Introduction
Von Willebrand disease (VWD) is the commonest inherited clotting disorder, occurring in approximately 1% of the population, though the number of those who are symptomatic is estimated at 0.01%. Individuals are commonly asymptomatic, however, some may present with recurrent bleeding episodes, typically epistaxis, post-dental procedures and in women, heavy menstrual bleeding.
It affects men and women equally and is primarily a congenital condition though there are acquired forms of the disease. This is caused by a deficiency in von Willebrand factor (VWF), which plays a main role in primary haemostasis.
It affects men and women equally and is primarily a congenital condition though there are acquired forms of the disease. This is caused by a deficiency in von Willebrand factor (VWF), which plays a main role in primary haemostasis.
Classification
The most common cause for VWD is due to an inherited gene mutation (~95-99%). This can be classified as:
Remaining cases (~1-5%) are due to acquired von Willebrand syndrome (AVWS) Typically presents in people >40 years old and with no prior bleeding history. This is mainly due to underlying conditions and not pathogenic variants of VWF such as:
- VWD type 1 (~70-80%):
- Functionally normal VWF, but reduced levels
- May have low levels of factor VIII (FVIII)
- Typically autosomal dominant (AD) inheritance pattern.
- The most common form of the disease
- Typically manifests as mild mucocutaneous bleeding, however symptoms can be more severe when VWF levels of <0.15 IU/ml.
- Epistaxis and bruising are the most common presentation in children
- Menorrhagia is the most common finding in women of child bearing age
- ABO blood group shown to influence VWF levels: individuals with non-O blood groups have higher levels than O blood group
- VWD type 2 (~20%):
- Normal levels of VWF, but functionally defective
- Sub types include A, B, M and N
- Type 2A: VWF multimers not the right size
- Type 2B: VWF not the right size and too active, leading to shortage of both VWF and platelets.
- Type 2M: low or absent binding to platelet receptors. FVIII still binds normally
- Type 2N: VWF has reduced affinity for FVIII, leading to reduced levels. Typically autosomal recessive inheritance.
- VWD type 3 (~5%):
- Virtually complete deficiency of VWF
- Typically autosomal recessive inheritance
Remaining cases (~1-5%) are due to acquired von Willebrand syndrome (AVWS) Typically presents in people >40 years old and with no prior bleeding history. This is mainly due to underlying conditions and not pathogenic variants of VWF such as:
- Lymphoproliferative disease
- Myeloproliferative disease
- Malignancy: due to aberrant binding of VWF to tumour cells
- Shear induced VWF conformational changes (e.g. aortic valve stenosis, ventricular septal defect)
- Autoimmune conditions
Epidemiology
- Incidence: 1.00 cases per 100,000 person-years
- Peak incidence: 30-40 years
- Sex ratio: more common in females 1:1
| <1 | 1-5 | 6+ | 16+ | 30+ | 40+ | 50+ | 60+ | 70+ | 80+ |
Pathophysiology
VWD is caused by a deficiency (either in function of level) of VWF. Its role is in:
- Mediating platelet adhesion to sites of damaged vascular endothelium
- As a bridging molecule for platelet aggregation.
- Indirectly it acts as a carrier for FVIII in its inactive form.
- Factor VIII works by interacting with factor IX and the intrinsic pathway.
Clinical features
Symptoms of VWD can vary greatly between individuals and can start at any age. The main symptoms include:
Other serious rarer complications (more commonly seen in VWD type 3) include:
- In women, menorrhagia (93-95%)
- If left untreated the former may lead to anaemia and iron deficiency
- Frequent or prolonged nosebleeds (53-74%)
- Excessive bruising (45-50%)
- Prolonged bleeding post surgery (40-47%)
- Bleeding gums (29-34%)
Other serious rarer complications (more commonly seen in VWD type 3) include:
- Haemarthrosis (2-30%)
- Gastrointestinal bleeding (~4%)
Investigations
Diagnosing VWD starts with a thorough clinical evaluation, taking into consideration the personal and familial history of bleeding. The use of a standardised bleeding assessment tool (BAT) such as the International Society on Thrombosis and Haemostasis (ISTH), can be helpful to evaluate likelihood of a bleeding disorder being present.
Initial lab investigations would include:
If VWD is suspected, the following tests can be used for primary diagnosis based on the British Society of Haematology Guidelines:
Initial lab investigations would include:
- FBC
- Typically normal
- Platelets: patients with Type 2B can develop a thrombocytopenia
- Activated partial thromboplastin time (APTT):
- Can be normal or increased
- In VWD, VWF is a carrier for FVIII, therefore APTT will only be prolonged if the FVIII level is sufficiently reduced
- Prothrombin Time
- Typically normal
- Fibrinogen
- Typically normal
If VWD is suspected, the following tests can be used for primary diagnosis based on the British Society of Haematology Guidelines:
- FVIII assay
- Typically low but can be normal
- VWF antigen (Ag):
- Diagnosis of VWD can be made when VWF levels are <0.30 IU/ml in the context of a previous mucocutaneous bleeding history
- If levels undetectable= Type 3
- VWF activity:
- Assessed by measuring ristocetin cofactor (RCo) and collagen binding (CB) as ratios of VWF antigen levels
- RCo/Ag and CB/Ag is >0.6= Type 1
- RCo/Ag or CB/Ag is <0.6= Type 2
Differential diagnosis
| DIfferential Diagnosis | History | Exam | Investigations |
|---|---|---|---|
| Purpura Simplex |
| ||
| Medication induced |
| ||
| Alcohol abuse/liver cirrhosis |
| ||
| Malignancy with bone marrow involvement |
| ||
| Haemophilia |
| ||
| DIC |
|
Management
There is currently no cure for VWD. Measures include prevention, simple lifestyle changes and medications to manage the symptoms: 7
First line management in all confirmed VWD patients:
For treatment of bleeding episodes:
- Informing doctor or dentist prior to any procedure that may cause bleeding (surgery, vaccination, dental extraction)
- Avoid aspirin, anti-inflammatory or anticoagulant medication (unless prescribed)
- Discuss with doctor about avoiding activities that may increase your risk of bleeding
First line management in all confirmed VWD patients:
- Desmopressin:
- A trial should be carried out with VWF antigen, activity and FVIII measured at baseline, 30-60 mins and 4-6 h
- This should be given preference over blood derived products if possible
For treatment of bleeding episodes:
- 1st line : administration of tranexamic acid and desmopressin
- Both can be used as prophylaxis prior to surgery
- 2nd line : if the patient is non responsive to desmopressin, a VWF-FVIII concentrate should be used
- Also used as prophylaxis prior to surgery
- In menorrhagia, hormonal management and use of IUD can be considered