Von Willebrand disease

Von Willebrand disease, named after Finnish doctor Erik Adolf Von Willebrand, who first described the condition, is a bleeding condition associated with either a low amount or poor quality of von Willebrand factor.

Imagine you are repotting a cactus and a spine pricks you, damaging the tiny blood vessels in your fingertip. As a result, the body triggers primary hemostasis, which is a well-coordinated process that stops bleeding. This injury exposes the collagen in the blood vessel wall, which is rich in von Willebrand factor, and triggers local endothelial cells to release more von Willebrand factor into circulation.

Once released, the von Willebrand factor sticks to the damaged area and acts like glue, providing a foundation for platelet attachment. Circulating platelets use their glycoprotein IIb receptors to bind this glue-like substance, triggering their activation. They change shape and extend tentacle-like arms to grab onto nearby platelets. Once activated, they release more Von Willebrand factor, along with serotonin and calcium.

Platelets also release adenosine diphosphate and thromboxane A2, which together activate other platelets that haven’t bound the Von Willebrand factor. These two substances also spark platelets to express new surface proteins called GPIIB/IIIA. Acting like hooks, these proteins enable platelets to catch fibrinogen, which acts like a pair of handcuffs, linking two platelets together. Eventually, this results in a snowball effect, with more platelets piling up, creating a plug that seals the injury.

Once the body creates the platelet plug, it triggers secondary hemostasis to reinforce the clot with a strong fibrin mesh. This process involves the extrinsic and intrinsic coagulation pathways, which ultimately converge into the common coagulation pathway.

In the extrinsic pathway, blood vessel injury exposes factor III, also known as tissue factor, which activates factor VII. Next, activated tissue factor, activated factor VII, and calcium come together to activate factor X, eventually triggering the common pathway.

Activated factor X joins forces with factor V and calcium to form the prothrombinase complex, which converts factor II called prothrombin into activated factor II called thrombin. Next, thrombin converts factor I, known as fibrinogen, into activated factor I called fibrin. Finally, thrombin activates factor XIII, which binds calcium to create fibrin crosslinks to stabilize the clot.

On the flip side, the intrinsic pathway begins when collagen of the blood vessel wall activates factor XII, also known as the Hageman factor. Activated factor XII activates factor XI, which, with the help of calcium, activates factor IX.

Next, let’s focus on factor VIII, which circulates through the bloodstream bound to the von Willebrand factor. Think of the von Willebrand factor as a protective shield, guarding factor VIII from proteins C and S, which would otherwise break it down. Now, during secondary hemostasis, thrombin releases factor VIII from the von Willebrand factor and activates it. Together, activated factor VIII, activated factor IX, and calcium form a complex, which activates factor X and triggers the common pathway.

Now, in von Willebrand disease, there isn’t enough functional von Willebrand factor to help platelets stick to the site of injury or carry factor VIII. As a result, the body struggles to stop bleeding. In most cases, von Willebrand disease is inherited and caused by mutations in the von Willebrand gene, but not all inherited forms are the same. That’s why the condition is subdivided into three main types.

The most common type is type 1, an autosomal dominant condition where a mutation in just one allele results in insufficient production and lowers circulatory levels of the von Willebrand factor. In other words, these individuals have a partial quantitative defect.

Type 2 is a bit more complex and covers several different subtypes, including 2A, 2B, 2M, and 2N. The first three follow an autosomal dominant inheritance pattern, while type 2N follows an autosomal recessive pattern, meaning both alleles must be affected for the condition to appear. Regardless of the subtype, all type 2 forms result in a qualitative defect, where the body produces enough von Willebrand factor, but the protein doesn’t function properly.

Now, in type 2A and 2M, the von Willebrand factor attaches well to subendothelial collagen and factor VIII but is unable to bind platelets. So, in this case, it's like having expired glue that can’t properly stick platelets to the damaged area.

On the other hand, in type 2B, the von Willebrand factor is way too sticky, causing platelets to clump together in the bloodstream even without injury. Next, in type 2N, the von Willebrand factor binds well to the subendothelial collagen and platelets but binds poorly to factor VIII. As a result, factor VIII is unprotected and broken down by proteins C and S, leading to low factor VIII levels.

Finally, type 3 follows an autosomal recessive inheritance pattern and involves a severe quantitative defect of the von Willebrand factor. In this case, von Willebrand factor levels are extremely low, which results in impaired platelet aggregation and severely low factor VIII levels.