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Introduction
Von Willebrand disease (VWD) is a genetically inherited disorder of the blood clotting system. It is caused by a deficiency or dysfunction of von Willebrand factor (vWF), a protein involved in the hemostatic process. Due to significant genetic and clinical heterogeneity, the exact prevalence of this disease is difficult to determine. However, it is estimated that 1-5 per 10,000 people worldwide are affected by the disorder, although clinical signs and symptoms requiring treatment are identified in only 1 per 8,500-50,000 individuals (1).
This disease was first described in 1924 by the Finnish physician Erik Adolf von Willebrand while consulting a 5-year-old patient with recurrent mucosal bleeding. He diagnosed the patient and approximately one-third of her relatives with an unusual blood clotting disorder that was unknown at the time. A genealogical study revealed that similar clinical symptoms of varying severity had occurred across three generations of the family: 16 of 35 female relatives and 7 of 31 male relatives reported symptoms. The identified autosomal dominant inheritance pattern and the observation that symptoms occurred as frequently in women as in men led the physician to suspect that the condition was not hemophilia, the best-known bleeding disorder of that era. He initially referred to the condition as hereditary pseudohemophilia; however, over time the disease became known by the name of its discoverer—von Willebrand. Later, as scientific advances clarified the underlying mechanism of the disease, the same name was given to the factor whose defects cause the disorder (2).
Pathophysiology
vWF is synthesized in vascular endothelial cells, subendothelial connective tissue, and megakaryocytes (platelet α-granules). In a healthy individual, this factor plays a crucial role in primary hemostasis. Following vascular injury, when the vessel lumen narrows and blood flow slows, vWF released from tissues and platelets binds to the site of injury. Platelets interact with vWF and collagen types IV and V within the subendothelial basement membrane and adhere to the damaged endothelium. By releasing additional biologically active substances, platelets aggregate and form a primary hemostatic plug, thereby preventing further blood loss until secondary hemostasis (blood coagulation) is initiated.
In von Willebrand disease, hemostasis is impaired because platelets cannot adhere effectively either to the endothelium or to one another. As a result, the primary platelet plug is more likely to be dislodged by blood flow, leading to persistent bleeding. Although the coagulation process itself is usually unaffected, it cannot proceed normally until primary hemostasis has occurred, resulting in prolonged bleeding. In addition, vWF protects coagulation factor VIII, which participates in secondary hemostasis, from rapid degradation and inactivation. In severe forms of von Willebrand disease, factor VIII deficiency may also be present (3).
Forms of the Disease
Three inherited forms of von Willebrand disease and one acquired form are distinguished according to the severity and nature of clinical manifestations.
Type 1 accounts for 60-70% of all cases. It results from a partial quantitative deficiency of vWF. This disorder is inherited in an autosomal dominant manner and is associated with vWF gene polymorphisms and molecular abnormalities that reduce gene expression and vWF synthesis. Less commonly, Type 1 disease is caused by accelerated clearance of vWF from the plasma. Although vWF levels are reduced, clinical symptoms are generally mild, and many affected individuals do not seek medical attention or receive a diagnosis. Typical manifestations include recurrent epistaxis, mucosal bleeding, easy bruising, and heavy menstrual bleeding in women of reproductive age (4).
Type 2 accounts for approximately 20% of all cases. It is a qualitative disorder in which plasma vWF levels are usually normal, but structural and functional abnormalities are present. Several subtypes are recognized (5, 6, 7):
- Type 2A is characterized by ineffective interaction between vWF and platelets. It is most commonly inherited in an autosomal dominant manner. The absence of medium and large vWF multimers leads to impaired primary hemostasis. This is the most common subtype of Type 2 disease. Clinical manifestations are usually of moderate severity.
- Type 2B is unique because it involves spontaneous and premature binding of vWF to platelets within the circulation rather than at the site of endothelial injury. Patients may develop thrombocytopenia, and their condition may worsen during infections, surgical procedures, and pregnancy. The most common symptoms are mild to moderate mucosal bleeding.
- Type 2M is also characterized by impaired interaction between vWF and platelets, but without significant deficiency of vWF multimers. Various heterogeneous genetic mutations cause functional defects in vWF, disrupting formation of the primary platelet plug. Patients typically experience mild to moderate mucosal bleeding, although severe bleeding episodes may occasionally occur.
- Type 2N is caused by homozygous or heterozygous mutations that impair the binding of vWF to coagulation factor VIII. As a result, factor VIII is not adequately protected and undergoes premature degradation before reaching the site of injury, leading to impaired secondary hemostasis (coagulation). Clinically, severe bleeding is observed, and these patients are often initially suspected of having another bleeding disorder—hemophilia A. One of the most important distinguishing features is the autosomal inheritance pattern of Type 2N disease, whereas hemophilia A is inherited in an X-linked manner.
Type 3 is the most severe form of the disease and is detected in 1-2% of cases. A gene defect inherited in an autosomal recessive manner results in a complete deficiency of vWF and a consequent reduction in factor VIII activity. Patients with this form of the disease experience severe mucosal bleeding, bleeding into muscles and joints, joint damage, and the formation of multiple subcutaneous hematomas.
Acquired von Willebrand disease is a rare disorder most commonly caused by the development of specific antibodies against vWF. This secondary condition may arise in association with various underlying diseases, including autoimmune disorders (e.g., autoimmune thyroiditis, systemic lupus erythematosus), lymphoproliferative or myeloproliferative disorders, and cardiovascular diseases. The prognosis is generally favorable because treatment of the underlying condition often resolves the bleeding disorder as well (4, 6, 7).
Clinical Symptoms and Signs
The clinical presentation of the disease is highly variable and may differ even among relatives with the same disease subtype. Some patients remain completely asymptomatic and therefore are unlikely to receive a diagnosis. In others, manifestations range from mild symptoms that do not affect quality of life to severe bleeding complications. The most severe clinical manifestations are typically observed in patients with Type 3 von Willebrand disease. Symptoms may develop at different stages of life, appearing in infancy in some patients and only in adulthood in others (5, 7).
- Mucosal bleeding is the most common manifestation of the disease. Patients frequently report recurrent and seemingly unexplained epistaxis, which is usually not profuse but tends to be prolonged and difficult to control. Gingival bleeding is also common and is often noticed during tooth brushing. Because this symptom frequently leads patients to seek dental care, they may not mention it during a medical consultation unless specifically asked about it (7).
- Easy and frequent bruising. Another common manifestation is the spontaneous appearance of subcutaneous hematomas. Patients are often unable to identify a specific traumatic event that caused the bruising, and bruises may be present almost continuously on various parts of the body (5).
- Heavy menstrual bleeding may be the first symptom that prompts women to seek medical attention and affects up to 70% of patients (4). Many women also experience irregular and painful menstruation. Without appropriate treatment, chronic heavy menstrual bleeding may lead to iron deficiency anemia (7). Symptoms have been observed to improve with the use of oral contraceptives (5).
- Prolonged and excessive bleeding after invasive procedures. This manifestation is most commonly observed after dental and otorhinolaryngological procedures, including tooth extraction and surgical removal of the tonsils or adenoids, and less frequently after other surgical interventions. It is typically seen in patients with severe Type 3 disease and may occur during either the early or late postoperative period (6).
- Severe bleeding during and after childbirth. It has been observed that women with Type 1 von Willebrand disease often experience normalization of vWF levels toward the end of pregnancy, allowing childbirth to proceed without major complications. In contrast, women with Type 2A, Type 2B, or Type 3 disease usually require prophylactic therapy to prevent severe early and late postpartum hemorrhage (6).
- Gastrointestinal bleeding occurs more frequently in patients with Type 2A von Willebrand disease and can be challenging to diagnose and manage.
- Bleeding into muscles and joints is a rare but severe manifestation. These symptoms are particularly important because recurrent hemarthrosis increases the risk of long-term joint damage and degeneration, potentially resulting in impaired joint function and reduced range of motion (5, 7).
- Thrombocytopenia may occur throughout the course of the disease but tends to worsen during physiological stress, including severe infections, surgical procedures, pregnancy, and treatment with desmopressin (4).
- Worsening bleeding symptoms during aspirin use may also occur (5).
- Clinical manifestations in infants and children include bleeding from the umbilical stump after cord separation, cephalohematoma, bruising of the cheeks, subconjunctival hemorrhage, and excessive or prolonged bleeding after circumcision in boys or venipuncture procedures (5).
Diagnosis
Clinical Examination
Clinical examination most commonly reveals nonspecific findings. When evaluating patients with suspected bleeding disorders, it is important to assess bruising and hemorrhagic skin lesions, including their type (ecchymoses, hematomas, petechiae), number, location, and size, and, when possible, monitor changes over time. Photographing these findings may facilitate disease monitoring. It has been suggested that von Willebrand disease should be suspected when a patient presents with three different hemorrhagic symptoms (4). When this disease is suspected, a detailed medical history should be obtained, including information regarding bleeding disorders among family members and the use of medications that may affect hemostasis (5).
Complete Blood Count
Several parameters should be evaluated:
- Hemoglobin and hematocrit levels, which may be reduced due to prolonged heavy bleeding. Such abnormalities represent complications of chronic untreated von Willebrand disease.
- Platelet count, which is usually normal. Thrombocytopenia should raise suspicion of Type 2B disease.
Coagulation Studies
Historically, prolonged bleeding time was considered one of the diagnostic indicators of von Willebrand disease. However, with the development of more advanced diagnostic methods, this test is no longer routinely used. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are generally within normal limits, particularly in patients with mild disease. aPTT may be prolonged when secondary factor VIII deficiency develops due to significant vWF deficiency. These abnormalities are most commonly observed in Type 2N and Type 3 von Willebrand disease (4).
Specific Tests
- vWF antigen assay (vWF:Ag): Measures plasma vWF concentration using enzyme-linked immunosorbent assay (ELISA) or latex agglutination techniques. Plasma vWF levels are influenced by blood group and should be interpreted accordingly. Individuals with blood group O typically have only 50-75% of the vWF levels found in individuals with blood groups A, B, or AB (4, 8).
- Ristocetin cofactor activity assay (vWF:RCo): A highly sensitive functional test that evaluates the interaction between vWF and platelets (4).
- Factor VIII activity assay (FVIII:C): A nonspecific functional test assessing the ability of vWF to bind, stabilize, and transport factor VIII to the site of injury. Reduced activity is consistently observed in patients with Type 2N and Type 3 von Willebrand disease (7, 8).
- vWF multimer analysis: A protein electrophoresis-based test involving radioactively labeled or immunofluorescent multimers. The assay distinguishes large, intermediate, and small multimers and evaluates quantitative abnormalities. This test is useful for differentiating among various von Willebrand disease subtypes (4).
- Less commonly used tests that may aid in differential diagnosis include the vWF-collagen binding assay (vWF:CBA), vWF-factor VIII binding assay (vWF:FVIIIB), and ristocetin-induced platelet aggregation test (RIPA) (4, 8).
Genetic Counseling and Testing
Von Willebrand disease is most commonly inherited in an autosomal dominant manner; however, Type 3 disease and certain Type 2 subtypes are inherited in an autosomal recessive manner. Genetic counseling is recommended to inform patients about disease severity, assess risk among relatives, and facilitate early diagnosis through pedigree analysis. Genetic counseling is particularly important for couples at risk of having a child with Type 3 von Willebrand disease.
Genetic testing can identify mutations associated with specific disease subtypes. It also assists in differentiating von Willebrand disease from other inherited bleeding disorders, particularly hemophilia, which is characterized by X-linked inheritance and does not involve typical vWF gene mutations.
Read more in "Internistas" No. 10, 2018.
Gabija Visockytė
Vilnius University Faculty of Medicine
