Appendix D: Annotated Bibliography

Arya, S., Wilton, P., Page, D., Boma-Fischer, L., Floros, G., Dainty, K. N., ... & Sholzberg, M. (2020). Healthcare provider perspectives on inequities in access to care for patients with inherited bleeding disorders. PloS one, 15(2), e0229099.

Arya et al. investigate the ways in which social determinants of health affect patients with inherited bleeding disorders. This study investigated healthcare provider perspectives regarding access to care and diagnostic delay among this patient population. The results showed that healthcare providers felt there were diagnostic delays for patients with mild symptomatology (71%, N = 50), women presenting with abnormal uterine bleeding as their only or primary symptom (59%, N = 41), and patients living in rural Canada (50%, N = 35). Fewer respondents felt that factors such as socioeconomic status (46%, N = 32) or race (21%, N = 15) influenced access to care, particularly as compared to the influence of rural location (77%, N = 54). This study identified at risk populations for inequitable access to care. This source will be used to support more research into equitable access for care in the VWD community.

Arya, S., & Sholzberg, M. (2018). Are There Inequities in Access to Care Amongst Women with Inherited Bleeding Disorders? a Systematic Review. Blood, 132, 5813.

Arya et el. conducted a literature review on access to care for women with inherited bleeding disorders. They found that literature was lacking on this topic. Therefore, they recommended ongoing efforts are needed to understand women’s experiences, especially as hemophilia carriers. This is important to understanding inequities in care and where they exist. They identified possible demographic, geographic, and systems level factors hindering patients' access to care, in the hopes to increase healthcare provider awareness around existing barriers and, through targeted interventions, promote patient self-advocacy. This source will be used to apply the health equity lens to reviewing the toolkit.

Atiq, F., Saes, J. L., Punt, M. C., van Galen, K. P., Schutgens, R. E., Meijer, K., ... & Schols, S. E. M. (2021). Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders. EClinicalMedicine, 32, 100726.

Atiq et al. investigated sex differences in a large cohort of patients with autosomal inherited bleeding disorders (VWD, rare bleeding disorders, and congenital platelet defects). Their surveyed population was 60.9% women. The age of first bleeding was similar between men and women. However, the major difference was diagnostic delay, women were diagnosed much later (11.6+/- 16.4 years) compared to men (7.7 +/- 16.6 years). Women with bleeding disorders are more often referred for bleeding, have a longer diagnosis delay, and often require treatment due to sex-specific bleeding. This source will be used to include information on VWD in men, as this was requested to be included in the toolkit per Lena and Nikole.

Connell, N. T., Flood, V. H., Brignardello-Petersen, R., Abdul-Kadir, R., Arapshian, A., Couper, S., ... & Mustafa, R. A. (2021). ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood advances, 5(1), 301-325.

Connell et al. reports on the updated guidelines on the management of VWD to limit variability in management options. The evidence-based guidelines were established by a multidisciplinary panel including patients and representatives from the American Society of Hematology (ASH), the International Society on Thrombosis and Hemostasis (ISTH), the World Federation of Hemophilia (WFH), and NHF. The panel agreed on 12 recommendations to improve decisions about the management of VWD. These recommendations include prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting. I will use this source to make updates to the VWD toolkit and ensure information is aligned with the current guidelines.

Connell, N. T., James, P. D., Brignardello-Petersen, R., Abdul-Kadir, R., Ameer, B., Arapshian, A., ... & Flood, V. H. (2021). von Willebrand disease: proposing definitions for future research. Blood Advances, 5(2), 565-569.

Connell et al. proposed standard definitions to be used in the treatment and future research of VWD. These standard definitions were recommended to improve the ability of researchers to achieve consistent endpoints in future VWD clinical trials. This will ultimately enable improved treatments for affected patients. This source is useful because it provides education for my own understanding of VWD. The source would assist NHF and the greater VWD community to have standard communication regarding the disorder.

FitzGerald, C., & Hurst, S. (2017). Implicit bias in healthcare professionals: systematic review. BMC medical ethics, 18(1), 19. https://doi.org/10.1186/s12910-017-0179-8

FitzGerald et al. reviewed the levels of implicit bias in healthcare professionals compared to the general population. They found that healthcare professionals exhibit the same level of implicit bias. They reported that biases are likely to influence diagnosis and treatment decisions and levels of care. They reported the most effective way to limit bias is to use the Implicit Association Test to score professionals and then measure the quality of treatment in the world. The article highlighted the need for the healthcare profession to address the role of implicit biases in disparities in health care including research in actual care settings. I will use this article as background and support on the importance of health equity in the inheritable blood disorders community.

Fogarty, H., Doherty, D., & O'Donnell, J. S. (2020). New developments in von Willebrand disease. British journal of haematology, 191(3), 329-339.

Fogarty, Doherty, and O’Donnell reported on recent advancements that have been made into defining the mechanisms for VWD. They describe new laboratory assays that have been developed to enable more precise assessment of specific aspects of VWF activity. They discuss how these advancements will impact clinical diagnosis and routine clinical practice. Additionally, they discuss new treatment options as well. This source will be used as supplemental information on new advances in the VWD community and can be incorporated into the project.

James, P. D., Connell, N. T., Ameer, B., Di Paola, J., Eikenboom, J., Giraud, N., ... & Mustafa, R. A. (2021). ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood advances, 5(1), 280-300.

James et al. reports on the updated guidelines on the diagnosis of VWD as established by a multidisciplinary panel including patients and representatives from the American Society of Hematology (ASH), the International Society on Thrombosis and Hemostasis (ISTH), the World Federation of Hemophilia (WFH), and NHF. These guidelines were developed to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. The panel reported 11 recommendations including the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. I will use this source to make updates the VWD toolkit and ensure all information is aligned.

Lyles, C. R., Wachter, R. M., & Sarkar, U. (2021). Focusing on digital health equity. JAMA, 326(18), 1795-1796.

Lyles et al. discussed the importance of digital health equity in today’s world. They discussed disparities to care and how addressing these disparities equites fundamental changes to health care delivery. They discussed how Black, Hispanic/Latinx, and lower income communities are the most affected. They describe digital access to health information as being paramount today, especially with the effects of the COVID-19 pandemic. They encouraged health professionals and organizations to ensure information is available on multiple sources, especially in digital format as it is easier to access and can reach populations in rural communities as well. This source is used as support for ensuring the toolkit promotional plan is equitable and can be accessed by all in the VWD community.

Mannucci, P. M. (2019). New therapies for von Willebrand disease. Hematology 2014, the American Society of Hematology Education Program Book, 2019(1), 590-595.

Mannucci describes new therapies and treatment options available for VWD. He described the advantages and limitations to current therapies including desmopressin, FVIII/VWF plasma derived concentrations. He also described newer therapeutic products containing only VWF and how they have been produced through plasma fractionation and recombinant DNA technology. Finally, he described the potential applications of these new replacement therapies in the treatment of VWD and how they could be used in combination with adjunctive therapies. This source will be used to provide additional information on available treatments, and this will be cross-referenced with Connell et al. (2021) and James et al. (2021).

Sidonio, R. F., Jr, Zia, A., & Fallaize, D. (2020). Potential Undiagnosed VWD Or Other Mucocutaneous Bleeding Disorder Cases Estimated From Private Medical Insurance Claims. Journal of blood medicine, 11, 1–11. https://doi.org/10.2147/JBM.S224683

Sidonio, Zia, and Fallaize investigated the number of cases of undiagnosed VWD or other mucocutaneous bleeding disorders. They constructed a model to identify patient based on 12 pre-diagnosis variables. Over 507,000 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). 91% of female patient identified were <46 years with heavy menstrual bleeding as their common symptom. They estimated that 35,000-387,000 patients may have symptomatic, undiagnosed VWD or other bleeding disorder. This source will be used to support enhanced awareness for individuals and healthcare professionals about VWD. This will be used as evidence to support the toolkit.

Skinner, M. W., Nugent, D., Wilton, P., O’Mahony, B., Dolan, G., O’Hara, J., & Berntorp, E. (2020). Achieving the unimaginable: Health equity in haemophilia. Haemophilia, 26(1), 17-24.

Skinner et al. proposed a treatment model to meet the needs of the bleeding disorders community. The treatment model was developed to establish specific treatment milestones and targeted outcomes linked to level of factor deficiency. They also agreed that the ultimate goal should be functional cure and health equity. Seven levels to achieve these goals were identified as sustain life, minimal joint impairment, freedom from any spontaneous bleeds, attainment of normal mobility, able to sustain minor trauma without additional intervention, ability to sustain major surgery or trauma, and normal hemostasis. The source suggests that once treatment is not limited by plasma supply for the manufacture of recombinant factors and the success of gene therapy, health equity would be achievable. This source includes great information on the importance of health equity in the treatment of bleeding disorders, therefore I will use it ensure the toolkit is revised with a health equity lens.

Arya, S., Wilton, P., Page, D., Boma‐Fischer, L., Floros, G., Winikoff, R., ... & Sholzberg, M. (2021). “They don’t really take my bleeds seriously”: Barriers to care for women with inherited bleeding disorders. Journal of Thrombosis and Haemostasis, 19(6), 1506-1514.

Arya et al. (2021) conducted a qualitative descriptive study to investigate barriers to care for women with bleeding disorders. They identified four themes surrounding barriers: (1) lack of health-care provider awareness of bleeding disorders, (2) health-care provider dismissal of symptoms, (3) limited access to specialized care and treatment plans, (4) need for sex-education and advocacy. Women with inherited bleeding disorders experience tension in the health care system, feeling unheard, and poorly understood. Therefore, the authors recommended that knowledge and care gaps be addressed with awareness and educational initiatives: patient education on vaginal blood loss, updated medical curricula, clear referral guidelines, and telehealth initiatives for patients residing far from HTCs. This source supports the update of toolkit materials to have education with clear/updated guidelines to improve awareness. Furthermore, recognition of patients in rural areas or who have difficult access to HTCs need equitable access to education. Therefore, supports the use of digital health equity and use of health equity lens.

Oladapo, A., Wu, Y., Lu, M., Farahbakhshian, S., & Ewenstein, B. (2019). Estimation of the Economic Burden Associated with Major Surgery Due to Von Willebrand Disease Based on Claims Data from the USA. Blood, 134, 4692.

Oladapo et al. (2019) investigated the economic burden associated with major surgeries in patients with VWD compared to patients without VWD who had similar types of surgeries. They found that patients with VWD were significantly more likely to have IP admissions, ER visits, and OP visits. Patients with VWD also incurred significantly higher total heath care costs than patients without VWD. This will be used to show support of the burden of living with VWD, highlighting the importance of a toolkit to improve education and awareness to lead to better health outcomes.

Lu, M., Oladapo, A., Wu, Y., Farahbakhshian, S., & Ewenstein, B. (2018). Prevalence and Burden of Major Bleeding Events in Patients with Von Willebrand Disease Based on Claims Data from the USA. Blood, 132, 2222.

Lu et al. (2018) investigated the burden of major bleeding events (MBE) in individuals with VWD. They found that GI bleeding was the most prevalent MBE. Intracranial bleeds were slightly higher in males than females. Patients with MBEs were more likely to have IP admissions, ER visits, OP visits, and will have longer IP stays, more frequent IP admissions, ER visits, and OP visits compared to those patients without MBEs. Patients with MBEs incurred significantly higher total healthcare costs than those without MBEs. The readmission rate was 3.1% for any MBE and 2.5% for the same type of MBE. MBEs were associated with additional comorbidities and higher healthcare costs. Therefore, optimal therapy is essential to prevent MBEs, highlighting the importance of the toolkit.