What factors influence the bleeding phenotype in von Willebrand disease (VWD)?

From the Guidelines

The bleeding phenotype in von Willebrand disease (VWD) is influenced by multiple factors, including the type and severity of the VWD itself, von Willebrand factor (VWF) levels, Factor VIII levels, blood type, age, hormonal status, medications, comorbidities, genetic modifiers, and the presence of antibodies against VWF. The primary determinant is the type and severity of the VWD itself, with Type 3 (complete deficiency) causing more severe bleeding than Type 1 (partial deficiency) or Type 2 (qualitative defects) 1. The specific level of VWF in the blood directly correlates with bleeding risk, with levels below 30% generally associated with increased bleeding 1. Factor VIII levels also impact bleeding severity since VWF serves as a carrier protein for Factor VIII 1. Blood type affects baseline VWF levels, with type O individuals having approximately 25% lower VWF levels than non-O blood types 1. Age and hormonal status play important roles, with bleeding symptoms often worsening during puberty in females and improving with age in some patients 1. Concurrent use of medications like aspirin, NSAIDs, or anticoagulants can significantly worsen bleeding tendency 1. Comorbidities such as liver disease, hypothyroidism, or uremia can alter VWF production or function 1. Genetic modifiers beyond the VWF gene itself can influence the bleeding phenotype, explaining why family members with identical VWF mutations may have different bleeding severities 1. Lastly, the presence of antibodies against VWF, though rare, can dramatically worsen bleeding symptoms by neutralizing both endogenous and therapeutically administered VWF 1. It is essential to consider these factors when evaluating and managing patients with VWD to minimize the risk of bleeding complications and improve their quality of life. Some key points to consider in the management of VWD include:

• The use of desmopressin to increase VWF levels in patients with mild to moderate VWD 1
• The use of factor concentrates, such as VWF and Factor VIII, in patients with severe VWD or those who are unresponsive to desmopressin 1
• The avoidance of medications that can worsen bleeding tendency, such as aspirin and NSAIDs 1
• The management of comorbidities, such as liver disease and hypothyroidism, to optimize VWF production and function 1
• The consideration of genetic testing to identify genetic modifiers that may influence the bleeding phenotype 1
• The monitoring of patients for the development of antibodies against VWF, which can worsen bleeding symptoms 1. Overall, a comprehensive approach to the management of VWD is necessary to minimize the risk of bleeding complications and improve patient outcomes.

From the Research

Factors Influencing Bleeding Phenotype in VWD

The bleeding phenotype in von Willebrand disease (VWD) is influenced by several factors, including:

• VWF and FVIII levels after desmopressin administration, which mimic hemostatic response to hemostatic challenges 2
• Von Willebrand factor antigen levels, with lower levels (<20 IU/dL) associated with a more severe bleeding phenotype 3
• Plasma VWF level, with higher levels associated with a thrombotic phenotype and lower levels associated with a bleeding disorder 4
• Blood group, with subjects with O blood group having 25% less VWF than those of non-O blood groups 4
• Age and sex, with females having a higher bleeding score than males, but similar interim bleeding scores 5
• VWD subtype, with type 3 VWD having a more severe bleeding phenotype than type 1 VWD 3, 5

Bleeding Assessment and Scoring

Bleeding assessment is critically important in the diagnosis of VWD, and several tools are available, including:

• The ISTH BAT, which forms the original bleeding score (0 BS) 5
• The International Society on Thrombosis and Haemostasis BAT, which is repeated at follow-up to evaluate interim bleeding (Interim BS, 1 BS) 5
• The Tosetto bleeding score, which is used to assess the severity of bleeding symptoms 2
• The MCMDM-1VWD bleeding questionnaire, which is used to compute the bleeding score (BS) 3

Treatment and Management

Treatment and management of VWD depend on the subtype and severity of the disease, and may include:

• Desmopressin, which is the treatment of choice for most patients with type 1 VWD 2, 6
• Replacement therapy, which is used to treat bleeding episodes in patients with type 3 VWD 4
• Enoxaparin and PEG-hirudin, which may be used to blunt the VWF rise in patients with unstable angina pectoris and are associated with a more favorable clinical outcome 4