Main characteristics of von Willebrand disease types.
| Type of VWD . | Laboratory . | Multimers . | Mutations associated . | Comments . |
|---|---|---|---|---|
| * Mutation responsible for VWD in the original family described by E von Willebrand. | ||||
| Type 1 | Concurrent reduction of FVIII:C and VWF in plasma; VWF:RCo/VWF:Ag ≥ 0.6 | All multimers present; some minor abnormalities may be evident using sensitive methods | Missense mutations scattered over the entire gene. Possible dominant-negative effect. Y1584C in about10%, causative role uncertain.9,10 Single null allele not associated with bleeding | Usually co-dominant or dominant-negative. Ideal candidates for desmopressin. Short VWF half-life in VWD Vicenza (R1205H)34 and other rare mutations.31,53 |
| Type 2A | Usually VWF:RCo/VWF:Ag < 0.6 | Lack or relative decrease of the high molecular weight (HMW) and of intermediate multimers | Mutations in A2 domain; R1597W or Q or Y and S1506L represent about 60% of cases.51 | Usually co-dominant. Two mechanisms demonstrated by expression experiments. Group I: impaired secretion of HMW multimers, due to defective intracellular transport. Group II: normal synthesis and secretion of a VWF with greater susceptibility to in vivo proteolysis.52 Patients of the latter group may respond to desmopressin.27 |
| Type 2B | Usually VWF:RCo/VWF:Ag < 0.6; RIPA occurs at low ristocetin concentration | Lack of HMW multimers; a normal pattern is present in New York/Malmö variant | Mutations in A1 domain; 90% of cases are due to R1306W, R1308C, V1316M and R1341Q.51 P1266L associated with gene conversion and New York/Malmö phenotype.12 | Usually co-dominant. Enhanced affinity of abnormal VWF for platelet GpIb receptor. Thrombocytopenia after desmopressin and sometimes during pregnancy or stress situations; thrombocytopenia may aggravate bleeding risk conferred by the abnormal VWF.28 |
| Type 2M | Usually VWF:RCo/VWF:Ag < 0.6; | Large multimers present; inner abnormalities may be evident (eg, “smeary pattern”) | A few heterogeneous mutations recurrent (eg, R1315C, G1324S/A, R1374C/H) | Usually co-dominant. Some overlap with Type 2A may occur. Desmopressin may be useful in selected cases. |
| Type 2N | VWF may be normal or only slightly reduced; FVIII:C/VWF:Ag < 0.5; defective FVIII-VWF binding | All multimers present | Mutations in NH2-terminus; R854Q largely the most frequent mutation. | Usually recessive. Bleeding only for homozygosity or compound heterozygosity. Heterozygosity for R854Q in up to 2% of population in Northern Europe.7 Desmopressin may be useful for the majority of minor bleedings |
| Type 3 | Virtual absence of VWF; markedly reduced FVIII:C (< 5 IU/dL) | Lack of multimers | Mutations scattered over the entire gene, but some (eg, 2430delC exon 18* or Arg2535stop) are particularly recurrent in North Europe. High prevalence of null mutations (stop codons, frameshift, gene deletions).32,51 | Recessive. Homozygosity for gene deletion associated with an increased risk of inhibitor, causing anaphylactic reactions to exogenous VWF.33 Desmopressin does not work since cellular storage is devoid of VWF |
| Type of VWD . | Laboratory . | Multimers . | Mutations associated . | Comments . |
|---|---|---|---|---|
| * Mutation responsible for VWD in the original family described by E von Willebrand. | ||||
| Type 1 | Concurrent reduction of FVIII:C and VWF in plasma; VWF:RCo/VWF:Ag ≥ 0.6 | All multimers present; some minor abnormalities may be evident using sensitive methods | Missense mutations scattered over the entire gene. Possible dominant-negative effect. Y1584C in about10%, causative role uncertain.9,10 Single null allele not associated with bleeding | Usually co-dominant or dominant-negative. Ideal candidates for desmopressin. Short VWF half-life in VWD Vicenza (R1205H)34 and other rare mutations.31,53 |
| Type 2A | Usually VWF:RCo/VWF:Ag < 0.6 | Lack or relative decrease of the high molecular weight (HMW) and of intermediate multimers | Mutations in A2 domain; R1597W or Q or Y and S1506L represent about 60% of cases.51 | Usually co-dominant. Two mechanisms demonstrated by expression experiments. Group I: impaired secretion of HMW multimers, due to defective intracellular transport. Group II: normal synthesis and secretion of a VWF with greater susceptibility to in vivo proteolysis.52 Patients of the latter group may respond to desmopressin.27 |
| Type 2B | Usually VWF:RCo/VWF:Ag < 0.6; RIPA occurs at low ristocetin concentration | Lack of HMW multimers; a normal pattern is present in New York/Malmö variant | Mutations in A1 domain; 90% of cases are due to R1306W, R1308C, V1316M and R1341Q.51 P1266L associated with gene conversion and New York/Malmö phenotype.12 | Usually co-dominant. Enhanced affinity of abnormal VWF for platelet GpIb receptor. Thrombocytopenia after desmopressin and sometimes during pregnancy or stress situations; thrombocytopenia may aggravate bleeding risk conferred by the abnormal VWF.28 |
| Type 2M | Usually VWF:RCo/VWF:Ag < 0.6; | Large multimers present; inner abnormalities may be evident (eg, “smeary pattern”) | A few heterogeneous mutations recurrent (eg, R1315C, G1324S/A, R1374C/H) | Usually co-dominant. Some overlap with Type 2A may occur. Desmopressin may be useful in selected cases. |
| Type 2N | VWF may be normal or only slightly reduced; FVIII:C/VWF:Ag < 0.5; defective FVIII-VWF binding | All multimers present | Mutations in NH2-terminus; R854Q largely the most frequent mutation. | Usually recessive. Bleeding only for homozygosity or compound heterozygosity. Heterozygosity for R854Q in up to 2% of population in Northern Europe.7 Desmopressin may be useful for the majority of minor bleedings |
| Type 3 | Virtual absence of VWF; markedly reduced FVIII:C (< 5 IU/dL) | Lack of multimers | Mutations scattered over the entire gene, but some (eg, 2430delC exon 18* or Arg2535stop) are particularly recurrent in North Europe. High prevalence of null mutations (stop codons, frameshift, gene deletions).32,51 | Recessive. Homozygosity for gene deletion associated with an increased risk of inhibitor, causing anaphylactic reactions to exogenous VWF.33 Desmopressin does not work since cellular storage is devoid of VWF |