Discussion

Von Willebrand’s Disease (vWD) is the most common inherited bleeding disorder, occurring in some form in up to 1 percent of the general population. Over 20 variants of the disorder have been identified and are generally divided into three types. Type 1 accounts for more than 70 percent of vWD and involves a quantitative von Willebrand Factor (vWF) defect. The rare type 3 vWD is also a quantitative vWF defect but is much more severe than type 1 with low or undetectable levels of vWF. Type 2 vWD has many subtypes that involve various qualitative defects in vWF and accounts for 20-30% of vWD cases.

Von Willebrand Factor is produced only in endothelial cells and megakaryocytes. The vWF gene resides on the short arm of chromosome 12 (12p 13.3). The vWF is synthesized initially as a large precursor monomer polypeptide. The monomers are assembled to dimers through disulfide bonds in the endoplasmic reticulum where glycosylation also begins. Further posttranslational modification and finally multimerization occur in the Golgi apparatus. The vWF is stored in platelet alpha granules and in Weibel-Palade bodies of endothelial cells. Functionally, vWF is a large multivalent protein involved in platelet binding to subendothelial surfaces and platelet-platelet binding. Plasma vWF also is important for the stability of circulating Factor VIII to which it binds noncovalently.

Type 1 and type 3 vWD both involve a reduction in the amount of circulating vWF.  Type 1 is generally autosomal dominant and involves usually a 20-50 percent reduction in vWF with proportional decrease in Factor VIII and ristocetin cofactor activity.  The structure of the multimers present in type 1 is generally normal.   In the autosomal recessive type 3 vWD, the vWF and ristocetin cofactor activity are extremely low or undetectable, and factor VIII level is usually 3-10 percent of normal.  The type 2 vWD subtypes show varying inheritance patterns in addition to the different qualitative defects.  Type 2A is autosomal dominant and involves a loss of the intermediate and large vWF multimers.  Type 2B is autosomal dominant and involves increased affinity of the large vWF multimers for platelet binding.  This results in accelerated clearing of the vWF and platelets with resulting thrombocytopenia and reduced large multimer vWF.  Type 2N is autosomal recessive and results in a normal level of vWF which has a decreased affinity for Factor VIII.  This results in a disorder very similar to Hemophilia A.  Pseudo- or platelet-type von vWD is autosomal dominant and involves a defect in the vWF-binding domain of platelets.

Clinical symptoms vary with the type and subtype of vWD.  Type 1 patients may report epistaxis, increased bruising, menorrhagia, gingival bleeding, or GI bleeding.  The more severe type 3 patients can experience hemarthrosis and muscle hematomas.  The symptoms in type 2 vary with subtype with the type 2B notable for thrombocytopenia not seen in other vWD types.

Laboratory evaluation usually begins with factor VIII, vWF, and ristocetin cofactor activity. All three tests can vary greatly with various medications, diseases, and normal physiologic conditions so repeat testing is often indicated. Factor VIII tends to be decreased in all vWD types, especially so in types 1, 2N, and most severely in type 3. The vWF antigen is usually decreased in vWD but may be normal in some type 2A patients. Ristocetin cofactor activity is the most sensitive and specific screening test for vWD. It is a measure of aggregation of washed platelets mixed with the patient’s plasma upon addition of ristocetin. Ristocetin cofactor activity is decreased in vWD since the large multimers of vWF are important in ristocetin induced platelet aggregation. Bleeding time has been used in vWD screening but has decreased in use secondary to operator dependence and other difficult to control variables. Platelet function analysis using collagen with epinephrine and ADP is being increasingly used in lieu of bleeding time and is increased in all vWD. 

Ristocetin induced platelet aggregation (RIPA) and multimer analysis can be used in diagnosis and classification of vWD. RIPA involves addition of ristocetin to platelet-rich plasma and measuring platelet agglutination. RIPA is decreased in most vWD but agglutination is increased with low concentrations of ristocetin in type 2B vWD and pseudo-vWD (platelet-type). Multimer analysis, shown above by agarose gel electrophoresis separates multimers with large multimers moving more slowly than small ones. This can aid in identifying type 2A and 2B, which involve disproportionate loss of the larger multimers.

Treatment for most vWD is with Desmopressin (DDAVP), which increases release of vWF from cells. DDAVP has been shown to increase factor VIII activity, vWF, and ristocetin cofactor activity. Approximately 25% of vWD will not respond to Desmopressin, including nearly all type 3 and many type 2 patients. DDAVP is often considered contraindicated in type 2B secondary to potential for increased platelet binding and clearance by the increased release of high affinity vWF. A vWF containing factor VIII precipitate is also used in type 3 and other vWD that are poorly responsive to Desmopressin.

References

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