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Michiels JJ, Smejkal P, Zapletal O, Penka M, Blatny J, Budde U, Mayger K, Moore GW, Vangenechten I and Gadisseur A
The VWF: RCo/VWF: Ag, VWF: GPIbM/VWF: Ag and VWF: GPIbR/VWF: Ag ratios are normal (above 0.7) in all variants of VWD type 1 and lowVWF and decreased (below 0.7) in VWD type 2 A, 2B and 2M. The VWF: RCo/VWF: Ag, GPIbR/VWF: Ag and GPIbM/VWF: Ag ratios are variable around the cut off level of 0.70 in VWD type 2A (II E) due to a multimerization defect in the D3 domain and therefore diagnosed as either type 1E or type 2E. The mutation W1144G/WT and Y1146C/WT result in dominant VWD type 1E or 2E associated with a secretion and clearance defect in the situtation S979N/WT result in dominant VWD 2 E with the absence of a clearance defect.Heterozygous R924Q/WT and homozygous R924Q/E924Q result in reduction of VWF and FVIII consistent with VWD type in particular when associated with blood group O. In dominant VWD 2A (IIA) due to G1597R mutations in the A2, the VWF: GPIbM/VWF: Ag and VWF: GPIbR/VWF: Ag ratios are markedly decreased to a similar degree as VWF: RCo/VWF: Ag and VWF: CB/VWF: Ag ratios due to the proteolysis loss of large and intermediate VWF multimers. In VWD 2B the VWF: GPIbM/VWF: AG ratios were more markedly decreased (below 0.40, range 0.14-0.37) compared to decreased VWF: RCo/VWF: Ag and VWF: CB/VWF: Ag ratios (range 0.17-0.68) due to the proteolytic loss of large VWF multimers. For the R1306W, R1308C and R1341W VWD 2B mutations (N=7) the activity/antigen ratios ranged from 0.15 to 0.88 for VWF: RCo, 0.44 to 0.80 for VWF: CB and markedly lower ratios from 0.15 to 0.48 for VWF: GPIbM and 0.09 to 0.33 for vWF: GPIbR. VWD 2M mutation R1359K due loss of RIPA function mutation in the A1 domain is featured by normal VWF: CB/VWF: AG ratio (range 0.80-1.05) with decreased VWF: RCo/VWF: Ag ratio (range 0.10-0.38) and similarly decreased VWF: GPIbR/VWF: Ag ratio (range 0.14-28) but the VWF: GPIbM/VWF: Ag ratio was somewhat higher (range 0.32 to 0.36) indicating the need to retain the VWF: CB and RIPA assay to differentiate between VWD 2M and VWD 2B. Mild VWD 2M due to mutations G1415D, P1266L/V1281I and E1292D/WT (N=7) have decreased VWF: RCo/Ag ratios but normal VWF: CB/Ag, VWF: GPIbM/Ag and VWF: GPIbR/Ag ratios in the majority of them. Addition of VWF propeptide (VWF: PP) assay, VWF multimer analysis, mutation detection and responses of VWF parameters to DDAVP will significantly better characterize the phenotype of each individual VWD patient. The Platelet Function Analyzer Closure Times (PFA-CT) are moderately prolonged between the upper limit of normal to 300 seconds in mild VWD type 1 patients due to heterozygous/WT mutations, including mild VWD due to mutations located in the A1 (P1266L) and A2 (Y1584C) domains. The PFA-CT are strongly prolonged (>300 sec) in VWD 2A, 2B, 2C, 2D and 2M due to mutations in the A1, A2, D2 and CK domains respectively and in recessive severe type 1 VWD due to double heterozygous null/missense mutations in the A2/D1 and A2/D domains.