1. Potpourri of bleeding disorders Kimo C. Stine, MD Professor of Pediatrics UAMS Medical Director of the Arkansas Center for Bleeding Disorders and Thrombosis

2. The Cascade http://pharmacologycorner.com/coagulation- cascade/

3. The Cascade VWF facilitates the adhesion of activated platelets to the injured vessel wall (primary hemostasis) FVIII and FIX are vital in the thrombin generation process (secondary hemostasis) stabilization propagation amplification initiation

4. Hemophilia Inheritance is X-linked Symptomatic carriers –Women with symptoms related to low factor levels Spontaneous mutations do occur Mandatory carriers versus possible carriers Genotyping

5. Symptoms of bleeding disorders Hemophilia easy bruising, joint swelling due to bleeds, easy or prolonged bleeding with dental procedures, excessive bleeding with minor procedures VWD easy bruising, epistaxis, prolonged oral bleeding, excessive bleeding with minor procedures, GI bleeding, lack of joint involvement except in Type 3 patients.

6. Dysmenorrhagia Definition is patient or family dependent –In other words what is a normal period or normal amount of blood loss with menses –Severe enough to cause some women to undergo hysterectomies

7. VWD types? VWD can be caused by a quantitative or qualitative defect of VWF 1 Quantitative defects Type 1 –Any degree of reduced levels of VWF (most common and usually the mildest form) Type 3 –Virtual absence of VWF (the most severe form, only occurring in 1 to 3 persons per million) 1 Qualitative defects Type 2 –Divided into 4 subgroups (2A, 2B, 2M, and 2N) 1

8. Assessment process for VWD requires a thorough personal and family history The importance of family and personal bleeding history when evaluating patients with suspected VWD: –Probe patient regarding personal and family history of bleeding that required medical attention during/after surgery, during dental procedures, with trauma, or during childbirth or heavy menses –Focus on personal history of excessive bleeding including spontaneity, severity, duration, and site of the bleed; ease with which it could be stopped; type of injury associated with the episode; and concurrent medications at time of the bleed (eg, NSAIDs, Plavix ®, warfarin, or heparin)

10. Additional probes: –Spontaneous nosebleed that persisted for 10 minutes or needed medical attention –Prolonged bleeding (duration of 15 minutes or spontaneous recurrence within 7 days) from minor wounds –Easy bruising with minimal trauma, with a lump under the bruise –Anemia requiring treatment or blood transfusion There is currently no standardized questionnaire for the assessment of VWD, making the diagnosis process of this complex disorder even more difficult

11. VWF has different functions in the hemostatic process, requiring multiple lab tests for diagnosis Specialized testing required, involving: –Measuring a person’s level and activity of VWF and factor VIII –Further evaluations to determine if the disorder is due to a deficiency, an abnormality of the protein affecting function, or both

12. Women typically experience several obstetric and gynecological complications as a result of bleeding disorders Women of childbearing age with VWD may be affected by 1,2 : Menorrhagia Bleeding complications during and after pregnancy Increased risk of miscarriage Hemorrhagic cysts Postpartum hemorrhage Endometriosis Hysterectomy at an early age

13. Most common manifestation of a bleeding disorder in women 1 Studies over the past decade indicate that 5%– 32% of menorrhagia sufferers have a bleeding disorder 1,2 Bleeding disorders tend to be overlooked as an underlying cause of menorrhagia 3

14. Defined as loss of >80 cc of blood per cycle 1 May result in iron deficiency anemia –1 mg iron lost per cc of blood Patient recall/report –Menorrhagia since menarche in 65% of women with VWD 1 Pictorial blood assessment chart (PBAC) –PBAC score greater than 100 in 74% of women with VWD 2

15. Pictorial Blood Assessment Chart (PBAC) for Assessment of Menstrual Blood Loss

16. Menorrhagia may indicate a bleeding disorder, especially in these circumstances 1 : –For acute adolescent menorrhagia requiring hospitalization –When pelvic pathology has been excluded –If hormonal treatment has failed Contraceptives or hormone therapy may be ineffective in treating some cases of menorrhagia

17. A history of endometriosis was reported in 30% of the VWD patients compared with 13% in the control group Endometriosis –May result from retrograde menstruation Possible explanations for the increased prevalence of endometriosis in VWD patients include: –Heavier menses resulting in more retrograde menstruation, –A greater likelihood of symptomatic bleeding from extra-uterine endometrial implants, and, –Because VWD patients are more likely to experience intra-peritoneal bleeding, a greater likelihood of a misdiagnosis of endometriosis

18. Antepartum management: VWF and FVIII levels increase significantly beginning at the end of the first trimester, but often drop to below baseline after delivery 1 –It is recommended that levels be obtained in the third trimester to prepare for delivery 2 Postpartum management: VWF and FVIII levels rapidly fall after delivery, putting women with VWD at increased risk of primary (first 24 hours) and secondary (24 hours to 6 weeks) postpartum hemorrhage 3 –Monitoring of VWF and FVIII levels post-delivery is recommended –Current studies are underway evaluating VWF levels postpartum

19. The mainstay of treatment is replacing the missing VWF 1 Non-replacement therapy –Use of desmopressin to increase plasma concentration of VWF by stimulating the release of the protein stored in endothelial cells 2 –Oral contraceptives and the levonorgestrel-releasing intrauterine system 2 Replacement therapy –Plasma-derived, virus-inactivated VWF concentrates to replace the missing factor 2 Supplemental therapies –Antifibrinolytics such as aminocaproic acid and tranexamic acid to help stabilize clots that have formed 2

20. A Public Health Concern— Bleeding disorder prevalence in the US population –von Willebrand disease (VWD), the most common bleeding disorder, is found in 1%–2% of the population affecting men and women equally 1 –Hemophilia, another well-known bleeding disorder, affects about one in every 5,000 males 1,2 An estimated 2.5 million women in the US may unknowingly have a bleeding disorder 3 References: 1. Centers for Disease Control and Prevention. Bleeding disorders. Available at: http://www.cdc.gov/ncbddd/hbd/hemophilia.htm. Accessed July 15, 2008. 2. National Hemophilia Foundation. Hemophilia A (factor VIII deficiency). Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=179&contentid =45&rptname=bleeding. Accessed July 9, 2008. 3. The National Women’s Health Information Center. US Department of Health and Human Services. womenshealth.gov: bleeding disorders. Available at: http://www.womenshealth.gov/faq/bleed.htm. Accessed July 16, 2008

21. The Diagnosis, Evaluation, and Management of von Willebrand disease—February 2008 1 The National Heart, Lung, and Blood Institute has developed extensive guidelines that will help healthcare professionals learn more about VWD –Because of the complexity in diagnosing and treating this disorder, the NHLBI was urged by Congress to develop a set of treatment guidelines –An expert panel of scientists and physicians (hematology, family medicine, OB/GYN) helped develop these guidelines Reference: 1. National Heart, Lung, and Blood Institute. Full report: The diagnosis, evaluation, and management of von Willebrand disease. December 2007. Available at: http://www.nhlbi.nih.gov.

22. Your Vital Role in Bleeding Disorder Diagnosis Women with bleeding disorders appear to be more severely affected by obstetric and gynecologic conditions associated with bleeding 1 Bleeding disorders can be especially difficult to diagnose in women, as symptoms may be attributed to other causes or go unexplained 2,3 Undiagnosed bleeding disorders can lead to –Unnecessary medical procedures, prolonged bleeding, joint damage, and anemia 4 –Reduced quality of life and days away from school or work 5 Consultation with an HTC may be a patient’s best opportunity to obtain proper diagnosis and treatment

23. References: 1. James AH. More than menorrhagia: a review of the obstetric and gynaecological manifestations of bleeding disorders. Haemophilia. 2005;11:295–307. 2. The National Women’s Health Information Center. US Department of Health and Human Services. womenshealth.gov: bleeding disorders. Available at: http://www.womenshealth.gov/faq/bleed.htm. Accessed July 16, 2008. 3. National Hemophilia Foundation. Bleeding disorders and women. Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=192&c ontentid=20&rptname=bleeding. Accessed July 9, 2008. 4. National Hemophilia Foundation. What is a bleeding disorder. Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=26&co ntentid=5&rptname=bleeding. Accessed July 9, 2008. 5. James AH, Kouides PA, Abdul-Kadir R, et al. von Willebrand disease and other bleeding disorders in women: Consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. 2009;201:12.e1-8.

24. Other deficiencies of clotting factors Factor X Factor V Factor XI Factor XII Factor XIII

26. Factor V deficiency Parahemophilia Mild to moderate bleeding disorder Autosomal Mucocutaneous bleeding and hematomas Rare hemarthrosis Menorrhagia may occur Both PT and APTT prolonged Combined deficiency with Factor VIII:due to abnormal chaperone protein from ER to Golgi apparatus

28. Factor X deficiency Rare autosomal Mucocutaneous and post-traumatic bleeding Prolonged PT and APTT Associated with amyloidosis in adult patients due to absorption of Factor X

30. Factor VII 1 in 500,000 Autosomal recessive Severe deficiency may result in hemarthrosis Neonates may have ICH Prolonged PT and normal APTT

32. Factor XI deficiency Autosomal recessive Prolonged PTT and norma PT More common in Ashkenazi (1-3 per 1000 Ashkenazi in Israel) Hemophilia C: bleeding usually associated with surgery or trauma Mucocutaneous bleeding or menorrhagia

33. Factor XII or contact factor deficiencies Very prolonged APTT with normal PTT NO BLEEDING

35. Factor XIII deficiency Clot stabilization by cross-linking of fibrin Deficiency associated with reduced clot stability Autosomal recessive Delayed hemorrhage Delayed separation of the umbilical stump Intracranial hemorrhage with little or no ttrauma, poor wound healing, recurrent spontaneous abortions Normal PT, aPTT, TT Increased solubility of clot

36. Hemophilia Treatment Center (HTC)— Overview Specialty clinic that provides comprehensive healthcare to those with bleeding disorders Approximately 140 government-funded centers are part of the Centers for Disease Control and Prevention (CDC) network 1 Team of hematologists, nurses, and other healthcare professionals from several disciplines

37. HTC Role in Patient Care Diagnosis Treatment plan development and follow-up (in conjunction with other outside healthcare professionals and primary care providers) Emotional support Community outreach and education Clinical research Data surveillance and collection for the Universal Data Collection project, a system established by the CDC to monitor blood safety and research healthcare outcomes 1 Reference: 1. Centers for Disease Control and Prevention. Bleeding and clotting disorders in women. Available at: http://www.cdc.gov/ncbddd/hbd/women.htm. Accessed July 9, 2008

38. Healthcare professionals –www.nhlbi.nih.gov –www.cdc.gov –www.signsofbleeding.com Patients –www.projectredflag.org –www.AllAboutBleeding-us.com –www.hemophilia.org