Basic Insights into the Molecular Etiology and Pathology of Von Willebrand Factor (VWF) Behind the ISTH And ECLM Classifications of Von Willebrand Disease Using a Complete Set of VWF Parameterss

The authors present a novel focus on the molecular basis of von Willebrand disease (VWD) phenotype classifications behind the International Society on Thrombosis and Haemostasis (ISTH) and the European Clinical Laboratory and Molecular (2019 ECLM). The ECLM molecular-based classification of VWD type 1, 2 and 3 in this study starts with the detection of the mutation defect located to the D1, D2, D”, D3, A1, A2, A3, D4, C1 to 6 or the CK domains of the VWF gene and than phenotyping each individual VWD patient by a complete set of FVIII:C and von Willebrand factor (VWF) parameters. Recessive VWD type 3 is caused by homozygous or double heterozygous null/null mutations and present with pseudo-hemophilia A first decribed by Erik von Willebrand. Recessive severe VWD type 1 due to homozygous or double heterozygous missense mutation in the D1 domain is featured by persistence of proVWF as the cause of secretion/multimerization and FVIII binding defect mimicking VWD type 3 (pseudo-hemophilia A). Carriers of heterozygous/wild type mutations in the D1 and D2 domains have decreased values for VWFpp, VWFpp/Ag ratios (0.51 to 0.99) indicating a secretion defect. ISTH defined VWD patients type 1 or 2 due to a multimerization defect in the D3 domain typically have VWF:RCo/Ag and VWF:CB/Ag ratios around the cut off level of 0.70 are diagnosed as VWD type 1E and type 2E patients when the ECLM criteria are applied. Twenty two reported VWD type 1E and 2E patients due to different missense mutations in the D3 domain are multimerization defects associated with an additional secretion defect (increased FVIII:C/VWF:Ag ratio) and/or clearance defect (increased VWFpp/Ag ratio). Ristocetine Induced Platelet Agglutination (RIPA) is decreased in VWD 2M, increased in VWD 2B , normal in VWD 1, normal in mild to moderate 2A, but decreased in pronounced VWD 2A, 2C and 2D. Dominant VWD 2A caused by mutations in the A2 domain have decreased VWF:RCo/Ag and VWF:CB/Ag ratios due to proteolytic loss of large VWF multimers. Dominant VWD 2B caused by gain of RIPA function mutations in A1 domain have decreased VWF:RCo/Ag and VWF:CB/Ag ratios due to spontaneous platelet-VWF interaction in vivo followed by proteolytic loss of large VWF multimers. Dominant VWD 1m caused by mutations in the A3 domain is featured by normal VWF:RCo/Ag ratio and decreased VWF:CB/ Ag ratio (2CB) or a decreased VWF:RCo/Ag ratio and normal VWF:CB/Ag (2M). The majority of VWF mutations in the D4 and C1 to C6 result in VWD phenotype 1 secretion defect (SD) with smeary (1sm) or normal (1m) multimers with normal clearance or a minor clearance defect. VWD type 1C (Vicenza) due to heterozygous R1205H/WT mutation in the D3 domain uniformally result in a prounounced FVIII/VWF clearance defect featured by a high VWFpp/Ag ratio and normal FVIII:C/VWF:Ag ratio. Heterozygous S2179F/WT mutation in the D4 domain is featured by pronounced VWD type 1m due to a Secretion Defect (SD) with increased FVIII:C/VWF:Ag ratio in combination with a Clearance (C) defect with increased VWF:pp/Ag ratio.