Women who bleed: recognizing a common genetic disorder Heavy menstruation, pejoratively called the curse, can be a blessing, revealing the presence of a common and treatable genetic defect in blood clotting, Von Willebrand disease In the Three Little Bears Mama and Papa bear always had things too hot, too cold, too big or too small; baby bear had it just right. When it comes to the clotting of blood we want to be like baby bear and have just enough hemostasis so we don’t bleed but not so much that we clot (a process called thrombosis). Thrombotic disorders, such as pulmonary embolism, stroke and myocardial infarction, are prevalent. Consequently, most of our focus, as physicians, and most of our medical therapies are anticoagulants, intended to prevent the aggregation of platelets and/or the formation of thrombus. We inhibit platelets, using aspirin and clopidigrel, block the coagulation system using inhibitors of thrombin (direct-dabigitran, indirect-heparin) or factor 10 (rivoroxaban) and lyse existing clots using tissue plasminogen activator (tPA). However, for an estimated 35,000 Canadian the problem is not clotting it is bleeding. They have inherited disorders that cause them to bleed excessively. For them, the first challenge is achieving a diagnosis. Diagnosis relies on education of the public and general practitioners to recognize the common signs of a bleeding disorder. Fortunately, once diagnosed therapies exist, although this requires the expertise of a special type of physician, a haematologist or “bleeder”. At Queen’s University, we are fortunate to have Dr. Paula James, a hematologist who specializes in the diagnosis and management of people with bleeding disorders. Visit her website to learn more and also listen to an excellent interview she recently gave on VWD and women who bleed to CTV. There are many bleeding disorders and each presents in its own way. Haemophilia is the best known because it has afflicted the rich and famous (transmitted from Queen Victoria of England to the family Tsar Nicholas of Russia). Haemophilia is an X-linked disease occurring primarily in men, that presents in its most severe form with bleeding into joints and muscles in patients. Women carry the mutation in one of their genes encoding factor VIII or IX and have historically been considered to be unaffected. Recent work has shown however, that up to 30% have low coagulation factor levels from skewed X inactivation, and that even carriers with normal factor levels can have abnormal bleeding. Men having only one X chromosome get the disease whenever they are dealt the mutated gene However, while haemophilia has royal roots, the most common bleeding disorder is von Willebrand disease (VWD). VWD is named after Dr. Erik von Willebrand, a Finnish physician who described the syndrome in 1926. In 1925 von Willebrand examined a 5- year old girl named Hjordis. Hjordis lived in a village on the Äland islands. Both her parents came from families where abnormal bleeding was common. Four of her siblings had died from uncontrolled bleeding as children. Dr. von Willebrand travelled to the Äland islands to study the family. His careful genetic history revealed 23 of 66 family members had bleeding problems. Intriguingly, he noted more women than men were affected. Over the next 90 years VWD has come to be recognized as a bleeding disorder characterized by a lifelong tendency toward easy bruising, frequent epistaxis (nose bleeds), menorrhagia (heavy menstrual periods) post-partum bleeding and in its most severe forms, bleeding into muscles and joints. Although initially confused with haemophilia, VWD was eventually discovered to be due to mutations in the von Willebrand factor (VWF) gene in most cases. This encodes VWF, a large, multimeric glycoprotein that binds platelets to components of the blood vessel wall that lie below the normal endothelial cell lining. In this manner, VWF normally promotes formation of a clot at the site of endothelial injury.
Dr. von Willebrand
Historical prevalence studies reported that the disease affects ~ 1 percent of the population (as assessed by laboratory screening) although only 1 percent of those with an abnormal blood tests have symptoms. VWD is transmitted as an autosomal dominant trait, which means the chance of inheriting it from an affected parent, is 50/50 and that, unlike haemophilia, both males and females are affected. However, women have a unique challenge in that their lives inherently involve bleeding. Menstruation and childbirth both demand an effective means of terminating the blood loss. It is this failure to control bleeding during menstruation or childbirth that offers a clue to VWD. Menorrhagia (heavy or prolonged menses) or peripartum haemorrhage (bleeding occurring in large amounts or late after childbirth) are signs of VWD that are all too often overlooked. Dr. James has highlighted that women and their physicians need to be recognize that menorrhagia and peripartum haemorrhage may well be due to VWD. By considering this diagnosis, testing can reveal (or eliminate) the diagnosis, thereby sparing the woman a life of anemia (low haemoglobin due to iron deficiency) and the embarrassing and debilitating bleeding consequences of excessive menstrual bleeding. A diagnosis of VWD with appropriate therapy may obviate the need for hysterectomy or reduce the risk of surgery should it be necessary. The diagnosis of VWD is also important to permit a safe delivery of the baby. To enhance public awareness that excessive bleeding during menstrual periods could be due to an underlying bleeding disorder Dr. James and her team have developed a simple, self-administered bleeding assessment tool (Self- BAT). This is a test that I encourage all women who have concerns about heavy bleeding to take. It will help inform people about their bleeding and guide them toward the help they need. Dr. James advises women who have the following attributes need to talk to their doctor about being assessed for VWD. Diagnosis and Therapy: For most physicians (and patients) the key is get to the point of a suspected diagnosis. At this point they can be referred to a specialist, such as Dr. James. However, the diagnostic testing and therapy are summarized below. It is important to keep in mind that there are 3 types of VWD and therapy should involve a specialized hematologist. Although this blog focuses on women men also bleed excessively (usually with surgery or trauma or with nose bleeds). In addition a diagnosis requires the following blood tests. Plasma VWF antigen: as measured by ELISA. An abnormal result is a low level of antigen. If VWF activity and/or antigen level of < 30 international units/dL establishes a diagnosis of VWD Plasma VWF activity: as measured by either the VWF:RCo or VWF:G1bM which both reflect the ability of VWF to bind and aggregate platelets Factor VIII activity: because VWF normally protects factor VIII from degradation factor VIII levels can be low in VWD Therapy: Treatments include the combined oral contraceptive pill, tranexamic acid, desmopressin and VWF replacement therapy. Gynecologic options for the management of heavy menstrual bleeding include the Mirena IUD, an endometrial ablation or hysterectomy. To refer a women who bleeds excessively to Dr. James: Known or suspected patients can be referred to Dr. Paula James, tel: 613-533-6329, FAX: 613-533-6855 and appropriate patients will be followed in the monthly Women and Bleeding Disorders Clinic jointly attended by Hematology (Dr. James) and Gynecology (Dr. Mary Anne Jamieson). Pediatric patients are also managed in this clinic by Dr. Mariana Silva.
Images of VWF in blood outgrowth endothelial cells
Dr James has provided a nice image showing VWF (in green) in a normal endothelial derived cell on left) vs a VWD patient on right. In closing, Dr. James’s recently launched website, Let's Talk Period has had already had 1200 hits in its first week and 240 people have taken the Self-BAT!