Von Willebrand Disease A Coagulopathy Disorder University of Mary Primary Care of Women and Children NUR 620 Sonia Takacs, FNP-S

Objectives Factor- von Willebrand-pathophysiology Learn Von Willebrand F.A.S.T. F Factor- von Willebrand-pathophysiology A Autosomal dominant- Inheritance & Acquired S Scenarios-common clinical presentation and differential diagnosis T Treatment and management plan

Von Willebrand Disease Introduction Von Willebrand Disease Deficiency (vWF) Autosomal dominant 3 main types Von Willebrand disease (VWD) is actually a group of disorders that involve the von Willebrand factor (vWF), which is a multimeric glycoprotein complexed to factor VIII in the plasma (Buttaro et al., 2017). Von Willebrand disease is also the most common coagulopathy, and is autosomal dominant, as are other clotting factor deficiencies (Burns et al., 2017). vWF serves as a bridge between damaged endothelium and adhering platelets, and facilitates platelet attachment (Saladin, 2012). (National Heart, Lung, and Blood Institute, 2015)

Pathophysiology Von Willebrand factor allows the platelets to form a blood clot to prevent bleeding. Previously mentioned: Von Willebrand disease (VWD) is actually a group of disorders that involve the von Willebrand factor (vWF), which is a multimeric glycoprotein complexed to factor VIII in the plasma (Buttaro et al., 2017). Von Willebrand disease is also the most common coagulopathy, and is autosomal dominant, as are other clotting factor deficiencies (Burns et al., 2017). vWF serves as a bridge between damaged endothelium and adhering platelets, and facilitates platelet attachment (Saladin, 2012). Von Willebrand disease caused by qualitative or quantitative abnormalities in vWf (McCance & Huether, 2014). The disorder can be sub grouped in Three main types. Type I accounts for approximately 85% of the patients; is characterized by a quantitatively defect. Type II is characterized by an absence of high- molecular-weight multimers and occurs in 10% to 15% of vWd patients; Type III characterized with less than 1% FVIII, prolonged bleeding time (> 15 minutes) and reduced level (<1%) of vWF Type IV is also known as pseudo or platelet type von Willebrand disorder. (But this is mixed with platelets disorder ) (McCance & Huether, 2014)

Autosomal dominant (Genetic Support Foundation, 2015) Autosomal dominant means that there is NOT sex-linked pattern (Saladin, 2012). This makes Von Willibrand disease unique. NOTE: Remember Factor VIII and Factor IX deficiencies are inherited in a sex-liked patterned so that females are carries and males are affected (McCance & Huether, 2014) (Genetic Support Foundation, 2015)

Acquired Syndrome Myoproliferation disorders Aortic stenosis Hypothyroidism Lymphoproliferative disorders (multiple myeloma Acquired VWD has been found to be associated with aortic stenosis, myoproliferation diroders, hypothyroidms and lymphoproliferative disorders such as multiple myeloma (Rao, Pfeifer,Winters, Nichols & Pruthi, 2009). (Rao, Pfeifer,Winters, Nichols & Pruthi, 2009)

Prevalence Won Willebrand Disease, affecting up to 1% of the general population (CDC, 2016). Type I 70 to 85% of patients with vWF Type II 10 to 15 % of patients with vWF Type III 1% of patients with vWF Type IV Less than 1% pseudo or platelet type Prevalence. Von Willebrand disease (VWD) occurs with equal frequency among men and women, affecting up to 1% of the general population. However, women are more likely to experience symptoms of VWD because of the increased bleeding it causes during their menstrual periods, during pregnancy, and after childbirth (CDC, 2016). Prevalence among subdivision: Type I accounts for approximately 70 to 85% of the patients; it is characterized quantitatively Type II is composed of four varients (2A, 2B, 2M, 2N). Type II is characterized by an absence of high- molecular-weight multimers (qualitative defect in the vWF) and occurs in 10to 15% of vWd patients; Type III characterized is a quantitative defect of vWF in which this factor is essentially absent. Bleeding time more than 15 minutes is common! Type IV is also known as pseudo or platelet type von Willebrand disorder. Reference Centers for Disease Control and Prevention (CDC).(2016). Von Willebrand Disease (VWD). Retrieved from https://www.cdc.gov/ncbddd/vwd/data.html

Clinical Presentation The First Step to Diagnosis In general, some of the most common signs and symptoms include(Laffan, et al., 2014) Mucosal bleeding Heavy periods (soaking pads within 1 hour, anemia, decreased ferritin) Prolonged bleeding after dental extraction Prolonged or normal PTT, and PT Epistaxis Easy or spontaneous bleeding Prolong bleeding after superficial cuts Severe cases may manifest spontaneous bleeding and will require assistance by specialized centers in case of surgery, dentistry, or at the time of delivery for pregnant women. (Medical News Today, 2016 & CDC, 2017)

Video : Possible scenarios Women and Bleeding Disorders: Living with von Willebrand Disease https://www.youtube.com/watch?v=XgMtQNXJCf4 (CDC, 2014)

Initial Assessment Guidelines link: https://www.nhlbi.nih.gov/health-pro/guidelines/current/von-willebrand-guidelines Link to the pocket guide: https://www.nhlbi.nih.gov/files/docs/guidelines/vwd_pocketguide.pdf The National Heart, Lung, and Blood Institute, (2015) guidelines recommend the following initial assessment (National Heart, Lung, and Blood Institute, 2015)

Differential Diagnosis Von Willebrand Disease Hemophilia A Hemophilia B Thrombophilia Glanzmann thrombasthenia Bernard Soulier syndrome (Nicoll et al., 2012 & Burns et al., 2016) The diagnosis can be challenging because some medications, inflammation, stress, and pregnancy can elevate vWF, from abnormal low level into normal range, thus making a true deficient state (Burns et al., 2017). In may cases PT, and aPTT may be normal with vWD leading to underdiagnosis (Nicoll et al., 2012) .

Initial Evaluation CBC aPTT PT Factor VIII vWF antiguen (vWF: Ag) vWF activity (vWF:Act) Ristocetin cofactor assay (vWF:RCoF) The diagnosis of Von Willebrand Disease most not be made on the basis of single test result! The results of the common coagulation tests usually done for general screening or before surgery may be normal in patients with mild VWD (National Heart, Lung, and Blood Institute, 2015. Individuals may undergo standard blood screening tests including a complete blood count (CBC), which may be normal or may show microcytic anemia or low platelet count, especially in individuals with VWD type 2B(National Organization for Rare Disorders, 2015). Activated partial thromboplastin time (aPTT) or promthrombin time (PT). APTT may be normal in individuals with VWD or can be prolonged if deficiency of factor VIII is present (National Organization for Rare Disorders, 2015). In suspected cases, the diagnosis should be made by specifically measuring VWF and factor VIII, preferably in specialized centers (National Heart, Lung, and Blood Institute, 2015). Actually, factor VIII is usually also decreased since it is transported by VWF (National Organization for Rare Disorders, 2015). (National Heart, Lung, and Blood Institute, 2015) (National Organization for Rare Disorders, 2015)

Expected laboratory values in VWD For more detailed information please visit the link below. Reference National Heart, Lung, and Blood Institute. (2015). The diagnosis, Evaluation and Management of Von Willebrand Disease. Retrieved from https://www.nhlbi.nih.gov/files/docs/guidelines/vwd.pdf (National Heart, Lung, and Blood Institute, 2015)

Treatment Depends of the severity of bleeding Desmopressin Hormonal therapy (Lethaby, 2015) Antifibrinolytic therapy (8 hrs. before surgery)( Laffan, et al., 2014). Cryoprecipitate (only for emergencies) Once the diagnosis is made, it is very important to identify the specific type of vWD so the appropriate treatment can be provided. For example, Desmopressin is the treatment of choice for type I vWD. However, it would not be helpful in some type 2 vWD. When dealing with type II, and III a referral for hematologist is necessary. Plasma concentration infusion is the treatment of choice when desmopressin is not appropriate (Buttaro el al., 2017). NOTE: most individuals do not require treatment, only during invasive procedures. Cryoprecipitate should be avoided because of lack of viral inactivation (Laffan, et al, 2014). Reference Laffan, M. A., Lester, W., O'Donnell, J. S., Will, A., Tait, R. C., Goodeve, A., & ... Keeling, D. M. (2014). The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. British Journal Of Haematology, 167(4), 453-465. doi:10.1111/bjh.13064 Lethaby, A. (2015). Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Of Systematic Reviews, (4), doi:10.1002/14651858.CD002126.pub3 (McPhee & Papadakis,2011, Buttaro el at., 2017)

Desmopressin recomendation Items From the Past Criteria for the use of Desmopressin. (Von Willebrand disease, 2014)

Treatment von Willebrand disease Type I Antifibrinolytic therapy. Desmopressin Hormonal therapy. Progesterone or progestogen releasing intrauterine systems Antifibrinolytic therapy. To illustrate main findings of this literature review in terms of treatment for a type I vWBD patient. ( Laffan, et al., 2014)

What is von Willebrand Disease? Videos : patient education What is von Willebrand Disease? https://stepsforliving.hemophilia.org/resources/videos/VWD (National Hemophilia Foundation, 2014) Women and Bleeding Disorders: Living with von Willebrand Disease https://www.youtube.com/watch?v=XgMtQNXJCf4 (CDC, 2014)

Conclusion Von Willebrand disease is caused by deficiency of VWF (adhesive protein). Clinical presentation of mild to moderate include mucocutaneous bleeding, epistaxis, gingival bleeding, cutaneous bruising, and menorrhagia Desmopressin is the treatment of choice. Thank you

Discussion questions Compare common bleeding disorders such as hemophilia A with Won Willebrand disease. What is Antifibrinolytic therapy? Discuss hormonal therapy for patients with Von Willebrand disease. Discuss the therapy (Desmopressin: 1-desamino-8-D-arginine vasopressin) in Von Willebrand Disease Compare common bleeding disorders such as hemophilia B with Won Willebrand disease.

Discussion questions-continued Discuss von Willebrand Disease type II. Discuss von Willebrand Disease type III. Discuss vitamin K deficiency. How do you manage a patient’s cardiac conditions and bleeding disorder? Discuss Hepatitis B vaccine in patients with von Willebrand Disease. Discuss preventive measures for patient with von Willebrand Disease. Discuss NSAIDs for patients with von Willebrand Disease.

Discussion questions-continued Discuss physical therapy in patients with von Willebrand Disease. Discuss psychosocial interventions for patients with von Willebrand Disease. What are the community resources available in your community for patients von Willebrand Disease and their families? Discuss immunization in patients with von Willebrand Disease. Discuss Cryoprecipitate therapy in patients with von Willebrand Disease.

Discussion questions-continued Find and discuss a recent research article regarding von Willebrand Disease. Do you have a professional experience caring for patients with with von Willebrand Disease? Please share your story. Discuss guidelines for dental work in patients with von Willebrand Disease. Discuss surgery protocols for patients with von Willebrand Disease. Discuss von Willebrand Disease and genetic counseling. Formulate a plan for patients with von Willebrand Disease to preform extracurricular activities (sports plan).

References Burns, C.E., Dunn, A.M., Brady, M.A., Starr, N.B., & Blosser, C.G. (2016). Pediatric Primary Care, (5th ed.). Philadephia: Elsevier Saunders. Buttaro, T.M., Trybulski, J., Bailey, P.P. & Sandberg-Cook, F.(2017). Primary care: a collaborative practice. St. Louis, MO: Elsevier. Centers for Disease Control and Prevention (CDC).(2016). Von Willebrand Disease (VWD). Retrieved from https://www.cdc.gov/ncbddd/vwd/data.html Centers for Disease Control and Prevention (CDC).(2017). Von Willebrand Disease (VWD). Retrieved from https://www.cdc.gov/ncbddd/vwd/facts.html Genetic Support Foundation. (2015). Autosomal Dominant Inheritance. Retrieved from https://geneticsupportfoundation.org/genetics-and-you/autosomal-dominant-inheritance Guidelines for The Diagnosis, Evaluation and Management of von Willebrand Disease. (2015). Retrieved from https://www.nhlbi.nih.gov/health-pro/guidelines/current/von-willebrand-guidelines Laffan, M. A., Lester, W., O'Donnell, J. S., Will, A., Tait, R. C., Goodeve, A., & ... Keeling, D. M. (2014). The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. British Journal Of Haematology, 167(4), 453-465. doi:10.1111/ bjh.13064

References-Continued Medical News Today. (2016). What Is Von Willebrand Disease? Retrieved from http://www.medicalnewstoday.com/articles/188979.php McCance, K. L., & Huether, S. E. (2014). Pathophysiology: The biologic basis for disease in adults & children. St. Louis, MO: Elsevier Mosby. McPhee, S. J., & Papadakis, M. A. (2011). Current Medical Diagnosis & Treatment 2011. New York: McGraw-Hill Medical. National Organization for Rare Disorders (NORD). Von Willebrand Disease. (2015). Retrieved from https://rarediseases.org/rare-diseases/von-willebrand-disease/ National Heart, Lung, and Blood Institute. (2015). The diagnosis, Evaluation and Management of Von Willebrand Disease. Retrieved from https://www.nhlbi.nih.gov/files/docs/guidelines/vwd.pdf National Hemophilia Foundation. (2014). What is von Willebrand disease (VWD)? Retrieved from https://stepsforliving.hemophilia.org/resources/videos/VWD National Organization for Rare Disorders (NORD). Von Willebrand Disease. (2015). Retrieved from https://rarediseases.org/rare-diseases/von-willebrand-disease/

References-Continued Nicoll, D., Lu, C.M., Pignone, M., & McPhee S.J. (2012). Pocket Guide to Diagnostic Tests. 6th ed. The McGraw Hill Companies Inc. Rao, A. N., Pfeifer, M., Winters, J., Nichols, W., & Pruthi, R. (2009). Acquired von Willebrand syndrome: transplacental transfer of maternal monoclonal antibodies and description of peripartum management. Haemophilia, 15(2), 636. Saladin, K. S. (2012). Anatomy & physiology: The unity of form and function. New York, NY: McGraw-Hill. Von Willebrand disease. (2014). Hematology, 19(6), 370-371. doi:10.1179/1024533214Z.000000000292 Women and Bleeding Disorders: Living with von Willebrand Disease (2014). Retrieved https://www.youtube.com/watch?v=XgMtQNXJCf4