The pattern of response to desmopressin in these patients may significantly vary in terms of magnitude of increase and half-life of elicited VWF post-desmopressin . De la Fuente et al.  first demonstrated that patients with type 1 VWD, similarly responsive, could have two different pattern of VWF response: the first, with a return to baseline of the raised FVIII and VWF not reached even after 6 h, and the second, with a fast return to baseline values occurring after 2 h. Casonato et al.  showed that patients with VWD Vicenza, characterized by severely reduced plasma FVIII and VWF levels, the presence of ultra-large VWF multimers in plasma, and R1205H mutation in D3 domain, had a marked increase of FVIII and VWF after desmopressin, followed by a rapid disappearance from circulation. An additional amino acid VWF change (M740I) has been identified in some patients with R1205H from the Vicenza area . Although its causative role has not been fully elucidated yet, it appears that its presence does not cause a VWF survival different from that observed with R1205H alone [10,18,19]. An elegant confirmation of these findings was represented by the demonstration that purified recombinant R1205H VWF infused in VWF-deficient mice had a very short residence time (0.3 h) compared with wild-type VWF (2.8 h) . Subsequently, Haberichter et al.  showed that two additional mutations (W1144G in the D3 domain and S2179F in D4 domain) were associated with reduced VWF survival after desmopressin, while a normal survival after infusion of a FVIII/VWF concentrate was observed (Table 1). Most importantly, these Authors clearly showed that increased clearance could be predicted by an increased steady-state VWFpp/VWF:Ag ratio, which differentiated affected individuals from unaffected individuals. Recently, it has been demonstrated that C1130F and C1149H mutations, both located in the D3 domain, and C2671Y mutation, located in the CK domain residue, had about 4-fold shorter half-life of mutant recombinant VWF infused into VWF-deficient mice compared with Wild Type VWF, but 2-fold longer than that of R1205H . Similarly, VWF half-life in the patients after desmopressin was 4.5-fold shorter compared with a control group. Consistent with previous results [4,18], also these patients showed an increased VWFpp/VWF:Ag ratio. Millar et al.  in a cohort of 26 patients with type 1 VWD showed that as a whole the clearance of VWF after desmopressin was 3-fold increased. This pattern however was neither VWF consistently related to basal VWF:Ag level nor with an increased ratio of VWFpp/VWF:Ag, probably becasuse VWFpp at steady-state was reduced in several patients. Thus, caution should be exercised in extrapolating post-desmopressin VWF clearance to steady-state plasma levels (Table 1). Again, no association between the pattern of VWF clearance and ADAMTS-13-mediated proteolysis was evident. In addition to six patients with significantly shortened VWF:Ag half-lives post-desmopressin, patients with a normal VWFpp/VWF:Ag ratio pre-infusion could have a shortened survival, suggesting that an increased clearance may be associated to a normal ratio. In addition to the R1205H mutation, two novel mutations at the same amino acid position were associated with an increased clearance phenotype (R1205S and R1205C). Interestingly, the shortest survival after desmopressin and the greatest steady-state VWFpp/VWF:Ag ratio was observed in R1205H mutation suggesting a significant role of His1205 in fostering VWF clearance. An additional novel mutation (I1416N in the A1 domain) with a typical type 1 phenotype also showed increased clearance . In a recent study , an increased clearance after desmopressin was probably observed in R1315C, R1379C and K1794E mutations in A1–A3 domain and in three patients with compound heterozygosity (Y1146C/S1378F, V1485fs/Y1584C, R2464C/Y1584C), suggesting that increased VWF clearance in VWD is more frequent than previously believed. Some of the mutations associated with this phenotype have been included among type 2 A (e.g. Y1146C) or 2 M (e.g. R1315C) VWD as some abnormalities of VWF multimeric pattern are detectable by using sophisticated methods . Thus, increased clearance of VWF neither is always associated with a typical type 1 VWD multimeric pattern nor exclusively with mutations in the D3 domain.
Why some mutants are more prone to reduced survival remains unclear and different mechanisms could be responsible. For example, although all localized in D3 domain and all having a reduced VWF survival, C1130F, C1149R and R1205H have a different impact on VWF functions . Unlike R1205H, C1130F and C1149R display impaired FVIII binding and do not multimerize normally (type 2 A VWD), probably because of a defective binding of VWFpp . On the contrary, an additional mutation associated with reduced survival (C2671Y) showed none of these abnormalities suggesting that this part of VWF could contribute to interactions with clearance receptors.