Von Willebrand Disease: When is a little bleeding too much Jan Kuhn, RN, MPH Central Virginia Center for Coagulatio

1. Von Willebrand Disease: When is a “little” bleeding too much?Jan Kuhn, RN, MPHCentral Virginia Center for Coagulation DisordersVirginia Bleeding Disorders Program

2. Objectives To review the clinical presentation of von Willebrand Disease, its treatment and the prevention of bleeding episodes. To identify strategies to adapt the home and school environment to meet the needs of children with inherited bleeding disorders. To identify a network of coordinated support systems to promote independence in families with this chronic condition.

3. What is von Willebrand Disease? Von Willebrand disease is an inherited bleeding disorder- meaning you are born with it. Less than normal amounts of von Willebrand factor in the blood or von Willebrand factor that does not work as well as it should Effects the normal ability to form a blood clot Other parts of the clotting process do still work, however.

4. von Willebrand Disease (vWD) A person with von Willebrand diseasedoes not bleed any faster than normal, but may bleed for a longer time. (In some situations) This is an important statement to remember. Although early treatment is best, there is time to seek treatment.This is an important statement to remember. Although early treatment is best, there is time to seek treatment.

5. Normal Clot Formation Vasoconstriction ( the blood vessel gets smaller) Platelets form a plug Other clotting factors make fibrin strands to make the platelet plug hold together better A clot forms The clot is dissolved when it is no longer needed Coagulation, or hemostasis, the process by which the body stops bleeding, involves vasoconstriction as well as two integrated processes Primary hemostasis: formation of a platelet plug Secondary hemostasis: fibrin clot formation Coagulation, or hemostasis, the process by which the body stops bleeding, involves vasoconstriction as well as two integrated processes Primary hemostasis: formation of a platelet plug Secondary hemostasis: fibrin clot formation

6. Clotting Illustration This illustration depicts normal hemostasis and hemostasis with a bleeding disorder. The deficiency, absence, or abnormal function of a clotting factor will result in incomplete platelet plug or fibrin clot formation.This illustration depicts normal hemostasis and hemostasis with a bleeding disorder. The deficiency, absence, or abnormal function of a clotting factor will result in incomplete platelet plug or fibrin clot formation.

7. Vasoconstriction Occurs spontaneously following injury to a blood vessel Slows and reduces flow of blood to injured area Prevents more blood loss Like pinching off a hose to decrease the water flow to a hole in the hose. Bleeding begins following an injury to the subendothelium. Vasoconstriction of the injured vessel occurs spontaneously in an effort to reduce the amount of blood to the area and prevent blood loss.Bleeding begins following an injury to the subendothelium. Vasoconstriction of the injured vessel occurs spontaneously in an effort to reduce the amount of blood to the area and prevent blood loss.

8. Platelet Plug Formation Platelets are round or oval-shaped, plate-like cells in the blood that Rush to the injury site and begin to stick to the surface of the blood vessel where the hole is Begin to stick to each other in groups and form a loose plug Plug is weak at this point without the stringy fibrin strands to strengthen it Platelets, round or oval-shaped, plate-like cells in the blood, begin to aggregate and adhere to the wall of the injured vessel and form a soft, loose platelet plug. vWF, an adhesive glycoprotein, is essential for platelet plug formation and is uniquely involved in key aspects of both primary and secondary hemostasis.Platelets, round or oval-shaped, plate-like cells in the blood, begin to aggregate and adhere to the wall of the injured vessel and form a soft, loose platelet plug. vWF, an adhesive glycoprotein, is essential for platelet plug formation and is uniquely involved in key aspects of both primary and secondary hemostasis.

10. Function of von Willebrand Factor in Clotting Process vWF is a glue-like protein needed for platelet plug formation Major functions Serves as a bridge between platelets and injury sites in the blood vessel Carries and protects one of the clotting factors (factor 8) in the blood that helps make the fibrin strands that strengthen the platelet plug von Willebrand factor (vWF) is a glue-like adhesive protein that is essential in both primary and secondary hemostasis. In primary hemostasis, it initiates adhesion of the platelets to the injured subendothelium to form the platelet plug. In secondary hemostasis, it serves as a carrier of factor VIII (FVIII), bringing FVIII to the site of injury where it assists in forming the fibrin clot. vWF also protects FVIII from rapid proteolytic degradation in the circulation. Circulating vWF does not bind to platelets; however, exposure to the subendothelial matrix allows it to bind to the platelets.von Willebrand factor (vWF) is a glue-like adhesive protein that is essential in both primary and secondary hemostasis. In primary hemostasis, it initiates adhesion of the platelets to the injured subendothelium to form the platelet plug. In secondary hemostasis, it serves as a carrier of factor VIII (FVIII), bringing FVIII to the site of injury where it assists in forming the fibrin clot. vWF also protects FVIII from rapid proteolytic degradation in the circulation. Circulating vWF does not bind to platelets; however, exposure to the subendothelial matrix allows it to bind to the platelets.

11. Prevalence of vWD Most common inherited bleeding disorder Estimated to affect ~1% of the population (mostly type 1) Males and females of all races may be affected May be diagnosed at any age Symptoms generally mild and may not require frequent treatment with type 1 vWD, a coagulation disorder of the blood, is considered the most commonly inherited bleeding disorder. It is estimated that approximately 1% of the population may have vWD. vWD affects both males and females and has a wide spectrum of clinical symptoms ranging from very mild to severe. The exact prevalence of vWD cannot be determined because of the difficulty in detecting mild forms of the disorder and the incidence of affected people who do not have symptoms. Individuals who do have symptoms and who have been diagnosed with vWD generally experience mild symptoms that may not require treatment. vWD, a coagulation disorder of the blood, is considered the most commonly inherited bleeding disorder. It is estimated that approximately 1% of the population may have vWD. vWD affects both males and females and has a wide spectrum of clinical symptoms ranging from very mild to severe. The exact prevalence of vWD cannot be determined because of the difficulty in detecting mild forms of the disorder and the incidence of affected people who do not have symptoms. Individuals who do have symptoms and who have been diagnosed with vWD generally experience mild symptoms that may not require treatment.

12. Types of von Willebrand Disease Three different types of von Willebrand Disease: Type 1, 2 and 3 The severity of the bleeding problem will depend on the type of von Willebrand Disease

13. Type 1 vWD Most common type; in >80% of cases Quantitative defect Normal structure and function of vWF Mild to moderate decrease in amount of vWF in the blood stream Bleeding symptoms may be absent, mild, or moderate Of the three types of vWD, type 1 is the most common, as it is present in >80% of cases. Type 1 vWD is a quantitative defect. The protein is normal in structure with small, intermediate, and large multimers present; however, the amount of protein is mildly to moderately decreased. Symptoms are generally mild. Transmission is usually autosomal dominant. Most patients respond clinically to desmopressin acetate.Of the three types of vWD, type 1 is the most common, as it is present in >80% of cases. Type 1 vWD is a quantitative defect. The protein is normal in structure with small, intermediate, and large multimers present; however, the amount of protein is mildly to moderately decreased. Symptoms are generally mild. Transmission is usually autosomal dominant. Most patients respond clinically to desmopressin acetate.

14. Type 2 vWD Qualitative defect- vWf does not work right Bleeding symptoms can be can be mild to severe Several sub-types related to the actual defect in the vWf:8 related to the ability to bind with platelets or factor 8 Type 2 vWD accounts for approximately 20% to 25% of cases of vWD. More than 50 distinct subtypes of type 2 vWD have been identified. Type 2 vWD is a qualitative defect of vWF. There are normal amounts of protein present; however, the protein does not function properly. Clinical manifestations vary from mild to severe. Transmission is either autosomal dominant or recessive. Large multimers are most beneficial for hemostasis, so patients with type 2 vWD, in which large multimers are missing, may have extremely heavy menses.Type 2 vWD accounts for approximately 20% to 25% of cases of vWD. More than 50 distinct subtypes of type 2 vWD have been identified. Type 2 vWD is a qualitative defect of vWF. There are normal amounts of protein present; however, the protein does not function properly. Clinical manifestations vary from mild to severe. Transmission is either autosomal dominant or recessive. Large multimers are most beneficial for hemostasis, so patients with type 2 vWD, in which large multimers are missing, may have extremely heavy menses.

15. Type 3 vWD Rare Quantitative defect-almost no von Willebrand factor Very low factor 8 level More severe bleeding symptoms seen in early childhood Soft tissue and joint bleeds common Type 3 vWD is also rare, with an estimated prevalence of 0.55 to 3.2 per 1 million people in Western countries, although regional differences are known to exist. Major deficits in both primary hemostasis and coagulation are present. There are markedly decreased or undetectable levels of vWF:antigen, vWF activity, and FVIII:C. Patients may experience bleeding similar to that seen in patients with hemophilia (ie, soft-tissue hemorrhage and hemarthrosis). As a result, diagnosis is often made in early childhood. Inheritance is autosomal recessive. Parents may have bleeding symptoms, but more often they are asymptomatic. Essentially no multimers are present. Treatment therefore requires factor products rich in vWF and FVIII. Type 3 vWD is also rare, with an estimated prevalence of 0.55 to 3.2 per 1 million people in Western countries, although regional differences are known to exist. Major deficits in both primary hemostasis and coagulation are present. There are markedly decreased or undetectable levels of vWF:antigen, vWF activity, and FVIII:C. Patients may experience bleeding similar to that seen in patients with hemophilia (ie, soft-tissue hemorrhage and hemarthrosis). As a result, diagnosis is often made in early childhood. Inheritance is autosomal recessive. Parents may have bleeding symptoms, but more often they are asymptomatic. Essentially no multimers are present. Treatment therefore requires factor products rich in vWF and FVIII.

17. Clotting Defect in people with von Willebrand Disease The platelets do not stick together as well to form the platelet plug The fibrin stands needed to strengthen the platelet plug are not as strong because there is less factor 8 at the site of the injury. (one of the clotting factors needed to help make the fibrin strands) There are several clotting factors in the blood. Each one plays a specific role and must interact in a specific order to form a clot. Fibrin clot formation is dependent on both intrinsic and extrinsic pathways to activate the clotting factors. Both pathways trigger the final common pathway to convert fibrinogen to fibrin.There are several clotting factors in the blood. Each one plays a specific role and must interact in a specific order to form a clot. Fibrin clot formation is dependent on both intrinsic and extrinsic pathways to activate the clotting factors. Both pathways trigger the final common pathway to convert fibrinogen to fibrin.

18. vWD: Sites of Bleeding Mucous membrane areas Nose (epistaxis) Mouth ( gingiva) Throat Digestive tract Urinary tract Reproductive tract (uterus) In vWD, sites of bleeding generally involve mucous membrane tissue. Mucocutaneous bleeding, including epistaxis (bleeding from the nose), and easy bruising are frequently encountered as presenting complaints. In vWD, sites of bleeding generally involve mucous membrane tissue. Mucocutaneous bleeding, including epistaxis (bleeding from the nose), and easy bruising are frequently encountered as presenting complaints.

19. Most Common Types of Bleeding This slide depicts the most common types of bleeding: epistaxis, gingival bleeding and/or prolonged bleeding after dental surgery, gastrointestinal (GI) bleeding, and menorrhagia. This slide depicts the most common types of bleeding: epistaxis, gingival bleeding and/or prolonged bleeding after dental surgery, gastrointestinal (GI) bleeding, and menorrhagia.

20. Symptoms of vWD Bleeding after surgery (especially involving mucus membranes) Prolonged or excessive bleeding after dental procedures Prolonged bleeding after delivery of a baby Heavy, prolonged menstrual periods Easy, excessive bruising Nosebleeds May vary in each person from time to time, throughout life Patients are often diagnosed with vWD following postoperative bleeding, (eg, after a tonsillectomy or a dental extraction, or after an episode of postpartum hemorrhage). Menorrhagia can be severe. Frequently a hysterectomy has been performed unnecessarily. An affected individual may have symptoms that vary from time to time and throughout life. For example, for reasons that are unclear, epistaxis is far more common in children with vWD than in adults with vWD. Affected persons in the same family may have varied symptoms and varied severity of bleeding.Patients are often diagnosed with vWD following postoperative bleeding, (eg, after a tonsillectomy or a dental extraction, or after an episode of postpartum hemorrhage). Menorrhagia can be severe. Frequently a hysterectomy has been performed unnecessarily. An affected individual may have symptoms that vary from time to time and throughout life. For example, for reasons that are unclear, epistaxis is far more common in children with vWD than in adults with vWD. Affected persons in the same family may have varied symptoms and varied severity of bleeding.

21. Characteristics of Normal Menstruation Normal menstruation Occurs every 28±7 days Duration of flow 2 to 7 days Blood loss 25 to 69 mL/cycle With vWD, one or all of above can be greater, resulting in increased blood loss, iron deficient anemia vWD is often diagnosed in adolescent girls when they begin their periods. Normal menstruation occurs every 28 days (±7 days) and lasts 2 to 7 days. Blood loss is usually <70 mL/cycle (25 to 69 mL/cycle); anemia should not occur as a result of a normal period. vWD is often diagnosed in adolescent girls when they begin their periods. Normal menstruation occurs every 28 days (±7 days) and lasts 2 to 7 days. Blood loss is usually <70 mL/cycle (25 to 69 mL/cycle); anemia should not occur as a result of a normal period.

22. Characteristics of Menorrhagia Prolonged flow >7 days Blood loss >80 mL/cycle Passage of clots, flooding, staining of clothes and bedding Menorrhagia is characterized by periods that are excessive in length, ie, >7 days, or blood loss >80 mL. Other characteristics include passage of clots, flooding, or staining of clothes and bedding. Menorrhagia often causes adolescents and women to miss school and work. Menorrhagia is characterized by periods that are excessive in length, ie, >7 days, or blood loss >80 mL. Other characteristics include passage of clots, flooding, or staining of clothes and bedding. Menorrhagia often causes adolescents and women to miss school and work.

23. Incidence of Menorrhagia Incidence in women with vWD: ~65% This is >4 times higher than in women without vWD. The incidence of menorrhagia is significantly higher in women with vWD than in women without vWD. Incidence in women with vWD: ~65% Incidence in women without vWD: 9% to 14% The incidence of menorrhagia is significantly higher in women with vWD than in women without vWD. Incidence in women with vWD: ~65% Incidence in women without vWD: 9% to 14%

26. Causes of variance in Von Willebrand levels vWF levels may be increased with Exercise, stress Inflammation Pregnancy, birth control pills, hormone replacement therapy Smoking Surgery, trauma, or blood transfusion Childbirth The diagnosis of type 1 vWD, the most common form of vWD, can be problematic because of the variability of the disorder. Levels of vWF vary from day to day and can be affected by numerous factors, as indicated on this slide. Testing at any one time may yield false-positive or false-negative results due to these factors. Because vWF levels are lower in people with type O blood, a diagnosis of vWD should be made using laboratory ranges that are normal for this blood group. The diagnosis of type 1 vWD, the most common form of vWD, can be problematic because of the variability of the disorder. Levels of vWF vary from day to day and can be affected by numerous factors, as indicated on this slide. Testing at any one time may yield false-positive or false-negative results due to these factors. Because vWF levels are lower in people with type O blood, a diagnosis of vWD should be made using laboratory ranges that are normal for this blood group.

27. Causes of variance in Von Willebrand levels vWF levels may be decreased with Menstruation Hypothyroidism Blood type O

28. Inheritance of vWD Gene is carried on chromosome 12 Not sex-linked: both males and females can have the defect in the gene. Transmission is autosomal dominant or autosomal recessive Spontaneous mutations can occur, where there is no parent with the genetic defect vWD is an inherited genetic disorder. Each cell has 23 pairs of chromosomes; 22 pairs are autosomes, ie, not the sex chromosomes, and 1 pair contains the X and Y sex chromosomes. The gene for vWD is carried on chromosome 12, an autosome. Inheritance is autosomal; subsequently, the disease affects males and females equally. Transmission can be autosomal dominant or autosomal recessive. Spontaneous mutations have also been reported.vWD is an inherited genetic disorder. Each cell has 23 pairs of chromosomes; 22 pairs are autosomes, ie, not the sex chromosomes, and 1 pair contains the X and Y sex chromosomes. The gene for vWD is carried on chromosome 12, an autosome. Inheritance is autosomal; subsequently, the disease affects males and females equally. Transmission can be autosomal dominant or autosomal recessive. Spontaneous mutations have also been reported.

29. Autosomal Transmission With autosomal-dominant transmission, one parent with vWD has a 50% chance of passing vWD to each of his or her children. With autosomal-recessive transmission, both parents have vWD but are asymptomatic. This occurs less often; however, children from these unions are severely affected by vWD. It is also possible for both parents to be symptomatic and to pass vWD on in a dominant pattern. In this case, parents have a 25% chance of having a severely affected child 50% chance of having a child with vWD 25% chance of having a child unaffected by vWD With autosomal-dominant transmission, one parent with vWD has a 50% chance of passing vWD to each of his or her children. With autosomal-recessive transmission, both parents have vWD but are asymptomatic. This occurs less often; however, children from these unions are severely affected by vWD. It is also possible for both parents to be symptomatic and to pass vWD on in a dominant pattern. In this case, parents have a 25% chance of having a severely affected child 50% chance of having a child with vWD 25% chance of having a child unaffected by vWD

30. Inheritance Pattern by Type of von Willebrand Disease Type 1- autosomal dominant-one parent has vWD and each child has a 50% chance of having vWD Type 2- autosominal dominant or recessive Type 3- autosominal recessive-both parents are carriers of the gene and have a 25% chance of a child with severe type 3

31. Spontaneous Mutation Change in gene occurs during prenatal development (in womb before birth) Occurs when neither parent has vWD Future inheritance pattern will be the same as in someone with a family history of vWD Some people have vWD as a result of a spontaneous mutation, that is, a change in the gene that occurs during prenatal development. Neither of their parents will have vWD. These individuals can then pass vWD on to their children in the same way as someone with a family history of vWD.Some people have vWD as a result of a spontaneous mutation, that is, a change in the gene that occurs during prenatal development. Neither of their parents will have vWD. These individuals can then pass vWD on to their children in the same way as someone with a family history of vWD.

32. Diagnosis of vWD Personal and family history of bleeding symptoms Blood work to check von Willebrand levels and type Type 1 disease often diagnosed later in life after extensive dental work or heavy menses. Often adult parent diagnosed after child found to have the disease Unlike hemophilia A, which is usually diagnosed early in childhood, a diagnosis of vWD can be made at any age. Because of the variable clinical manifestations of vWD, it is critical to - Obtain a detailed personal and family history, including clinical and bleeding history - Perform a comprehensive physical examination for evidence of ecchymosis (hemorrhagic spots) or signs of mucosal bleeding - Order a series of laboratory screening tests Persons with vWD may have mild and easily tolerated symptoms, or they may be asymptomatic; therefore, they may not be diagnosed with the disorder until another family member (eg, a child or sibling) has been diagnosed. Unlike hemophilia A, which is usually diagnosed early in childhood, a diagnosis of vWD can be made at any age. Because of the variable clinical manifestations of vWD, it is critical to - Obtain a detailed personal and family history, including clinical and bleeding history - Perform a comprehensive physical examination for evidence of ecchymosis (hemorrhagic spots) or signs of mucosal bleeding - Order a series of laboratory screening tests Persons with vWD may have mild and easily tolerated symptoms, or they may be asymptomatic; therefore, they may not be diagnosed with the disorder until another family member (eg, a child or sibling) has been diagnosed.

33. Suggested Questions for Screening Persons for a Bleeding Disorder Do you have a blood relative who has a bleeding disorder such as von Willebrand Disease or hemophilia? Have you ever had prolonged bleeding from trivial wounds, lasting more than 15 minutes or recurring spontaneously during the 7 days after the wound? Have you ever had heavy, prolonged or recurrent bleeding after surgical procedures, such as a tonsillectomy? National Heart, Lung and Blood Institute, The Diagnosis, Evaluation and Management of von Willebrand Disease, 2007

34. Suggested Questions for Screening Persons for a Bleeding Disorder Have you ever had bruising, with minimal or no apparent trauma, especially if you could feel a lump under the bruise? Have you ever had a spontaneous nosebleed that required more than 10 minutes to stop or needed medical attention?

35. Suggested Questions for Screening Persons for a Bleeding Disorder Have you ever had heavy, prolonged or recurrent bleeding after dental extractions that required medical attention? Have you ever had bleed in your stool, unexplained by a specific anatomic lesion (such an an ulcer in the stomach or a polyp in the colon) that required medical attention? Have you ever had anemia requiring treatment or received a blood transfusion?

36. Suggested Questions for Screening Persons for a Bleeding Disorder For women, have you ever had heavy menses? Presence of clots greater than an inch in diameter Changing a pad or tampon more than hourly Resulting in anemia or low iron level

37. Other considerations Liver or kidney disease Blood or bone marrow disorder High or low platelet count Taking aspirin, NSAIDS, clopidogrel ( Plavix), warfarin or heparin

38. Treatment of vWD Treatment decision influenced by Type of vWD Severity of bleeding Minor bleeding may not require treatment The proper approach to treatment of vWD is determined by the type of vWD, the patient’s bleeding history, a specific hemorrhagic event, or a planned invasive procedure or surgery. Most patients with type 1 vWD and some with types 2A or 2M can be treated successfully with the synthetic vasopressin analog, desmopressin acetate (DDAVP). Frequently, bleeding symptoms are mild and treatment is not required other than conservative measures such as the application of ice and firm pressure at the site of bleeding. However, prompt treatment, when required, is optimal.The proper approach to treatment of vWD is determined by the type of vWD, the patient’s bleeding history, a specific hemorrhagic event, or a planned invasive procedure or surgery. Most patients with type 1 vWD and some with types 2A or 2M can be treated successfully with the synthetic vasopressin analog, desmopressin acetate (DDAVP). Frequently, bleeding symptoms are mild and treatment is not required other than conservative measures such as the application of ice and firm pressure at the site of bleeding. However, prompt treatment, when required, is optimal.

39. Recommended Treatments Desmopressin acetate ( intravenous DDAVP, intranasal Stimate) Intravenous Factor concentrates with von Willebrand factor and factor 8 in them Amicar (oral medication) Birth control pills for heavy periods

40. Intranasal Desmopressin: Stimate Intranasal DDAVP Convenient; may be administered at home or school Can be stored in refrigerator; stable at room temperature for up to 3 weeks Peak effect within 90 minutes of administration Usually causes a temporary rise in the amount of von Willebrand factor in the blood stream An intranasal form of DDAVP (Stimate), containing a high concentration (150 or 300 mcg) of desmopressin, is frequently used in the treatment of type 1 vWD. The multidose vial of Stimate offers easy administration and can be stored at home in the refrigerator. It also remains stable at room temperature for up to 3 weeks. Administration of Stimate results in a significant increase in vWF, FVIII, and vWF antigen. It may not demonstrate an increase as high as that seen with IV DDAVP. Peak effect is seen within 90 minutes of administration. A trial dose of Stimate is recommended. Pre- and post-laboratory studies will determine hemostatic efficacy. An intranasal form of DDAVP (Stimate), containing a high concentration (150 or 300 mcg) of desmopressin, is frequently used in the treatment of type 1 vWD. The multidose vial of Stimate offers easy administration and can be stored at home in the refrigerator. It also remains stable at room temperature for up to 3 weeks. Administration of Stimate results in a significant increase in vWF, FVIII, and vWF antigen. It may not demonstrate an increase as high as that seen with IV DDAVP. Peak effect is seen within 90 minutes of administration. A trial dose of Stimate is recommended. Pre- and post-laboratory studies will determine hemostatic efficacy.

41. Intranasal Desmopressin: Stimate (cont) Dose 1 spray in either nostril (one puff) if patient is less than or equal to 110 pounds (<50 kg) 1 spray in each nostril (2 puffs) if patient is greater than 110 pounds (50 kg) Stimate challenge to document if you respond with increased von Willebrand factor in the blood after a dose The dose of intranasal desmopressin acetate is determined by body weight. If weight is <110 lb (<50 kg), the patient receives one spray in either nostril If weight is >110 lb (>50 kg), the patient receives one spray in each nostril It is important to prescribe Stimate for the treatment of vWD and to write the prescription correctly. Do not confuse Stimate Nasal Spray 1.5 mg/mL with DDAVP Nasal Spray 0.1 mg/mL, which is used for nighttime enuresis and diabetes insipidus. Stimate is 15 times the dose of DDAVP nasal spray The bottles and packaging are different Neither the nasal spray nor the oral preparation of DDAVP is effective for the treatment of vWDThe dose of intranasal desmopressin acetate is determined by body weight. If weight is <110 lb (<50 kg), the patient receives one spray in either nostril If weight is >110 lb (>50 kg), the patient receives one spray in each nostril It is important to prescribe Stimate for the treatment of vWD and to write the prescription correctly. Do not confuse Stimate Nasal Spray 1.5 mg/mL with DDAVP Nasal Spray 0.1 mg/mL, which is used for nighttime enuresis and diabetes insipidus. Stimate is 15 times the dose of DDAVP nasal spray The bottles and packaging are different Neither the nasal spray nor the oral preparation of DDAVP is effective for the treatment of vWD

42. Side-effects of Stimate Fluid retention- need to decrease what you drink for 24 hours after a dose and drink fluids with sodium in them to prevent decreased blood sodium Facial flushing Headaches

43. Stimate: Desmopressin Acetate 1.5 mg/mL

44. Amicar (aminocaproic acid) Oral medication (pills or liquid) Helps keep clot from breaking down as quickly Especially good for use with dental work May be used along with Stimate or intravenous factor concentrates May cause stomach upset Do not give if blood in urine! Antifibrinolytics stabilize and prevent clot lysis. These agents may be useful in the treatment of menorrhagia, epistaxis, and oral bleeding. Antifibrinolytics may be used as stand-alone treatment or in conjunction with other treatment modalities in more severe cases. Antifibrinolytics stabilize and prevent clot lysis. These agents may be useful in the treatment of menorrhagia, epistaxis, and oral bleeding. Antifibrinolytics may be used as stand-alone treatment or in conjunction with other treatment modalities in more severe cases.

45. Treatment of Epistaxis (Nosebleeds) Treat wih Amicar and/or Stimate if orders to do so Local measures: pressure, ice Nosebleed QR powder (OTC) If bleeding not stopped after 15 to 30 minutes, especially with bilateral heavy bleeding, needs medical attention Local prevention (humidity, saline gel, neosynepherine)

46. Hormonal Therapy for vWD Treatment with estrogen increases vWF levels in type 1 vWD Birth control pills can be useful in treating heavy menstrual periods A levonorgestrel intrauterine device. This is a contraceptive device that contains progestin. It’s placed in the uterus (womb) opposing estrogen induced growth of the endometrium or lining of the uterus. Endometrial ablation for women beyond childbearing or not interested in childbearing Not effective treatment for type 2 vWD as structural defect will not be corrected Oral contraceptives may reduce menstrual blood loss and increase vWF levels in many patients with type 1 vWD. Estrogen induces the production of vWF, which is why it tends to ameliorate the bleeding associated with type 1 disease, including menorrhagia. High doses of conjugated estrogens may be required in unusually severe cases. Hormonal therapy is not effective for type 2 vWD as the structural defect will not be corrected. Developing collaborative patient/physician relationships with OB/GYNs knowledgeable in vWD would be helpful in providing optimal treatment of females with vWD and menorrhagia. vWD testing should be avoided while patients are on hormonal therapy. Oral contraceptives may reduce menstrual blood loss and increase vWF levels in many patients with type 1 vWD. Estrogen induces the production of vWF, which is why it tends to ameliorate the bleeding associated with type 1 disease, including menorrhagia. High doses of conjugated estrogens may be required in unusually severe cases. Hormonal therapy is not effective for type 2 vWD as the structural defect will not be corrected. Developing collaborative patient/physician relationships with OB/GYNs knowledgeable in vWD would be helpful in providing optimal treatment of females with vWD and menorrhagia. vWD testing should be avoided while patients are on hormonal therapy.

47. Treatment With vWF Concentrates Intravenous factor with von Willebrand factor and factor 8 in them ( Humate-P or Alphanate) vWF concentrates are used for Severe bleeding episodes and major surgeries in patients with type 1 vWD Most bleeding episodes and surgery in type 2B and type 3 vWD Bleeding in any patient with vWD who does not respond well to DDAVP (Stimate or intravenous DDAVP) If there is a severe bleeding episode or an elective major surgery, a vWF concentrate will be used instead of DDAVP to ensure adequate hemostasis. A vWF concentrate will also be used for treatment of most bleeding episodes and surgeries in patients with type 2B or type 3 vWD. In patients where DDAVP is contraindicated or who experience an inadequate hemostatic response, exogenous sources of vWF concentrate are required.If there is a severe bleeding episode or an elective major surgery, a vWF concentrate will be used instead of DDAVP to ensure adequate hemostasis. A vWF concentrate will also be used for treatment of most bleeding episodes and surgeries in patients with type 2B or type 3 vWD. In patients where DDAVP is contraindicated or who experience an inadequate hemostatic response, exogenous sources of vWF concentrate are required.

48. Treatment With vWF Concentrates (cont) vWF concentrates contain both vWF and FVIII Blood product-obtained from screened, pooled human plasma – Treated to inactivate and remove viruses Administered intravenously over several minutes Costly Certain plasma-derived FVIII concentrates are rich in both vWF:ristocetin cofactor and high molecular weight vWF multimers. vWF concentrates derived from screened, pooled human plasma are treated to inactivate and remove viruses. Viral inactivation and removal minimizes the risk of transmission of hepatitis viruses and the human immunodeficiency virus (HIV). Concentrates are labeled for their FVIII and ristocetin cofactor activity. Predictable increases in FVIII and ristocetin cofactor levels are propor-tional to the quantity infused. Currently, Humate P (Aventis Behring) is the only licensed vWF concentrate available in the United States for the treatment of vWD. Alphanate (Alpha Therapeutics) is currently pending FDA approval for this indication. These medications must be dosed using ristocetin cofactor units, not FVIII units. Cryoprecipitate is no longer the mainstay of replacement therapy for patients with vWD because it has been linked to seroconversion of recipients to hepatitis A, B, and C, and HIV.Certain plasma-derived FVIII concentrates are rich in both vWF:ristocetin cofactor and high molecular weight vWF multimers. vWF concentrates derived from screened, pooled human plasma are treated to inactivate and remove viruses. Viral inactivation and removal minimizes the risk of transmission of hepatitis viruses and the human immunodeficiency virus (HIV). Concentrates are labeled for their FVIII and ristocetin cofactor activity. Predictable increases in FVIII and ristocetin cofactor levels are propor-tional to the quantity infused. Currently, Humate P (Aventis Behring) is the only licensed vWF concentrate available in the United States for the treatment of vWD. Alphanate (Alpha Therapeutics) is currently pending FDA approval for this indication. These medications must be dosed using ristocetin cofactor units, not FVIII units. Cryoprecipitate is no longer the mainstay of replacement therapy for patients with vWD because it has been linked to seroconversion of recipients to hepatitis A, B, and C, and HIV.

49. Psychosocial Issues: Adolescent Young Women In addition to the other psychosocial issues experienced by others with vWD, young women have unique issues including: Embarrassment- Managing heavy menses and the feeling that “everyone knows” Stigma -Related to use of oral contraceptives to control menses

50. Psychosocial Issues: Adolescent Women (cont) Isolation- Feeling they are the only one dealing with disorder Intimacy & Dating- Developmental tasks faced during adolescence are challenged by dealing with issues related to disclosing medical condition Concerns about Future Health -Teens begin to think about future health, specifically pregnancy and childbirth

51. Sports and Activities Regular exercise is encouraged to maintain strong muscles and joints Avoid high-contact sports such as football, hockey, and wrestling (Type 3) Recommended sports include biking, swimming, golf, tennis, baseball, and softball As with all bleeding disorders, physical fitness is strongly recommended. Being in good physical health can help reduce the number of bleeding episodes. Participation in regular exercise and physical activities also promotes strong, healthy muscles and joints. Fitness and good health can be achieved through a variety of sports. High-contact sports are contraindicated, especially in persons with type 3 vWD. An HTC provider can make recommendations regarding appropriate activities and those that should be avoided.As with all bleeding disorders, physical fitness is strongly recommended. Being in good physical health can help reduce the number of bleeding episodes. Participation in regular exercise and physical activities also promotes strong, healthy muscles and joints. Fitness and good health can be achieved through a variety of sports. High-contact sports are contraindicated, especially in persons with type 3 vWD. An HTC provider can make recommendations regarding appropriate activities and those that should be avoided.

52. Recommendations for Patients Have regular check-ups at your HTC Avoid the frequent use of aspirin and ibuprofen medications (can effect platelet function) Call your doctor before any planned surgeries, excessive dental work or other procedures that may cause bleeding All patients with bleeding disorders should have regular checkups at their HTC. Additionally, hepatitis A and hepatitis B immunizations are recommended as these patients are at an increased risk of receiving a plasma-derived factor concentrate or blood product. Aspirin and products that contain aspirin should be avoided. Nonsteroidal anti-inflammatory drugs (many of which are marketed under multiple names) should be used sparingly as they can affect platelet function. Patients are also encouraged to wear a MedicAlert bracelet or necklace or carry a wallet ID card to ensure prompt, appropriate treatment. It is also helpful to carry a letter from the HTC when traveling that lists the patient’s diagnosis and treatment, and the names and phone numbers of the HTC staff in order to facilitate treatment, when needed.All patients with bleeding disorders should have regular checkups at their HTC. Additionally, hepatitis A and hepatitis B immunizations are recommended as these patients are at an increased risk of receiving a plasma-derived factor concentrate or blood product. Aspirin and products that contain aspirin should be avoided. Nonsteroidal anti-inflammatory drugs (many of which are marketed under multiple names) should be used sparingly as they can affect platelet function. Patients are also encouraged to wear a MedicAlert bracelet or necklace or carry a wallet ID card to ensure prompt, appropriate treatment. It is also helpful to carry a letter from the HTC when traveling that lists the patient’s diagnosis and treatment, and the names and phone numbers of the HTC staff in order to facilitate treatment, when needed.

53. School Challenges Infusions Emergency care Liability Independence from family Relating to peers Early recognition and referral

54. Strategies in School Plan for Emergency Care Early treatment of bleeds “Home treatment” at school Home health nursing for routine infusions Self-infusion at school 4. Keeping medications at school

55. Strategies in School Accountability vs. accommodation Reducing risk: Changing classes Home bound instruction Books at home BUT, kids will be kids…. Sports and school Individualized approach Type of sport, when actively bleeding or recovering, on menstrual cycle Playground Communication!

56. Summary vWD is the most common inherited bleeding disorder It affects men and women equally Diagnosis requires detailed personal and family history and blood tests Symptoms are usually mild Bleeding sites generally involve mucous membrane tissue

57. Summary In VWD, you either have low levels of a certain protein in your blood or the protein doesn't work the way it should. There are three major types of VWD: type 1, type 2, and type  3. The signs and symptoms of VWD depend on the type and severity of the disease. Many people have such mild symptoms that don't know they have the disease. VWD is almost always inherited. Parents pass the gene for the disease on to their children.

58. Summary Women with VWD also may be treated with oral contraceptives, intrauterine devices, or a procedure that destroys the lining of the uterus, thus reducing menstrual blood loss. Preventing bleeding and staying healthy are important for people with VWD. Avoid over-the-counter medicines that can affect blood clotting; Always check with your doctor before taking any medicines Wear a medical ID bracelet if you have a serious form of VWD Alert people like your dentist, pharmacist, employee health nurse, gym trainer, and sports coach of your condition.

59. Summary Treatments for VWD include medicines and therapies to replace or increase the amount of von Willebrand factor in your blood, prevent the breakdown of clots, and control heavy menstrual bleeding in women If your child has VWD that’s severe enough to pose a significant risk of bleeding, anyone who is responsible for him or her should be told about the condition. This will help them handle the situation if your child has an injury. VWD can't be cured, but it can be treated. With the right treatment, people who have VWD can lead normal, active lives.

60. Who can help with this family? HELP!!

61. Hemophilia Treatment Center Team Members Patient / Family Hematologist Nurse Social Worker Physical Therapist Orthopedist Primary Care Infectious Disease Genetics Pharmacy Dental Hepatology OB/GYN

62. Role of Hemophilia Treatment Centers State-of-the-art medical treatment for persons with hemophilia through the life span Education Research Outreach Model of comprehensive care for chronic disease

63. Community Support for Students with Bleeding Disorders: The United VA Chapter of the National Hemophilia Foundation