Von Willebrand disease

Definitions & Key takeaways

Von Willebrand disease is a bleeding disorder caused by a deficiency in the quantity or quality of von Willebrand factor, a plasma glycoprotein that plays a key role in forming blood clots. Symptoms depend on the type of the disease and range from mild to severe. People with acquired von Willebrand disease present with new onset of bleeding in the context of other pathologic conditions or medication use. For treatment, people who present with minor bleeding are treated with desmopressin analogs, while those with severe bleeding receive exogenous von Willebrand factor and factor VIII concentrates.

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Von Willebrand disease, named after Finnish doctor Eric 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're 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 2B 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 GP2B/3A. 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 3, also known as tissue factor, which activates factor 7. Next, activated tissue factor, activated factor 7, and calcium come together to activate factor 10, eventually triggering the common pathway.
Activated factor 10 joins forces with factor 5 and calcium to form the prothrombinase complex, which converts factor 2 called prothrombin, into activated factor 2, called thrombin.
Next, thrombin converts factor 1, known as fibrinogen, into activated factor 1 called fibrin. Finally, thrombin activates factor 13, 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 12, also known as the Hagemann factor.
Activated factor 12 activates factor 11, which with the help of calcium, activates factor 9. Next, let's focus on factor 8, which circulates through the bloodstream bound to the Von Willebrand factor.
Think of the von Willebrand factor as a protective shield, guarding factor 8 from proteins C and S, which would otherwise break it down.
Now, during secondary hemostasis, thrombin releases factor 8 from the von Willebrand factor and activates it. Together, activated factor 8, activated factor 9, and calcium form a complex which activates factor 10 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 8.
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 one, 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 1st 3 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 8, 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 8.
As a result, factor 8 is unprotected and broken down by protein C and S, leading to low factor 8 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 8 levels.
Although most cases are inherited, some people can develop acquired von Willebrand disease. In these cases, certain acquired conditions can interfere with the function of the von Willebrand factor.
For example, in autoimmune disorders like systemic lupus erythematosis, the body produces antibodies that target self-proteins, including von Willebrand factor, leading to its destruction.
Now, clinical manifestations depend on the type. Individuals with type 1, type 2A, 2B, and 2M could be asymptomatic or present with mild mucocutaneous bleeding, such as gum bleeds.
Also, they might report easy bruising, excessive bleeding from wounds, and heavy menstruation. Most commonly they're unaware of the condition until some surgical or dental intervention reveals the bleeding issues.
However, clinical manifestations can become severe if they begin taking medications that can impair the body's ability to form clots.
These include anticoagulants and antiplatelet medications. On the flip side, individuals with type 2N and type 3 have severe bleeding manifestations, including joint and muscle bleeds, along with gastrointestinal hemorrhage.
Finally, acquired von Willebrand disease causes new bleeding symptoms that develop alongside certain underlying conditions like autoimmune diseases.
Moving on to diagnosis, which primarily relies on labs, a complete blood count typically reveals a normal platelet count.
However, in type 2B, the extremely sticky von Willebrand factor will clump platelets together, causing thrombocytopenia.
Next, the coagulation profile can help you assess the secondary hemostasis and coagulation pathways. Prothrombin time or PT evaluates factors of the extrinsic and common pathways, while activated partial thromboplastin time or APTT reflects factors of intrinsic and common pathways.
Finally, thrombin time or TT measures how long it takes for fibrinogen to turn into fibrine in the presence of thrombin.
In von Willebrand disease, PT is typically normal because the extrinsic pathway remains unaffected. Next, the APTT, which relies on factor 8, can be normal or prolonged.
In type 1, APTT remains normal because there's only a partial quantitative deficiency. Although factor 8 has less protection from the von Willebrand factor, proteins C and S don't break it down enough to disrupt the coagulation cascade.
However, in types 2 and 3, APTT is prolonged because this protection is compromised, allowing proteins C and S to break down factor 8, significantly lowering its levels and prolonging APTT.
In all types, thrombin time is typically normal, since there's no impairment of fibrinogen to fibrin conversion. Finally, let's focus on specific tests used in the diagnosis of von Willebrand disease.
Von Willebrand factor antigen assay measures the amount of this protein in the blood. Low levels can be suggestive of the condition.
Next, there's the ristocetin cofactor activity test. When you add ristocetin to a blood sample containing normal von Willebrand factor, it activates the protein to clump platelets together, resulting in visible coagulation.
However, no clumping indicates reduced activity, suggesting von Willebrand disease. Lastly, factor 8 activity measures how well this factor works.
Although it can sometimes be normal, it's usually decreased because protein C and S break it down. For managing bleeding episodes in types 1 and 2, the first choice treatment is desmopressin, a vasopressin analog.
It stimulates endothelial cells and megakocytes to release stored von Willebrand factor, boosting its levels in the blood and helping with blood clotting.
However, you should avoid desmopressin in type 2B, because the von Willebrand factor is overly sticky. Boosting its levels can induce platelet clumping, leading to severe thrombocytopenia, eventually worsening the bleeding.
Finally, in type 3, treatment relies on intravenous infusion of von Willebrand factor concentrate, often combined with factor 8.
All right, as a quick recap. In von Willebrand disease, there isn't enough functional von Willebrand factor to do its job.
First, it fails to help platelets stick to the site of injury. Second, it can't carry factor 8.
Inherited von Willebrand disease includes 3 types. In type 1, a person has reduced levels of the factor.
Type 2 involves a dysfunctional form, and in type 3, there is a severe deficiency. On the flip side, acquired forms can occur due to autoimmune conditions like systemic lupus erythematosis.