Laboratory misdiagnosis of von Willebrand disease in post-menarchal females: A multi-center study

Increased awareness of von Willebrand Disease (VWD) has led to more frequent diagnostic laboratory testing, which insurers often dictate be performed at a facility with off-site laboratory processing, instead of a coagulation facility with onsite processing. Off-site processing is more prone to preanalytical variables causing falsely low levels of von Willebrand Factor (VWF) due to the additional transport required. Our aim was to determine the percentage of discordance between off-site and onsite specimen processing for VWD in this multicenter, retrospective study. We enrolled females aged 12 to 50 years who had off-site specimen processing for VWF assays, and repeat testing performed at a consulting institution with onsite coagulation phlebotomy and processing. A total of 263 females from 17 institutions were included in the analysis. There were 251 subjects with both off-site and onsite VWF antigen (VWF:Ag) processing with 96 (38%) being low off-site and 56 (22%) low onsite; 223 subjects had VWF ristocetin co-factor (VWF:RCo), 122 (55%) were low off-site and 71 (32%) were low onsite. Similarly, 229 subjects had a Factor VIII (FVIII) assay, and 67 (29%) were low off-site with less than half, 29 (13%) confirmed low with onsite processing. Higher proportions of patients demonstrated low VWF:Ag, VWF:RCo, and/or FVIII with off-site processing compared to onsite (McNemar's test P-value <.0005, for all assays). These results emphasize the need to decrease delays from sample procurement to processing for VWF assays. The VWF assays should ideally be collected and processed at the same site under the guidance of a hematologist.

Pregnancy and delivery in women with von Willebrand disease.

Given the wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms associated with the disorder, pregnancy and delivery in von Willebrand disease (VWD) represent a significant clinical challenge. The variable pattern of changes observed during pregnancy of von Willebrand factor (VWF) and factor VIII (FVIII), the protein carried by VWF, prompts a careful evaluation of pregnant women with VWD to plan the most appropriate treatment at the time of parturition. However, there are also instances during pregnancy (amniocentesis, vaginal bleeding associated with placental detachment, sudden abortion) that may require urgent hemostatic treatment to prevent bleeding. Thus, women with VWD should start pregnancy after being well characterised as to their type, subtype and treatments. Women with VWD who have VWF and FVIII basal levels >30 U/dL typically normalise these levels at the end of pregnancy and specific anti-haemorrhagic prophylaxis is seldom required. On the contrary, those with basal levels <20 U/dL usually show a lesser increase and specific treatment is required. Some women with DNA variants associated with increased clearance can be treated with desmopressin, while those unresponsive or with contra-indications to this agent need replacement therapy. For these latter women, the risk of vaginal bleeding during pregnancy may be increased and prophylaxis with VWF concentrates required. Similarly, women with type 2 VWD who maintain reduced VWF activity throughout pregnancy require replacement therapy with FVIII/VWF concentrates. Delayed postpartum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid is useful at discharge to avoid excessive lochia.

Inherited Bleeding Disorders in the Obstetric Patient

Inherited bleeding disorders increase the risk of bleeding in the obstetric patient. Randomized controlled trials to compare prophylactic or therapeutic interventions are rare, and guidance documents rely heavily on expert opinion. Here we report the results of a systematic review of the literature for the treatment and prevention of peripartum bleeding in women with an inherited bleeding disorder. The highest-quality evidence is for the use of tranexamic acid in postpartum hemorrhage, which has been shown to decrease bleeding-related mortality in women without bleeding disorders. There is limited evidence for prophylactic use of this agent in women with inherited bleeding disorders. Desmopressin has also been used in observational studies of patients with von Willebrand disease and carriers of hemophilia A with some success, although concerns about the risk of hyponatremia persist. In patients with deficiencies of specific factors, replacement is generally the preferred approach, and concentrates have been studied in deficiencies of VWF and factors VII, VIII, IX, XI, and XIII as well as in patients with fibrinogen deficiency. Because of the small size of these studies, neither safety nor efficacy is well established, although the literature suggests that bleeding history may be more predictive of outcomes than factor levels in many cases. Goal factor levels have not been studied or systematically established in any of these diseases, although observational data suggest that achieving normal levels may be inadequate, particularly for VWF and factor VIII, which are physiologically elevated in pregnancy. For factor deficiencies in which no specific concentrate is available, such as factors II (prothrombin) and V, prothrombin complex concentrate or fresh frozen plasma may be used, and for platelet defects or deficiencies, such as Glanzmann thrombasthenia or Bernard-Soulier syndrome, platelet transfusion is generally first line, although use of recombinant FVIIa has been reported in patients with Glanzmann thrombasthenia to avoid development of, or treat patients with, antibodies to platelet glycoprotein IIbIIIa. Ultimately, data are lacking to definitively support an evidence-based approach to management in any of these disorders, and prospective, controlled studies are desperately needed.

Patterns of von Willebrand Disease Screening in Girls and Adolescents With Heavy Menstrual Bleeding

OBJECTIVE: To estimate the frequency of von Willebrand disease screening and factors that affect screening frequency in a national sample of girls and adolescents with heavy menstrual bleeding.

METHODS: In this retrospective cohort study, we used a national claims database for privately and publicly insured patients between 2011 and 2013 for girls aged 10–17 years. Diagnostic criteria of heavy menstrual bleeding were the presence of one inpatient or two outpatient International Classification of Diseases, 9th Revision codes for heavy menstrual bleeding. We defined severe heavy menstrual bleeding as heavy menstrual bleeding plus an inpatient stay for menstrual bleeding, iron deficiency anemia, or blood transfusion. To assess whether patient- or facility-level characteristics affected screening, we performed logistic regression analysis including patient age, health care provider type seen at first visit for menorrhagia, patient residence in a metropolitan statistical area (proxy for urban vs rural inhabitance), and approximate travel time to the nearest hemophilia treatment center.

RESULTS: We identified 23,888 postpubertal girls and adolescents with heavy menstrual bleeding (986 with severe heavy menstrual bleeding). Von Willebrand disease screening was performed in 8% of females with heavy menstrual bleeding and 16% with severe heavy menstrual bleeding. Younger age at diagnosis, commercial insurance, and living within a metropolitan statistical area were associated with higher screening rates. Patients who underwent testing for iron deficiency anemia had the highest likelihood of undergoing screening (odds ratio 7.08, 95% CI 6.32–7.93). Among patients living in a metropolitan statistical area, those 60 minutes or more from a hemophilia treatment center were less likely to undergo screening.

CONCLUSION: Despite recommendations by the American College of Obstetricians and Gynecologists for more than 15 years, fewer than 20% of postpubertal girls and adolescents with heavy menstrual bleeding underwent screening for von Willebrand disease in this cohort. Increased clinician awareness and adherence to recommended screening recommendation

Case-based Discussion on the Implications of Exogenous Estrogens in Hemostasis and Thrombosis: the Obstetrician's View.

This is the obstetrician's view on 3 different clinical scenarios involving bleeding and thrombotic disorders. In the first scenario, an 18 year old with a history of heavy menstrual bleeding since menarche presents with abdominal pain and ultrasound findings suggestive of a hemorrhagic ovarian cyst. The association with an underlying bleeding disorder is recognized. The goals of management, which are controlling hemorrhage and preserving fertility, are stated. Ovarian suppression, the most effective method to prevent recurrent hemorrhagic ovarian cysts, is outlined. Long-term management of heavy menstrual bleeding with hormonal contraception is described. In the second scenario, the same patient returns 5 years later for a preconception visit. The potential risks to an unborn baby with von Willebrand disease (VWD) are addressed. The natural rise in von Willebrand factor (VWF) during pregnancy is discussed, but the fact that women with VWD do not achieve the same VWF levels as women without VWD is emphasized and the implications are presented. In anticipation of pregnancy, the need for nonhormonal management of heavy menstrual bleeding and hemorrhagic ovarian cysts is mentioned. In the third and final scenario, the patient's cousin with factor V Leiden seeks consultation regarding the risks of thrombosis with in vitro fertilization. The steps of assisted reproductive technology are described. The strategies to prevent venous thromboembolism by preventing ovarian hyperstimulation and reducing the likelihood of multiple gestation are detailed.

 DOI: 10.1182/hematology.2019000071