Von Willebrand disease

von Willebrand disease (vWD) is the most common inherited bleeding disorder. It has different genetic causes which have varying levels of penetrance.

🔢 Pathophysiology and classification

Firstly, let’s recap what is von Willebrand factor (vWF): it is a glycoprotein synthesised in endothelial cells as well as megakaryocytes. It released when there is damage to the endothelium and exposure of the subendothelial layer, and it acts to mediate platelet adhesion. It is also necessary for stabilisation of factor VIII.

Now if there is a qualitative or quantitative deficiency of vWF then we get abnormal bleeding (mostly mucosal bleeding).

To understand the pathophsyiology better, let’s take a look at the classification of vWD according to the International Society on Thrombosis and Haemostasis Subcommittee on von Willebrand Factor:

1. Type 1 - the most common (75%) and least severe form. It is due to mutations affecting gene expression of vWF → partial quantitative deficiency (not enough vWF present). Individuals with this form often are asymptomatic unless they have surgery (this is where it is often identified) or have a large bleed due to injury.

2. Type 2 - can be subdivided into types A, B, M, N. They are all qualitative defects of vWF (enough present but it is not functional in the same manner as regular vWF).
1. Type 2A - incorrect sizing of vWF (due to a deficiency of high-molecular-weight multimers) decreases its ability for platelet adhesion → has impaired coagulation ability.
2. Type 2B - in this form, there is an increased affinity for platelet glycoprotein Ib causing binding when there is no injury. This causes a deficiency in both the number of platelets and in the available vWF.
3. Type 2M - there is simply decreased platelet adhesion.
4. Type 2N - normal platelet adhesion, but impaired adhesion to factor VIII → clearance of factor VIII and no coagulation as a result.
3. Type 3 - this is the most severe form in which there is little to no vWF. It is also the rarest form with only 3% having it. It is autosomal recessive.

⚠️ Risk factors

😷 Presentation

The usual presentation is a history of easy, prolonged or heavy bleeding. This is especially noticeable when bleeding from minor wounds.

• Postoperative & intraoperative bleeding - this is a common reason for identification. Patients may have to return to the hospital to control bleeding. This is noticeable with dental extractions or tonsillectomy and other mucosal membrane operations. Intraoperatively they may be bleeding more than expected.
• Menorrhagia
• Bleeding gums
• Epistaxis

🔍 Investigations

History of abnormal bleeding and family history are very important when suspecting vWD.

• Prolonged bleeding time - indicates abnormalities in primary haemostasis, therefore should be raised in vWD but is normal in haemophilia.
• Prothrombin time - usually normal with vWD. It is a measure of the extrinsic pathway (factor VII & TF) in which there are no deficiencies with vWF.
• Activated partial thromboplastin time (aPTT) - this is a measure of the intrinsic pathway (factors XII, XI, IX, VIII) and so it can be prolonged if factor VIII is reduced below <35% of normal. A normal aPTTT does not exclude diagnosis of vWD.
• vWF antigen - diagnostic for vWD if <0.3IU.
• vWF function assay (ristocetin cofactor test) - ristocetin is a glycopeptide that causes platelet aggregation. In vWD it will indicate defective platelet aggregation.
• Factor VIII activity - often within normal range but in type 2N it is decreased.
• FBC - usually unremarkable. However, type 2B may present with thrombocytopenia.

🧰 Management

On a normal day, vWD does not require any treatment. Treatment is only required with major bleeding or trauma or pre-operatively.