Von Willebrand factor is a glycoprotein that plays a part in hemostasis. It is synthesized in endothelial cells and megakaryocytes. After transcription and translation pro-vWF is covalently linked to form dimers in the endoplasmic reticulum, and subsequently, large dimers form in the Golgi complex and secretory granules. The pro-von Willebrand factor propeptide then undergoes cleavage and then both the propeptide and mature von Willebrand factor are secreted into the vessel lumen. It functions as a carrier for factor VIII to maintain its levels, as well as help in platelet adhesion and binding to endothelial components after a vascular injury. Any qualitative or quantitative deficiency of pro-von Willebrand factor will lead to the increased bleeding tendency, and this syndrome is called Von Willebrand disease.
Inherited phenotypic forms of Von Willebrand disease are:
The VWF gene is highly polymorphic, and this polymorphism leads to a big variation in the normal spectrum of von Willebrand levels function. Subsequently, there is a spectrum of presentations and disease severity.
Acquired von Willebrand disease occurs when secondary (acquired) processes lead to a functional impairment of von Willebrand factor, either by decreasing its available quantity or by interfering with the physiological hemostasis pathway. The most commonly associated conditions are lung cancer, Wilm's tumor, gastric cancer, MGUS, multiple myeloma, chronic lymphocytic leukemia, hairy cell leukemia, myeloproliferative neoplasms (MPN), plasma cell dyscrasias, lymphomas, systemic lupus erythematosus (SLE), Felty syndrome, autoimmune hemolytic anemia, or other autoimmune disorders, metabolic disorders (hypothyroidism), drug side effects, and states of high-vascular flow such as AS, VSD, VAD (ventricular assist devices), extracorporeal membrane oxygenation (ECMO), or metallic cardiac valves. The von Willebrand factor is a large multimeric glycoprotein, and it is susceptible to the shear stress associated with high flow states.
The autoimmune spectrum can be quite varied as von Willebrand factor occurs as a multimer, and this heterogeneity means that certain multimer sizes may escape the immune-mediated antibody response. The mechanism in malignancy includes the formation of non-specific antibodies which bind the von Willebrand factor forming an immune complex and hence increase clearance by the reticular endothelial system. The other mechanism is the absorption of the von Willebrand factor on the surface of malignant cells such as the case in multiple myeloma or solid tumors or proteolysis of von Willebrand factor multimers as is usually seen in MPN.
Von Willebrand disease is estimated to affect approximately 1% of the unselected population, but clinically significant disease prevalence is estimated to be about 125 per million, with severe disease affecting up to five per million.
There is an equal distribution between males and females. Acquired von Willebrand disease prevalence is unknown but may represent 1% to 5% of all von Willebrand disease. Its prevalence is higher in certain groups. For example, it has been reported in up to 20% of malignancies, and up to 100% of certain high flow states such as extracorporeal membrane oxygenation (ECMO) and metallic cardiac valves.
Von Willebrand factor is a multimer formed from a basic dimer subunit. It is produced in megakaryocytes and endothelial cells. The physiological hemostatic effect is determined by the size of the multimer. Bigger multimers are more active and even prothrombic. They are cleaved by circulating proteases into smaller units. These larger multimers are stored in cytoplasmic granules, and released in response to a trigger such as thrombin, fibrin, and histamine.
Larger multimers have more available sites for binding to platelets and endothelium. Von Willebrand factor increases factor VIII half-life by preventing its degradation. With regards to the subtypes, type I is characterized by a mild decrease in von Willebrand factor antigen (Ag), von Willebrand factor activity, and VIII:C.
Of note, von Willebrand factor levels of less than 30% are required for a diagnosis of Von Willebrand disease. Conversely, type III is characterized by a significant decrease in the parameters above.
Type II disease is characterized by qualitative decrease with specific variations:
Type 2A: variable decrease in von Willebrand factor Ag and VIII:C with a significant decrease in von Willebrand factor activity and absence of large and intermediate size multimers.
Type 2B: variable decrease in von Willebrand factor Ag and VIII:C and significant decrease in von Willebrand factor activity and absence of large multimers. However, most importantly this type is hypersensitive to ristocetin-induced platelets aggregation (RIPA).
Type M: vWF activity is decreased relative to Ag and multimers are present.
Type N: this is characterized variably by a decrease in vWF Ag and activity but is distinguished from the other types by the significant decrease in VIII:C, albeit usually more than 5%. This specific subtype can be confused with hemophilia A.
Low von Willebrand factor is quite common in the general population, but not all patients have clinically significant bleeding issues. Therefore, a significant proportion of the patient population goes undiagnosed. Most cases are diagnosed formally after investigating for significant bleeding problems such and recurrent and excessive bruising, prolonged bleeding from minor skin trauma, and prolonged bleeding from mucosal surfaces (epistaxis, dental extractions, menstruation).
Physical examination can be often normal. Sometimes evidence of bleeding/bruising (petechiae, hematomas) may be noted.
In case of a qualitative defect, von Willebrand disease may mimic hemophilia and presents predominantly with bleeding into soft tissues, joints, and hematuria rather than mucocutaneous bleeding. Sometimes, type 2N von Willebrand disease is misdiagnosed as hemophilia.
Patients with a clinical history consistent with von Willebrand disease are investigated further with the following labs:
Patients with von Willebrand disease activity/antigen levels between 30 and 50 should be designated as “low-von Willebrand factor” and be considered for treatment in high bleeding risk scenarios.
Stable patients with type 1, some type 2 (except type 2B) and acquired von Willebrand disease patients are given a trial of Desmopressin (DDAVP), this is a synthetic analogue of vasopressin to check for a response. This is usually performed when patients are not actively bleeding.
Type 1 usually shows a good response to DDAVP trial. Type 2A shows a variable and transient response which is often clinically adequate. Type 2M and Type 2N usually show a poor or minimal response. Type 3 von Willebrand disease does not respond to Desmopressin as there is a complete lack of von Willebrand factor. A successful trial sees von Willebrand factor activity levels of at least 30 IU/dL (ideally 50 IU/dL). Desmopressin causes von Willebrand factor release from endothelial cells. DDVAP can be administered subcutaneously, intravenously and via intranasal spray. It leads to increased von Willebrand factor and factor VIII levels with response persisting for up to 12 hours. It is useful for minor bleeding episodes (including epistaxis and menses) and elective minimally invasive surgical procedures.
Von Willebrand factor replacement can be considered in patients with type 3 von Willebrand disease, or severe variants of type 1 and two that do not demonstrate a sufficient DDAVP response in serious bleeding scenarios. There are many different preparations available, including factor VIII concentrates that also include von Willebrand factor. Von Willebrand factor replacement therapy often is used in serious bleeding scenarios such as trauma or major surgery. Usually, it is administered in as a short course. Examples of intermediate-purity vWF concentrates include Wilate, alphanate, and Humate-P which contain both vWF and FVIII. Patients with von Willebrand disease type III need the products mentioned above for episodes of bleeding or surgery, conversely, for mild type I and type II A disease (or minor procedures in this category) DDAVP might suffice, however, other scenarios might require von Willebrand and FVIII factors mentioned previously.
Tranexamic acid can also be used as an anti-fibrinolytic agent. It prevents break down of fibrin clots. It is useful in case of mucosal bleeding.
Von Willebrand disease in females is often a more clinically severe disease due to menorrhagia.
Von Willebrand factor levels vary with physiological stress. Some patients may occasionally be noted to have normal von Willebrand factor levels. A clinically suspect patient should be retested in a few weeks if initial von Willebrand factor levels are normal.
Von Willebrand factor levels are adjusted according to ABO blood grouping.
Sodium levels should be measured in patients taking DDAVP as multiple doses along with free fluid intake can cause severe Hyponatremia. Similarly, NSAIDs should be used with caution as they can worsen hyponatremia.
Prolonged DDAVP use can lead to tachyphylaxis.
DDAVP and anti-fibrinolytic agents carry a thrombosis risk. Von Willebrand factor replacement therapy is preferable in patients with cardiovascular or cerebrovascular disease.
Tranexamic acid is not recommended in gross haematuria. Clots can form and cause ureteric or urethral obstruction.
Though generally avoided due to viral transmission risk, cryoprecipitate and fresh frozen plasma (FFP) can be used in life-threatening scenarios.
DDAVP dosing is 0.3 micrograms/Kg administered over 20 to 30 minutes.
The management of Von Willebrand disease is with a multidisciplinary team. While the hematologist usually manages acute bleeding episodes, the follow up is usually by the primary caregiver or nurse practitioner. The key to prevention of bleeding is patient education. Patients should be told to avoid high-risk sporting activities or contact sports. More important they should be told about the signs and symptoms of bleeding and when to seek medical help.
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