Inherited von Willebrand Disease : The most common yet unheard bleeding disorder
ADITI SHIRODKAR
THADOMAL SHAHANI ENGINEERING COLLEGE
shirodkaran@gmail.com
Whenever we think about inherited bleeding disorders, the only one that strikes our mind is haemophilia. However, almost 1% of the world’s population (with more than 1 million cases per year in India) is affected by von Willebrand disease which is the most common bleeding disorder in the world. Von Willebrand disease is a lifelong bleeding disorder in which the blood doesn’t clot well due to a decrease in plasma levels or defect in von Willebrand factor (VWF). VWF is a large multimeric glycoprotein that performs primary functions like binding to other proteins (for e.g. factor VIII) and is important for platelet adhesion at wound sites and platelet aggregation under high shear conditions. Gene mutations in the VWF gene are responsible for either reduced production of VWF or the production of an abnormally functioning VWF. Although the cause of these mutations is unknown, it is observed that the majority of cases of VWD are inherited.
In some cases, it can be acquired later in life. Acquired von Willebrand disease can occur in individuals who have lymphoproliferative disease including multiple myeloma; cardiac defects, myeloproliferative disorders including essential thrombocythemia; certain forms of cancer; autoimmune diseases; diabetes mellitus; and exposure to certain drugs such as valproic acid. However, in this article, we will be discussing the inherited VWD types. Most common symptoms experienced by the affected individuals include recurrent and prolonged nosebleeds, gum bleeding, easy bruising, increased menstrual flow in women and, excessive bleeding from cuts.
VWD Types and Treatment
| VWD Types | Type I VWD | Type II VWD | Type III VWD |
| Occurrence | common | moderate | rare |
| Subtypes | – | Type 2A,2B,2M,2N | – |
| Inheritance pattern | Autosomal dominant | Autosomal dominant(2A,2B,2M), Autosomal recessive(2N) | Autosomal recessive |
| VWF alterations | no defects in the VWF but amounts are not sufficient to control the bleeding | Type 2A: defects in the size of the VWF multimers which stop the platelets from making a good platelet plug
Type 2B: VWF multimers become too active and attach to the platelets in the blood causing the body to quickly get rid of the VWF attached platelets and leads to a shortage of the two. Type 2M: VWF is not able to stick to the platelets and a proper platelet plug cannot be formed. Type 2N: VWF is unable to do its job as the carrier and fails to protect factor VIII
|
little to no presence of VWF in the blood |
| Symptoms | mild mucocutaneous bleeding, menorrhagia, epistaxis, or prolonged bleeding after trauma or surgical intervention. | Type 2A,2B,2M: mild to moderate mucocutaneous bleeding.
Type 2N: similar symptoms as mild haemophilia A which includes excessive bleeding at the time of surgery. |
mucocutaneous hemorrhage like epistaxis, postpartum hemorrhage, gastrointestinal bleeding, etc, and prolonged bleeding after surgical interventions |
| FVIII levels and their effects | low levels of FVIII observed owing to lesser quantities of VWF to protect the protein. | low levels of FVIII cause trouble to make a fibrin clot | severe FVIII deficiency, causing hematomas and hemarthrosis. |
| Treatment | Tranexamic acid for ENT (ear, nose, and throat) bleeding, estrogen-progesterone treatment for menorrhagia, Desmopressin (releases endogenous VWF stored in the epithelial cells),
Substitution therapy with purified human VWF (in case of major bleeding) |
Desmopressin (depends on type 2 subtype, contraindicated in patients with subtype 2B), Substitution therapy with purified human VWF (in case of abnormal bleeding events)
|
Substitution therapy with purified human VWF(associated with FVIII for 1st injection), long term prophylactic treatment with regular injections of purified human VWF(for patients with recurrent bleeding), continuous infusion of recombinant factor VIII or recombinant activated factor VII in patients who develop alloantibodies against VWF, emicizumab in immunised type 3 patients. |
The diagnosis and subclassification of VWD is still a great challenge, however, the pathogenesis mechanisms of VWD have become clear. For example, a self-administered bleeding assessment tool (BAT) for adults and pediatric populations is now a part of validated BAT options. The limitations of the ristocetin cofactor activity assay which is a traditionally used method of testing von Willebrand factor (VWF) function and assessing VWF collagen binding can now be overcome owing to new laboratory assays.
The first recombinant human VWF concentrate (rVWF; brand name Vonvendi® in the United States) was approved by FDA for the treatment of bleeding episodes in patients with VWD in 2015 and treatment of adult patients in 2018. According to the phase 3 trial published in 2015 in Blood, a single infusion of rVWF managed bleeding in 81.8% of 192 bleeding episodes among 22 patients with severe VWD. Hemostatic efficacy in 97% of these cases was considered excellent. A phase 3 trial, demonstrating the efficacy of rVWF to prevent bleeding in patients with severe VWD undergoing elective surgery was published in the Journal of Thrombosis and Haemostasis in 2019 and the safety profiles of rVWF are favorable according to the available evidence.
Apart from this, the prevention of VWD can be done by genetic testing. Due to developments in genetic screening and counseling services, patients can be informed about the risk of passing on the disease to the next generation, its severity, and other associated complications which can help them improve the quality of their lives.
Reference (Jun-21-A9)
Author Biography: I am Aditi Shirodkar and I am currently in my final year of BE Biotechnology Engineering. I wish to pursue my Master’s in Genetic Counselling and help the patients to understand the complications and risk factors about their genetic conditions.
