The condition known as von Willebrand disease (vWD) may be categorized into three types, of which types 1 and 3 are due to a deficiency in the level of von Willebrand factor. Type 2 shows normal vWF levels but with serious qualitative defects.
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The most common type of vWD is type 1, which makes up for 70% of all cases. This is mostly transmitted by autosomal dominant inheritance with incomplete penetrance (that is, all those who possess this inherited mutation do not have a bleeding tendency).
Here, vWF multimer levels are normal, and high molecular weight forms are also normal, but factor VIII levels are low. vWF antigens are somewhat or moderately reduced, along with ristocetin cofactor (vWF:RCo) activity in plasma.
This is characterized by bleeding at multiple mucocutaneous sites, the intensity of which varies with the level of vWF and factor VIII. Thus the phenotype varies from no clinical manifestation, through epistaxis and bruising in childhood, or menorrhagia in women, to severe hemorrhage from the skin and mucosa when vWF levels are below 15 IU/dL.
This group of vWD is characterized by normal multimer levels but structural-functional deficiency of vWF.
This is usually autosomal dominant and accounts for a fourth of all cases. The characteristic finding is the deficiency of large and intermediate vWF multimers resulting in defects in vWF-mediated platelet adhesion.
In most patients, there is a greater ristocetin-induced platelet aggregation, with resulting mild to moderate thrombocytopenia. Plasma shows a lack of large multimers. These patients report mild to moderate bleeding from the skin or mucosa.
Here also vWF-mediated platelet adhesion to each other and to connective tissue is reduced, because of increased cleavage of the large multimers, which are correspondingly decreased in the circulation.
Usually mild to moderate, bleeding manifestations may be severe if these patients undergo surgery, become pregnant, experience significant stress or receive desmopressin. Thrombocytopenia is marked at such times.
In this type, vWF multimers show a distribution pattern similar to that resulting from the original release of multimers from the endothelium, but with reduced platelet-mediated vWF adhesion because of functional defects. Bleeding is mild to moderate unless the vWF ristocetin cofactor ratio is very low.
Here the disease is recessively inherited, with a normal multimer distribution pattern in most cases. Despite this either normal or somewhat reduced levels of vWF antigen and vWF:RCo, the low binding affinity for factor VIII leads to its increased destruction and consequently to very low levels of factor VIII, appearing clinically identical to hemophilia A. Thus there is excessive bleeding during surgery.
In this type, which accounts for less than 5% of cases, vWD is inherited in an autosomal recessive manner, with a mutation that results in virtually absent vWF (in most cases it is below 3 U/dL). This leads to extremely low factor VIII levels, such as 1-5 U/dL. These patients show a severe bleeding tendency with hemorrhages from the mucocutaneous surfaces as well as hemarthroses and hematomas.
This type is not caused by vWF mutation, but is characterized by the rapid clearance of vWF from circulation as a result of its adhesion to tumor cells, or vWF antibodies, which are quickly catabolized, or by digestion of proteins. It is also seen in association with vWD when it manifests as gastrointestinal tract hemorrhage. Seen most often over the age of 40 years, it occurs in conditions such as:
- bone marrow dysplasias and related conditions, such as:
- lymphoproliferative disorders
- plasma cell disorders
- paraproteinemias and multiple myeloma
- Waldenstrom’s macroglobulinemia
- autoimmune disorders such as systemic lupus erythematosus and antiphospholipid antibody syndrome
- aortic stenosis and ventricular septal defect, which leads to shear stress and resulting vWF conformational changes and proteolysis
- marked thrombocytosis as in myeloproliferative disorders
- aberrant binding of vWF to tumor cells such as in Wilm’s tumor
- reduced vWF synthesis as in hypothyroidism
- the use of drugs such as valproic acid, griseofulvin or ciprofloxacin