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Von Willebrand Disease

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Overview

Von Willebrand disease is a common blood disorder characterized by an inability of the blood to clot properly due to low levels of von Willebrand factor. 
&nbsp;

Von Willebrand disease (VWD) is an inherited bleeding disorder in which the blood doesn&#39;t clot properly. This results from low levels of von Willebrand factor (VWF) - a protein that plays a role in blood clotting. Patients commonly present with bleeding after minor trauma, easy bruising, bleeding gums, or frequent nosebleeds. However, women are often more symptomatic due to heavy menstrual bleeding. In rare cases, excessive bleeding may damage joints or internal organs, and even be fatal.

&nbsp;

Globally, an estimated 23 to 110 in 1 million people suffer from von Willebrand disease (VWD)<a href="#accordion">[2]</a>. In the United States, it is the most common bleeding disorder, affecting 1% of the population<a href="#accordion">[1]</a>. Despite the fact that both men and women can develop VWD, women are more likely to experience the symptoms due to heavy or unusual bleeding during their periods and after giving birth. According to the CDC, more than 14,600 men, women, and children received treatment for VWD between 2012 and 2016, out of which 2/3 were females<a href="#accordion">[1]</a>.

Although the exact prevalence of VWD in Pakistan remains unknown, studies conducted at tertiary care centers have reported a prevalence of 3.2-7.7% among cases of hereditary bleeding disorders<a href="#accordion">[6]</a>. According to a study conducted in Karachi, Pakistan VWD is the second most common bleeding disorder and the most common coagulation defect in females experiencing menorrhagia<a href="#accordion">[6]</a>. 
&nbsp;

Usually Von Willebrand disease is an inherited diseases but in rare cases it can be acquired i.e. not inherited from a parent.

The inherited form is divided into 3 major types - Type 1, Type 2, and Type 3. 
&nbsp;

<ul>
	<li>Type 1: This is the most prevalent type of von Willebrand disease, and is present in 60% to 80% of the diagnosed cases7. It is an autosomal dominant disease caused by low amounts of von Willebrand factor in the blood. People with Type VWD may also have low levels of another blood-clotting protein, factor VIII. Most individuals present with mild symptoms.</li>
	<li>Type 2: This type affects 15-30% of patients with VWD<a href="#accordion">[7]</a>. Although people may have normal levels of VWF, the protein does not function properly. Thus, resulting in mild to moderate symptoms. Type 2 VWD is an autosomal dominant disease. 
	&nbsp;</li>
</ul>

Depending on the specific VWF defect, Type 2 is further divided into four subtypes 2A, 2B, 2M, and 2N. Knowing one&#39;s subtype is important because each variety has a different treatment strategy<a href="#accordion">[1]</a>. 
&nbsp;

<ol>
	<li>Type 2A, the VWF does not assist the platelets to stick together and form a clot as the factor is not the right size.</li>
	<li>Type 2B is characterized by the VWF binds incorrectly to platelets, when there is no injury. The platelets attached to the VWF are removed by the body, reducing the levels of VWF and platelets in the blood. Thus, when needed to form a clot, these two are deficient.&nbsp;</li>
	<li>Type 2M, the VWF does not adhere to platelets. Thus, decreasing the platelets&rsquo; ability to form a clot when needed.</li>
	<li>Type 2N is characterized by the platelets and VWF attaching normally. However, the VWF does not bind to factor VIII. As a result, the protein factor VIII is eliminated by the body.</li>
</ol>

&nbsp;

<ul>
	<li>Type 3: This is the most serious and rare type of von Willebrand disease. It is caused by little to no VWF and low levels of Factor VIII. Thus, people will experience severe bleeding problems, such as bleeding into the joints and muscles. Approximately 5-10% of VWD patients have type 3<a href="#accordion">[7]</a>. It is an autosomal recessive disease.&nbsp; 
	&nbsp;</li>
	<li>Acquired VWD - This type of VWD most commonly results from autoimmune diseases, such as <a href="https://merisehat.pk/disease/systemic-lupus-erythematosus">lupus</a>, or malignancies (<a href="https://merisehat.pk/disease/lung-cancer-67">lung cancer</a>, Wilms tumor, <a href="https://merisehat.pk/disease/gastric-cancer">gastric cancer</a>, multiple myeloma). Certain medications can also cause acquired VWD. 
	&nbsp;</li>
</ul>

Signs and Symptoms

Normally, when a person is hurt and begins to bleed, the VWF in the blood binds to platelets. This facilitates the platelets&#39; glue-like adhesion to one another, forming a clot at the injury site which stops the bleeding. Because the VWF isn&#39;t functioning correctly in a person with VWD, the clot may develop incorrectly or slowly, and bleeding may take longer to stop. This may cause significant and severe bleeding.

Many von Willebrand disease patients have the disorder yet exhibit no symptoms or only minor ones. Moreover, the symptoms typically vary depending on the type of VWD and the severity of the disease. The following signs and symptoms can be present in those with a more severe form of the condition<a href="#accordion">[2]</a>. 
&nbsp;

<ul>
	<li><a href="https://merisehat.pk/disease/nosebleed-101-epistaxis">Epistaxis (Nosebleed)</a>: These nosebleeds occur five or more times in a year and can last longer than ten minutes. They may start spontaneously, without any injury.</li>
	<li>Bleeding: Bleeding can start from a cut or any minimal injury, which may last longer than 10 minutes.</li>
	<li>Bruises: Von Willebrand disease patients bruise frequently. Their bruises are larger than a quarter and appear elevated, giving the impression that they are inflamed. They often occur with little or no trauma or injury.</li>
	<li><a href="https://merisehat.pk/disease/iron-deficiency-anemia-64">Iron-deficiency Anemia</a>: People with VWD are typically diagnosed with iron deficiency anemia due to a low amount of red blood cells and iron in their bodies.</li>
	<li>Post-surgery Bleeding: Any operation, including dental surgery, can cause longer than normal bleeding in people with von Willebrand disease. The surgery site can bleed for longer than 2 hours after surgery. Packing or cautery may be required to stop the bleeding</li>
	<li>Heavy Menstrual Bleeding: Women with VWD experience heavy menstrual periods that require them to change their pad or tampon every 1-2 hours. Their period may last longer than 7 days and be associated with passing blood clots larger than the size of grapes or strawberries. Due to the heavy bleeding, most women are diagnosed with <a href="https://merisehat.pk/disease/anemia">anemia</a>.</li>
	<li>Heavy bleeding after childbirth or miscarriage.</li>
	<li>Blood in stool.</li>
	<li>Blood in the urine (hematuria). 
	&nbsp;</li>
</ul>

Note: If you notice blood in your stool or urine, contact a healthcare professional immediately. 
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Causes

Von Willebrand disease develops when specific genes mutate or alter. Genetic changes impair the body&#39;s capacity to produce adequate amounts of or functioning von Willebrand factor (VWF). These are proteins that assist in blood clotting. The platelets, plasma, and blood vessel walls all contain the von Willebrand factor.&nbsp; When blood arteries burst due to injury or damage, platelets aid in the formation of a blood clot.

Normally, platelets work by sticking to damaged blood vessels to form blood clots and stop the bleeding. The von Willebrand factor aids in platelet adhesion. When there are low levels or an absence of VWF, the platelets are unable to stick together and form blood clots. Thus, resulting in longer and heavier bleeding episodes. 
&nbsp;

The majority of individuals with von Willebrand disease have actually acquired a mutant gene from one of their biological parents. This inheritance pattern is autosomal dominant. One or both biological parents may pass on altered genes to their offspring. The most severe type of von Willebrand disease is inherited autosomal recessively. Two copies of the mutated gene are required for the person to develop the condition. If a person carries the mutant gene, there is a 50% chance that they will spread the mutation to their biological children.

On the other hand, acquired VWD commonly occurs as a side effect of several cancers, autoimmune conditions, heart conditions, and blood vessel problems<a href="#accordion">[2]</a>. 
&nbsp;

A combination of blood tests may be conducted to screen whether the blood is clotting correctly. These include: 
&nbsp;

<ul>
	<li>Complete Blood Count (CBC): This measures the level of red blood cells, white blood cells, platelets, and hemoglobin in the body. The majority of von Willebrand disease patients have normal platelets and white blood cells. However, low hemoglobin and red blood cell counts can occur in those who bleed exceptionally heavily.</li>
	<li>Activated Partial Thromboplastin Time Test (APTT): This test helps determine how long it takes for the blood to clot. Ir measures the clotting ability of proteins other than VWF. These include factors VIII, IX, XI, and XII. While mild cases of VWD may have normal results, other people with VWD will show a longer clotting time.</li>
	<li>Prothrombin Time (PT) Test: Similar to APTT, this test also measures how long it takes for the blood to clot. However, it measures the clotting ability of factors I, II, V, VII, and X. Most people with VWD will have normal results.</li>
	<li>Fibrinogen Test: Fibrinogen (clotting factor I) is another protein that helps blood to clot. The test is typically ordered when a patient&rsquo;s PT or APTT test result, or both are abnormal. This test is normal in people with VWD. 
	&nbsp;</li>
</ul>

However, these tests cannot determine the type of bleeding disorder present. Therefore, more specific tests are required. 
&nbsp;

Treatment

Treatment typically depends on the type of VWD and its severity. Most mild cases with minimal bleeding do not require treatment. The following treatments are most frequently used: 
&nbsp;

<ol>
	<li>Desmopressin - Patients with minor bleeding episodes, such as nosebleeds are typically administered desmopressin. It is an antidiuretic and is given when patients are not actively bleeding. It can be administered intravenously, subcutaneously, and via intranasal spray. It works by causing the body to release more VWF into the blood. Additionally, it aids in boosting the blood&#39;s level of factor VIII.</li>
</ol>

Desmopressin (DDAVP&reg;) injections are given intravenously to those with less severe types of VWD (mainly Type 1). However, since it is an antidiuretic, it can lead to water retention, leading to hyponatremia. Therefore, it is important for patients to restrict fluids while on the medications. 
&nbsp;

<ol start="2">
	<li>Factor Replacement Therapy - For the treatment of patients with more severe types of VWD or patients with milder forms of VWD who do not respond well to the nasal spray, recombinant VWF and medications rich in VWF and factor VIII are utilized. They help restore the deficient blood component. 
	&nbsp;</li>
	<li>Antifibrinolytic Drugs - Antifibrinolytic medications are given intravenously or orally to aid in slowing or preventing the dissolution of blood clots. It is commonly prescribed in people undergoing dental surgery or if someone has heavy periods. 
	&nbsp;</li>
	<li>Birth Control Pills - The estrogen in birth control pills can increase blood levels of VWF and factor VIII, which can also lessen menstrual blood loss. These tablets may be recommended to patients who experience severe menstrual bleeding<a href="#accordion">[1]</a>. 
	&nbsp;</li>
</ol>

Diagnosis

The doctor will begin by asking the patient multiple questions regarding their symptoms, severity, medical history, and whether they have a family history of bleeding disorders. Next, the doctor will order a combination of blood tests to diagnose von Willebrand disease. 
&nbsp;

<ul>
	<li>Platelet Aggregation Tests: Platelets aid in blood clotting. These tests assess the platelets&#39; ability to adhere to one another and form blood clots.</li>
	<li>Von Willebrand Factor Antigen: This test determines levels of von Willebrand factor protein in the blood. People with VWD typically have less than 50% of normal VWF in their blood.&nbsp;</li>
	<li>Ristocetin Cofactor: This testing modality assesses the von Willebrand factor activity. Levels below 30 are diagnostic for VWD. .</li>
	<li>Von Willebrand Factor Multimers: This test measures the factor&rsquo;s structure. It can help identify the type of von Willebrand disease.</li>
	<li>Factor VIII Clotting Activity:&nbsp;This measures the level of factor VIII in the blood 
	&nbsp;</li>
</ul>

&nbsp;Since the levels of VWF can vary due to pregnancy, contraceptive pills, stress, medications, and infections, these tests may need to be repeated. 
&nbsp;

In rare cases, von Willebrand disease can result in life-threatening, uncontrollable bleeding. Other complications include<a href="#accrodion">[3]</a>:

<ul>
	<li>Anemia: In women, heavy menstrual bleeding can result in iron deficiency anemia.</li>
	<li>Swelling And Pain: Atypical bleeding in the joints or soft tissue can cause swelling and pain. 
	&nbsp;</li>
</ul>

The biggest risk factor of von Willebrand disease is a family history of the condition. Children receive the mutated gene from their parents and the illness very rarely skips generations.

Since the disease usually has an autosomal dominant pattern of inheritance, a defective gene from just one parent is typically required to develop the condition. Patients with the gene mutation have a 50% probability of passing the von Willebrand disease gene to their offspring

A severe form of the disease also exists and has an autosomal recessive pattern of inheritance. It requires both parents to pass on a defective gene to their child. 
&nbsp;

While there are no known ways to prevent von Willebrand disease, genetic counseling should be offered to those with a family history of the disease. This can help couples determine whether they carry the gene for VWD and the risk of passing it to their offspring<a href="#accordion">[3]</a>. 
&nbsp;

Key Points

<ul>
	<li>Von Willebrand disease is a common blood disorder characterized by an inability of the blood to clot properly due to low levels of von Willebrand factor.</li>
	<li>Normally, when a person is hurt and begins to bleed, the VWF in the blood bonds to platelets, which are tiny blood cells. Because the VWF isn&#39;t functioning properly in a person with VWD, the clot may develop incorrectly or slowly, and bleeding may take longer to stop.</li>
	<li>Patients commonly present with bleeding after minor trauma, easy bruising, bleeding gums, or frequent nosebleeds. However, women are often more symptomatic due to heavy menstrual bleeding.</li>
	<li>Globally, an estimated 23 to 110 in 1 million people suffer from von Willebrand disease (VWD). In the United States, it is the most common bleeding disorder, affecting 1% of the population</li>
	<li>The most prevalent kind of von Willebrand disease is type 1 which includes 60% to 80% of the diagnosed cases.</li>
	<li>Von Willebrand factor malfunctions in Type 2 patients. People who have this type may bleed lightly or moderately. Type 2 is further divided into four subtypes 2A, 2B, 2M, and 2N.</li>
	<li>In Type 2A, the VWF is too small and does not assist in the platelets&#39; ability to stick to one another and form a clot. The VWF binds incorrectly to platelets in Type 2B. In Type 2M, the capability of the platelets to form a clot is reduced. The VWF generally attaches to the platelets in Type 2N. However, the VWF does not bind to Factor VIII, another protein required for blood clotting.</li>
	<li>The most serious type of von Willebrand disease is type 3. It affects 5% to 10% of those who have the condition, making it the rarest kind.</li>
	<li>In order to screen a patient for bleeding disorders, the doctor might order a CBC, APTT test, PT, and fibrinogen test.</li>
	<li>To confirm the diagnosis, additional tests such as platelet aggregation test, VWF antigen, factor VIII clotting activity, and VWF activity are conducted.&nbsp;&nbsp;</li>
	<li>Treatment depends on the type and severity of the disease. Desmopressin is often the first treatment for the management of VWD. It can be used before minor procedures, such as dental surgery.&nbsp;</li>
	<li>For the treatment of patients with more severe types of VWD or patients with milder forms of VWD who do not respond well to the nasal spray, recombinant VWF and medications rich in VWF and factor VIII are utilized.</li>
	<li>Rarely, von Willebrand disease can result in life-threatening, uncontrollable bleeding. Other von Willebrand disease complications include anemia and joint pain.</li>
	<li>A family history of VWD or other bleeding disorders is a risk factor for the condition. 
	&nbsp;</li>
</ul>

[1] What is von willebrand disease? (2022) Centers for Disease Control and Prevention. Centers for Disease Control and Prevention.

[2] Von Willebrand disease: What it is, types, symptoms & treatment (no date) Cleveland Clinic.

[3] Von Willebrand disease (2021) Mayo Clinic. Mayo Foundation for Medical Education and Research.

[4] Henderson, R.by E. (2022) Blood clotting protein found to play a new role in repairing damaged blood vessels, News.

[5] Sabih A, Babiker HM. Von Willebrand Disease. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[6] Borhany M, Shamsi T, Naz A, et al. Clinical features and types of von Willebrand disease in Karachi. Clin Appl Thromb Hemost. 2011;17(6):E102-E105. doi:10.1177/1076029610387125.