Von Willebrand Disease - Classification, Causes, Symptoms, Diagnosis, and Treatment

What Is Von Willebrand Disease?

Von Willebrand disease is a bleeding disorder characterized by the quantitative and qualitative defects in Von Willebrand’s factor. It is the most common inherited bleeding disorder; it can also be acquired.

Von Willebrand was introduced by the scientist Erick Adolf Von Willebrand in 1926.

What Is the Von Willebrand Factor?

The Von Willebrand factor is a protein synthesized and stored by the endothelium of damaged blood vessels and megakaryocytes; its synthesis is regulated by the Von Willebrand factor gene located on the short arm of chromosome 12, which is responsible for the adherence of platelets and also leads to the survival and maintenance of factor VIII (antihemophilic factor) in plasma.

Von Willebrand factor helps in both the primary and secondary stages of hemostasis because the element used to support the platelets adheres and helps factor VIII in the intrinsic coagulation cascade, respectively.

Deficiency of the Von Willebrand factor leads to prolonged bleeding time as well as prolonged partial prothrombin time.

What Is the Function of the Von Willebrand Factor?

• The Von Willebrand factor functions as a protein that binds to the surface of glycoprotein 1b (GP1b), to which the platelets get attached.

• At the time of bleeding injury to the blood vessels, histamine and thrombin stimulates the endothelial cells and megakaryocytes to release the Von Willebrand factor into the bloodstream.

• As it releases, it gets attached to the exposed collagen fibers at the site of injured blood vessels, which tend to bind with the platelet receptors through glycoprotein 1b (Gp1b). This leads to the adhesion of platelets and the formation of a fibrin mesh resulting in clot formation.

• In addition, the Von Willebrand factor also carries the clotting factor VIII (antihemophilic factor). Factor VIII (antihemophilic factor) plays a significant role in blood clot formation.

• Factor VIII (antihemophilic factor) must bind with the Von Willebrand factor because it is protected from early degradation by proteins C and S.

• The presence of protein C and protein S can remove factor VII (antihemophilic factor) from circulation.

What Is the Structure of the Von Willebrand Factor?

The Von Willebrand is a monomer structure produced by the endothelial cells and megakaryocytes; these monomers bind with other monomers forming dimers through cellular manipulation. Multiplication of dimers leads to the formation of multimers. These multimers are the functional state of the factor. High molecular weight Von Willebrand factor multimers are highly active and stable.

What Are the Causes of Von Willebrand's Disease?

• The Von Willebrand Disease is caused by the mutation of the Von Willebrand gene, which is genetically transferred.

• It can be acquired with the symptoms of the disease.

What Is the Classification of the Von Willebrand Disease?

The Von Willebrand Disease can be classified into two types -

Inherited Von Willebrand Disease -

Inherited Von Willebrand Disease is defined as a genetically transferred disorder due to

the mutation of the Von Willebrand gene.

It is classified into three main types -

Type I -

The Von Willebrand disease type I is the most common, affecting 75% of all the cases.

The autosomal dominant meaning characterizes that the mutation is present only on one allele resulting in insufficient or even defective production of the Von Willebrand factor in the bloodstream. It is also characterized by reduced Von Willebrand factor and its activity with reduction of factor VII (Antihemophilic factor).

Type II -

In Von Willebrand disease type II, the quantity of the factor is regular, but the quality gets affected.

Type II is divided into four subtypes -

• Type II-A.

• Type II-B.

• Type II-M.

• Type II-N.

• In Type II-A and Type II-M, the Von Willebrand factor attaches to sub-endothelial collagen and binds with factor VII (antihemophilic factor). Still, it cannot adhere to the platelets to form a plug at the site of injury needed to stop the bleeding vessel.

• In Type II-B, the Von Willebrand factor binds to the platelets, flowing in the bloodstream everywhere, anywhere in the blood vessel, even when there is no injury. This causes large bundles of platelets in the bloodstream, which are taken up by the spleen and liver, resulting in a low platelet count.

• In Type II-N, the Von Willebrand factors bind with both subendothelial collagen and platelets but cannot bind with factor VIII (antihemophilic factor). So factor VIII (antihemophilic factor) gets degraded by proteins C and S, causing its low level in the bloodstream and increasing the risk of bleeding.

Type III -

In Von Willebrand, disease type III refers to the rarest and most severe kind of disorder. It is an autosomal recessive disorder meaning both alleles must be defective. Because both alleles are deficient, there is no presence of the Von Willebrand factor in the bloodstream. This also leads to a deficiency of factor VIII (antihemophilic factor).

Acquired Von Willebrand Disease -

Acquired Von Willebrand Disease refers to normal genes but the presence of symptoms.

This can happen due to other physiological diseases and some autoimmune disorders.

It can also be caused by some adverse effects of medications affecting the synthesis of the factor, such as - Valproic Acid and Ciprofloxacin.

What Are the Signs And Symptoms of Von Willebrand Disease?

The signs and symptoms of Von Willebrand disease are as follows -

1. Epistaxis (prolonged and frequent nose bleeding).

2. Heavy menstrual cycle.

3. Easy and dark-colored bruise.

4. Prolonged bleeding after or no injury.

5. Blood in stool and urine.

6. Bleeding gums.

What Are the Investigations for Von Willebrand Disease?

The following investigation can diagnose Von Willebrand Disease -

1. Complete blood count.

2. Bleeding time.

3. Clotting time.

4. Prothrombin time.

5. Partial prothrombin time.

6. D- dimer.

7. Thrombin time.

How to Diagnose Von Willebrand's Disease?

1. The Von Willebrand disease can be diagnosed by studying personal and family history.

2. Repeating blood investigations.

3. Looking for dark-colored bruises over the skin.

4. Most of the time, the disease is inherited. Recording family history for bleeding disorders is very important.

What Is the Treatment for Von Willebrand Disease?

The treatment planning for Von Willebrand Disease is done based on the severity. For example, some mild bleeding problems do not need any treatment.

1. Desmopressin - It is a manufactured hormone injected into the body or inhaled by nasal sprays. This treatment is advised for patients suffering from mild symptoms. Injection of Desmopressin into the body releases stored Von Willebrand factor and clotting factor VIII (antihemophilic factor), resulting in coagulation.

2. Factor Replacement Therapy - A concentration of Von Willebrand factor and Factor VIII (antihemophilic factor) is injected into the vein and replaces the missing Von Willebrand factor.

3. Oral Contraceptive - It is a hormonal therapy for females suffering from heavy menstrual bleeding. Oral contraceptives increase the Von Willebrand factor and factor VIII (antihemophilic factor) and stop the bleeding.

4. Antifibrinolytic Therapy - Agents like fibrin and thrombin are placed at the injury site to enhance blood clot formation.

5. Other Drugs - Such as Tranexamic Acid and Aminocaproic acid, can also be used.

Conclusion-

Suffering from a bleeding disorder with mild symptoms does not affect the lifestyle. Therefore, it can be taken care of without any treatment. However, patients with severe symptoms need to take proper precautions and treatment. Before going for minor surgery and dental treatment, a patient should inform the healthcare practitioner about the bleeding history to plan the treatment accordingly.