rs61750579 — VWF V1607D

VWF V1607D — A Cleavage Site Variant That Unmakes the Bleeding Brake

Von Willebrand factor is the primary bridge between a damaged blood vessel wall and the platelet plug that stops bleeding. It circulates as a series of multimers of varying size; the largest, high-molecular-weight (HMW) multimers are the most haemostatically active because they unfurl under shear stress to capture platelets at injury sites. Size is regulated by ADAMTS13¹¹ ADAMTS13
A metalloprotease that cleaves VWF at the Tyr1605-Met1606 bond in the A2 domain, converting ultra-large multimers into smaller circulating forms. The rs61750579 variant encodes the Val1607Asp substitution²² Val1607Asp substitution
valine-to-aspartate change at position 1607, immediately C-terminal to the ADAMTS13 scissile bond — one of the most mechanistically direct causes of type 2A von Willebrand disease (VWD) identified to date.

The Mechanism

The A2 domain of VWF normally folds so that the Tyr1605-Met1606 scissile bond is buried and inaccessible to ADAMTS13 in the absence of mechanical force. When large shear stress stretches VWF at sites of high flow, the A2 domain transiently unfurls, exposing the cleavage site for regulated proteolysis. The Val1607Asp substitution introduces a charged aspartate residue immediately adjacent to this bond, destabilising the folded A2 domain and promoting a constitutively open conformation³³ destabilising the folded A2 domain and promoting a constitutively open conformation
structural studies using FRET constructs showed that most type 2A mutations — including those at the cleavage site — separate the domain's N and C termini without requiring applied force. The result is that ADAMTS13 can cleave VWF continuously, even without mechanical provocation. HMW multimers are selectively degraded, leaving only small multimers in circulation that are unable to support effective platelet adhesion under physiological shear conditions.

Hassenpflug et al. expressed all 13 known A2 domain VWD type 2A mutations in recombinant form⁴⁴ Hassenpflug et al. expressed all 13 known A2 domain VWD type 2A mutations in recombinant form
using a standardised proteolysis assay with ADAMTS13 at physiological concentrations and found that 11 of 13 mutants showed increased susceptibility to cleavage compared to wild-type VWF — a finding that mirrors the selective HMW multimer loss seen in patients' plasma. V1607D was among the mutations that increased proteolytic susceptibility. The biochemical outcome — accelerated cleavage — exactly accounts for the absent HMW multimers that define VWD type 2A on gel electrophoresis.

The Evidence

Type 2A VWD caused by the Val1607Asp variant is classified as pathogenic in ClinVar (VCV000000286)⁵⁵ pathogenic in ClinVar (VCV000000286)
Three independent submitters, with classification criteria provided; OMIM allelic variant 613160.0003. ClinVar records document the selective loss of HMW VWF multimers in individuals carrying this variant, consistent with ADAMTS13 hyperactivity at the mutant A2 domain.

Structural modelling by Pozzi et al.⁶⁶ Pozzi et al.
2012, Biophysical Chemistry showed that the Val1607Asp mutation — in contrast to oxidative modifications at the nearby Met1606 residue that impair cleavage — shifts the VWF-ADAMTS13 interaction toward accelerated proteolysis, producing a net haemorrhagic phenotype. The model correctly predicts the clinical observation that these patients bleed rather than clot.

Inheritance is autosomal dominant⁷⁷ autosomal dominant
one mutant allele is sufficient to produce disease, because VWF multimers assembled from a mixture of wild-type and mutant subunits are still hypersusceptible to ADAMTS13 if even one Val1607Asp subunit is incorporated. This distinguishes type 2A VWD from the recessive type 3 VWD — heterozygous carriers of V1607D have full clinical disease, not a silent carrier state.

Practical Actions

Diagnosis of VWD type 2A requires a panel of laboratory tests: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo or VWF:GPIbR), factor VIII coagulant activity (FVIII:C), and VWF multimer analysis. The hallmark is a discordant VWF:RCo to VWF:Ag ratio below 0.6 (more activity loss than antigen loss), with absent HMW multimers on gel electrophoresis.

Desmopressin (DDAVP) releases stored VWF from endothelial Weibel-Palade bodies but is only partially effective in type 2A VWD. Atiq et al. found that only ~31% of type 2 VWD patients achieve complete desmopressin response⁸⁸ Atiq et al. found that only ~31% of type 2 VWD patients achieve complete desmopressin response
compared to 100% of type 1 VWD patients without VWF gene variants, and response is highly variant-dependent. For the V1607D mutation — where accelerated proteolysis rapidly degrades the released VWF — the haemostatic benefit from DDAVP is typically short-lived and incomplete. A formal DDAVP trial under clinical supervision is required to determine individual response before relying on it for procedures.

For bleeds and surgical prophylaxis where desmopressin is insufficient, plasma-derived or recombinant VWF concentrate (Vonvendi, Wilate, Humate-P) restores all multimer sizes and is the established treatment. Antifibrinolytic agents (tranexamic acid) are effective adjuncts for mucosal bleeding.

Interactions

ABO blood group independently modulates circulating VWF levels — blood group O reduces VWF by approximately 25% through increased ADAMTS13-mediated clearance. Carriers of V1607D who also have blood group O (tagged by rs505922) may have compounded VWF deficiency beyond what the genotype alone predicts.

The rs1800380 variant (VWF p.Arg854Gln, type 2N VWD) affects the factor VIII binding domain of VWF rather than the A2 domain; compound heterozygotes carrying both V1607D and R854Q would have combined quantitative, qualitative, and FVIII-transport defects, requiring specialist assessment. Other VWF A2 domain variants (rs61750630 and related exon 28 mutations) can co-occur in the same gene and produce compound phenotypes.