Von Willebrand disease

Role of von Willebrand factor (vWF)

To clearly understand the clinical picture and the classification principles of the disease, one must understand the pathophysiology of the factor itself.

Structurally, it is a large multimeric protein synthesized in vascular endothelial cells and megakaryocytes. It acts as a subunit for coagulation factor VIII (FVIII). von Willebrand factor performs crucial functions in both phases of blood coagulation:

• In primary (platelet) hemostasis: The protein ensures adhesion — the attachment of platelets to the exposed subendothelium at the site of vascular injury. It also promotes aggregation, i.e., the clumping together of blood platelets.
• In secondary (coagulation) hemostasis: The factor acts as a protective carrier protein for FVIII. It stabilizes the FVIII molecule in blood plasma and prevents its premature degradation.

Classification

Logically, all variants of the disease are divided into quantitative (protein deficiency) and qualitative (structural and functional impairment) defects.

Quantitative defects:

• Type 1: Characterized by a partial deficiency of vWF. It is the most common and, as a rule, the mildest variant of the course.
• Type 3: Distinguished by the virtually complete absence of the factor in the blood. This is an extremely severe form of the disease.

Qualitative defects (Type 2): The factor is produced, but its functional activity is defective. It is divided into four subtypes depending on the nature of the defect:

1. 2A: The protein's ability to bind platelets is reduced. Furthermore, the largest multimers of the factor, which possess the highest hemostatic activity, are completely absent in blood plasma.
2. 2B: A paradoxical defect. Characterized by an abnormally increased affinity of vWF for specific platelet receptors (glycoprotein Ib).
3. 2M: Similar to type 2A, platelet-binding capacity is reduced; however, the principal difference is that large multimers are preserved in plasma.
4. 2N (Normandy): The defect is localized in the secondary hemostatic pathway. The factor loses its ability to bind to FVIII. Consequently, FVIII loses protection and rapidly degrades, clinically mimicking the picture of hemophilia A.

Clinical presentation

The severity of symptoms directly correlates with the severity of the defect. The disease frequently manifests as early as infancy or childhood.

Manifestations of primary hemostasis impairment: Cause a microcirculatory bleeding pattern. Patients experience:

• Spontaneous hemorrhages from mucous membranes (regular epistaxis, gingival, and gastrointestinal bleeding).
• Cutaneous manifestations in the form of petechial rash and ecchymoses (bruises).
• In girls during puberty, a typical sign is menorrhagia — heavy and excessively prolonged menstruation.

Manifestations of secondary hemostasis impairment: Account for the hematoma bleeding pattern. In severe forms (especially types 3 or 2N), secondary deficiency of FVIII leads to the formation of deep muscle hematomas and joint hemorrhages (hemarthrosis). This makes the clinical picture strikingly similar to the manifestations of classical hemophilia.

Management principles for mild forms

In mild cases of the disease, the baseline drug of choice is desmopressin.

By mechanism of action, it is a synthetic analogue of the antidiuretic hormone. The drug does not contain the factor itself, but stimulates the release of endogenous stores of von Willebrand factor from storage sites in endothelial cells directly into the systemic circulation.

Class and exam questions

What else to study on this topic

• Laboratory diagnostics of von Willebrand disease
• Differential diagnosis with hemophilia A
• Management specifics for female patients with menorrhagia
• Principles of replacement therapy in severe forms (types 3 and 2N)
• Molecular and genetic basis of qualitative defects (type 2)

Other topics in "Chapter 10. Diseases of the Blood and Blood-Forming Organs"

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