Von Willebrand Disease [VWD] - Summary
Subtype Inheritance Prevalence Bleeding Phenotype APTT VIII:C VWF:Ag VWF:RCo VWF:Act [VWF:Ag]: VWF:RCo] Ratio FVIII Binding RIPA - Low Dose1 RIPA - High Dose1 Platelet Count PFA-100 Multimers Comments
Normal - - - Normal Normal Normal Normal Normal 1 Normal Absent Normal Normal Normal    
1

[Partial quantitative deficiency]
Autosomal dominant Common - accounts for 80% of cases of VWD.
Prevalence in the general population may be as high as 1%.
Mild to moderate May be normal or abnormal- depends upon the severity of the disorder and the level of VIII:C Normal or ↓ ↓ or ↓↓ ↓ or ↓↓ ↓ or ↓↓ 1 [i.e. a parallel reduction in VWF:Ag and VW:RCo Note: In Type 1 the VWFpp:VWF:Ag ratio is normal but in Type 1 Vicenza [=Type 1C VWD] - the ratio is ↑ Usually Normal Absent Often Normal Normal Normal or ↑ Normal distribution There are a wide spectrum of mutations associated with Type 1 VWD. Mutations include those that interfere with the intracellular transport of VWF, or which accelerate the clearance of VWF from the plasma e.g Type 1 Vicenza.
2A

[Qualitative deficiency:
Decreased VWF-dependent platelet adhesion with selective loss of HMWM]
Autosomal dominant [or recessive] Uncommon Variable - usually moderate Normal or ↑ Normal or ↓ ↓ ↓ or ↓↓↓ ↓ ↓ or ↓↓↓ Normal Absent Normal ↑↑↑ High and intermediate molecular weight multimers absent. Frequent abnormal triplet sub-bands Type 2A VWD is due to a qualitative abnormality of VWF in which the proportion of HMW multimers is reduced. Type 2A VWD can be caused by mutations that interfere with VWF assembly or by mutations that increase its susceptibility to proteolytic cleavage in plasma.
Mutations that affect multimer assembly usually lead to the secretion of multimers that are unable to bind to platelets efficiently.
Homozygous mutations in the VWF prepropeptide interfere with multimer assembly within the Golgi of the cell - historically this was classified as Type IIC VWD.
Heterozygous mutations within the cysteine knot region of VWF [XXXX] can impair dimerisation of VWF within the ER and lead to a phenotype historically known as Type IID VWD.
Heterozygous mutations within the D3 domain can also impair multimer assembly leading to a phenotype historically known as Type IIE VWD.
2B

[Qualitative deficiency: Increased affinity for platelet GpIb]
Autosomal dominant Uncommon Variable - usually moderate Usually Normal or ↑ Normal or ↓ Normal or ↓ ↓↓ ↓↓ Normal ↑↑↑ Usually normal Usually ↓ but may be normal ↑↑↑ Variable loss of high-molecular weight multimers. Occasionally multimer distribution is normal with all high-molecular weight multimers present. Type 2B VWD is caused by mutations that increase platelet-VWF binding leading to proteolytic degradation and depletion of HMW functional VWF multimers. This is similar to Pseudo/platelet type VWD in which mutation in the GpIb receptor leads to an increased affinity for VWF leading to a depletion of the HMWM in the plasma.
Type 2B mutations occur within or adjacent to Domain 1. These mutations appear to stabilise platelet-VWF interaction so enhancing platelet binding.
2M

[Qualitative deficiency: Decreased VWF-dependent platelet adhesion without selective deficiency of HMWM]
Autosomal dominant [or recessive] Uncommon Variable - usually moderate Usually Normal or ↑ ↓↓ Usually ↓ ↓↓ ↓↓ Normal Absent Normal The full range of VWF multimers is present. Occasionally ultra-large multimers are present Type 2M mutations reduce the interaction of VWF with platelet GpIb of with connective tissue and do not substantially impair multimer assembly.
Mutations in Type 2M have been reported in the A1 domain and in the A3 domain.
2N

[Qualitative deficiency: Markedly decreased binding affinity for FVIII]
Autosomal recessive Uncommon Variable - usually moderate ↑↑ ↓↓ Normal Normal Normal Normal but VIII:C/VWF:Ag ratio is decreased Abnormal Absent Normal Normal Normal Normal distribution Type 2N VWD is due to homozygous mutations that impair binding to FVIII leading to a reduction in circulating FVIII. 2N VWD was frequently mistaken as mild-moderate haemophilia A as the VWF levels are normal but FVIII is reduced. However, the pattern of inheritance in 2N VWD is autosomal recessive whilst in Haemophilia it is X-linked.
Most mutations causing 2N VWD lie in either the D' or D3 domain.
3

[Virtually complete deficiency of VWF]
Autosomal recessive Rare
1:250,000 - 1:1,000,000. Possibly as high as 6:1,000,000 where consanguinity is common
Severe ↑↑↑ ↓↓↓ Usually very low or undetectable Usually very low or undetectable Usually very low or undetectable   Normal Absent Absent Normal ↑↑↑ No multimers visualized. May be faint low-molecular weight bands present. No consistent genetic abnormality has been identified in Type 3 VWD.
Individuals with complete gene deletions may be at risk of developing inhibitors following treatment with VWF-containing concentrates.
Individuals who are heterozygous for mutations that when present either in the homozygous state or compound heterozygous state may have none or only a minor bleeding phenotype.
Pseudo/Platelet-Type VWD
[Abnormality of the Platelet membrane GpIb receptor]
Autosomal recessive Rare Variable Usually normal but may be increased Normal or ↓ ↓↓ ↓↓ ↓↓ Normal Normal ↑↑↑     Presence of ultra HMWM  
Type 1 C: VWD Vicenza and similar variants with accelerated clearance of a variant protein Autosomal dominant Uncommon Uncommon Mild to moderate May be normal or abnormal- depends upon the severity of the disorder and the level of VIII:C Normal or ↓ ↓ or ↓↓ ↓ or ↓↓ In Type 1 the VWFpp:VWF:Ag ratio is normal but in Type 1 Vicenza [=Type 1C VWD] - the ratio is ↑ Normal Absent Often Normal Normal Normal or ↑ Normal distribution The mutation in Type 1 VWD Vicenza [Arg1205His] leads to the accelerated clearance of the variant VWF from the plasma. VWF:RCo is reduced [commonly around 15 IU/dL].
Measuring the VWFpp/VWF:Ag ratio can be of value in establishing the presence of a variant VWF with an accelerated clearance. In this and similar mutants with accelerated clearance both VWF and FVIII levels are reduced.