold more common than VWF deficiency in association with menorrhagia. The management of menorrhagia with an underlying disorder of hemostasis involves consideration of the patient's age, childbearing status and preference in terms of several options: hemostatic (oral tranexamic acid, intranasal desmopressin), hormonal (oral contraceptive, levonorgestrel intrauterine system) and surgical (endometrial ablation, hysterectomy). Pending ongoing comparative trials in bleeding disorder-related menorrhagia of intranasal desmopressin (DDAVP), tranexamic acid and further study of the levonorgestrel intrauterine device, specific recommendations cannot be made at present regarding whether one intervention is superior to the other. It should also be noted that the dose and schedule and combination of intranasal DDAVP and tranexamic acid have not been well established and warrant further study. It is imperative to establish algorithms of effective menorrhagia interventions in order to justify widespread hemostasis screening of the menorrhagia patient.

Current understanding of von Willebrand's disease in women - some answers, more questions.

Considerable progress has been made in the past decade in describing the obstetrical and gynaecological aspects of von Willebrand's disease (VWD). In addition, epidemiological studies have established an approximately 11-16% prevalence of the laboratory diagnosis of VWD in women presenting with menorrhagia. However, it is not established presently whether an upfront VWD screening should be a part of the standard evaluation of menorrhagia. This is because it is presently not known whether therapy in the VWD patient tailored specifically for VWD will appreciably alter the natural history of menorrhagia compared with the non-VWD menorrhagia patient. There are also subtleties involved in securing the diagnosis of VWD in women presenting with menorrhagia in terms of fluctuation of von Willebrand factor (VWF) levels vis-à-vis the menstrual cycle and the potential impact of oral contraceptive on VWF levels. Regarding management of VWD-related menorrhagia, pending ongoing comparative trials of intranasal desmopressin (DDAVP), tranexamic acid, oral contraceptive and the levonorgestrel intrauterine device, specific recommendations cannot be made presently regarding the superiority of one intervention compared with the other. The management of VWD-related postpartum haemorrhage is also an area of active debate in terms of 'best practice' in type 1 (? prophylactic DDAVP), type 2 [? expectant management if factor VIII:C (FVIII:C) level normalizes] and type 3 patients (? intensity and duration of infusional therapy with a VWF-containing plasma-derived FVIII concentrate). This review summarizes the present state of knowledge and highlights numerous questions for future study based on our present understanding of VWD in women.

Endometrial ablation for von Willebrand disease-related menorrhagia--experience with seven cases.

BACKGROUND: Endometrial ablation has recently gained popularity as a treatment of menorrhagia in the general population. In the von Willebrand disease (VWD) patient, intuitively, it would appear that the failure rate would be higher because of the underlying hypocoaguability increasing the likelihood for re-bleeding. In a consecutive series of seven patients, we assessed the efficacy and safety of endometrial ablation in VWD-related menorrhagia. PATIENTS AND METHODS: We performed a retrospective analysis using chart review and a 21-item questionnaire administered to seven (six type 1, one type 2A) women who underwent endometrial ablation between the years 1997 and 2001. Parameters assessed included operative complications, the development of abdominal pains, recurrence of menstrual bleeding post-ablation and the change in the pre-/post-ablation quality of life (QOL). Three patients underwent endomyometrial resection and one each underwent rollerball, thermal, electrocautery and balloon ablation. All patients were pre-treated with i.v. desmopressin (DDAVP) except the 2A patient who received Humate P. Mean age of the patient was 41 +/- 6 years and follow-up was for 45 months (range 31-73) post-ablation. RESULTS: No significant perioperative bleeding complications were observed in any of the patients. All patients initially responded (two amenorrhoea, four hypomenorrhoea, one moderate improvement). In all patients, QOL assessed by 10 parameters improved significantly following the ablation procedure, regardless of the specific technique used. However, at the end of follow-up, only one patient remained amenorrheic, one was hypomenorrheic, one had moderate improvement and four patients experienced recurrence of menorrhagia, three eventually requiring a hysterectomy at a median of 11 months post-ablation. CONCLUSION: Endometrial ablation appears to be a safe procedure that improves the QOL in patients with VWD-related menorrhagia. However, its long-term efficacy appears to be lower in VWD patients when compared with women with menorrhagia without VWD.

Menorrhagia from a haematologist's point of view. Part I: initial evaluation.

The evaluation of menorrhagia should no longer be solely the task of the gynaecologist. In women with ovulatory bleeding (regular cycles), the prevalence of von Willebrand disease (vWD) in about 15% of these, as well as disorders of platelet function and fibrinolysis causing menorrhagia, warrants an active role by the haematologist. Initial intake should include documentation of menorrhagia by the pictorial chart assessment of menstrual flow. Baseline characteristics of menstrual flow should also be documented, including the frequency of changing the sanitary pad on the heaviest day, use of more than one sanitary pad at a time, number of days lost from school/work and the impact of menses on various quality-of-life parameters. Menorrhagia since menarche, a past history of surgical- and/or dental-related bleeding and a past history of postpartum haemorrhage are items of the bleeding symptom audit that appear in part to predict vWD in women with menorrhagia. Epistaxis and easy bruising do not appear to be clearly discriminatory symptoms. Initial testing should include the complete blood cell count, prothrombin time, activated partial thromboplastin time, iron profile, serum creatinine, thyroid stimulating hormone level, factor VIII level, vWF antigen, ristocetin cofactor and platelet aggregation studies. Additional haemostatic studies may also include a factor XI level and euglobulin clot lysis time. This extensive medical evaluation should assure both the patient and the gynaecologist that the possibility of an underlying haemostatic disorder has been thoroughly investigated, to avoid the patient undergoing further costly procedures and surgical interventions if an underlying haemostatic disorder remains unrecognized.

Menorrhagia from a haematologist's point of view. Part II: management.

The management of menorrhagia has until recently been the domain of the gynaecologist. As haematologists, we are now addressing the issue of optimal management of menorrhagia in our patients with bleeding disorders. Addressing three life periods, the menarche, reproductive years, and postchildbearing years, this review will discuss the use of oral contraceptive agents, antifibrinolytics, non-steroidal anti-inflammatory drugs, intranasal DDAVP and the new levonorgestrel-impregnated IUD. Management of specific bleeding disorders will also be reviewed for von Willebrand disease, haemophilia A and B carriers, women with factor XI deficiency and PAI-1 deficiency.

Obstetric and gynaecological aspects of von Willebrand disease.

The impact of von Willebrand disease in females is pronounced in terms of menorrhagia and postpartum haemorrhage. There is a very high proportion of von Willebrand disease patients with menorrhagia and associated anaemia, impairment of quality of life, including loss of time from work or school, and a high rate of the use of hysterectomy for ultimate control of the bleeding. The 'early' detection of von Willebrand disease in females may avert these complications. Consequently, there have recently been ongoing international efforts to determine the prevalence of von Willebrand disease in females presenting with menorrhagia, providing a prevalence of 7-20% combined from three studies including a total of 300 patients. Issues remain regarding the optimal dose/schedule of intranasal or subcutaneous desmopressin use for menorrhagia and the relative efficacy of anti-fibrinolytic agents. The proper role of oral contraceptives deserves further study in von Willebrand disease patients with menorrhagia as recent studies have paradoxically demonstrated a lower response rate in type 1 than type 2 or 3 von Willebrand disease. Despite the well-known adage of the 'gestational palliation' of von Willebrand disease, there is also a high proportion of postpartum haemorrhage in type 1 patients, especially after the 24 hour post-delivery period. This may occur despite a normalization of the factor VIIIc level in the third trimester, particularly in type 2 and 3 patients. The care-giver must be aware that haemorrhage can occur up to 5 weeks postpartum. In sum, studies over the past decade have documented a substantial impact of menses and childbirth on von Willebrand disease patients. These results should serve as a basis for interventional studies to reduce the morbidity of menstruation and childbirth.

Prophylactic treatment of severe factor X deficiency with prothrombin complex concentrate.

Factor X (FX) deficiency is an autosomal recessive trait that occurs in fewer than 1 in 500 000 people. Not surprisingly, reports of prophylactic treatment for FX deficiency are exceedingly rare. We now report our experience of the use of prophylactic therapy in a FX-deficient patient. This 18-year-old African-American male presented at the age of 4(1/2) years with an FX level < 1%. Treatment was on demand with prothrombin complex concentrates (PCCs) given at two times the dose per kilogram of body weight for factor IX. He experienced frequent epistaxis, soft tissue bleeding and joint bleeding. The development of a target joint (right ankle) prompted the initiation of prophylactic treatment in the beginning of 1998 to the present with 30 units kg(-1) Profilnine twice per week via a home infusion programme. If breakthrough bleeding occurred, he was instructed to infuse another dose. He was instructed that Profilnine should not be infused in more than two doses in 24 h or on more than three consecutive days. A trough level drawn 48 h post-infusion showed an FX level of 30%. In the initial 12 months with prophylactic treatment, there was no breakthrough bleeding. Subsequently, with an additional 11 months of follow-up, he has reported one bleed. He rates his quality of life improved since starting prophylactic treatment. There have been no thrombotic events. Prophylaxis with PCC for FX deficiency with adequate education and follow-up can be performed capably in the home setting with a resultant decrease in the frequency of bleeding and attendant complications.

Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: results of a patient survey.

Type 1 von Willebrand disease (vWD) is generally regarded clinically as 'mild' and the obstetrical-gynaecological features have not been fully described. We administered a patient questionnaire and provider survey of the medical and quality of life aspects of childbirth and menstruation to 99 type 1 vWD patients and compared the patients presently menstruating (n=81) to a cohort of 150 menstruating females in the general population. The following measurements had a statistically higher proportion in the vWD group: number of tampons/towels used for a typical menstrual cycle (P=0. 002); percentage reporting that clothes are stained by menses (P = 0. 001); past or present history of anaemia (P = 0.001); childbirth-related bleeding (P=0.001); and childbirth-related bleeding necessitating RBC transfusion (P=0.002). Quality of life assessment of the impact of menses in both of the above cohorts was measured by a Likert scale using seven quality of life parameters. Compared to the control group, the vWD patients had a significantly higher score, with P-values of < 0.0001 for each parameter. Hormonal interventions for menorrhagia in the vWD patients were < or = 50% effective. Menorrhagia resulted in red blood cell transfusions in 6% of patients, dilatation and curettage in 17% and hysterectomy in 13%. Despite the common connotation of type 1 vWD as clinically 'mild', childbirth and the monthly challenge to haemostasis presented by menstruation result in a substantial degree of morbidity in females with type 1 vWD. These results support the rationale for ongoing international efforts to increase awareness of vWD as a cause for menorrhagia and to improve the quality of life in females with known vWD.

Hematologic neoplasia and the central nervous system.

Central nervous system (CNS) involvement with malignant cells is a well recognized complication of hematologic neoplasms. A number of disorders such as acute lymphoblastic leukemia and high grade lymphoma frequently involve the CNS and prophylactic therapy is advised. Disorders such as acute myeloid leukemia (AML) and multiple myeloma are less likely to be associated with CNS involvement. This series describes three cases of CNS involvement by malignant hematologic disease: myelomatous meningitis, CNS chloromas complicating AML, and primary lymphomatous meningitis.