JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 6, NO.

7, 2021

ª 2021 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

TRANSLATIONAL PERSPECTIVE

Von Willebrand Factor Activity in

Thrombosis
An Overlooked Target for Intervention?

Theodor W. Shalmi, BMED, Jens P. Goetze, MD, DMSC

v on Willebrand disease (VWD) is the most

common heritable bleeding disorder. Low
von Willebrand factor (VWF) activity occurs
in as much as 1% of the general population. The clin-
to facilitate hemostasis, due to larger multimers
having more collagen and glycoprotein Ib a (GPIba )
binding sites. Because of this, a high proportion of
ultramultimeric VWF is a potent risk factor for
ical phenotype of VWD is, however, markedly lower. developing thrombosis. In some cases, a high pro-
VWD can be caused by mutations within the VWF portion of ultramultimeric VWF can even lead to the
(von Willebrand factor) gene located on Chromosome disease thrombotic thrombocytopenic purpura, which
12 or by variants occurring outside the VWF locus, is characterized by multiple thromboses within the
which either reduce the total amount of translated smaller blood vessels.
protein (types 1 and 3 disease) or the functional activ- The diagnosis of VWD can be a cumbersome mat-
ity of the protein (type 2 disease). Acquired VWD ter. First and foremost, VWF is not measured by
based on development of autoantibodies against the routine coagulation screening tests, for example
protein also exists, albeit very rarely. VWF is a central prothrombin time (international normalized ratio)
component in the primary hemostasis, where it binds and activated partial thromboplastin time, which
platelets to the injured vessel wall (Figure 1). This often is the cause of a lack of diagnosis before a major
generates a primary platelet-rich clot that acts as a bleeding event in the cardiovascular setting. Gener-
scaffold for the secondary hemostasis. In addition, ally, a diagnosis of VWD requires a repeated activity
VWF serves as a carrier of coagulation factor VIII in measurement of <30% of normal activity in steady
circulation. Binding of factor VIII to VWF protects state, for example in individuals without concurrent
the former against rapid degradation. As a central inflammation (the protein expression is regulated as
component in hemostasis, it is worth highlighting an acute phase reactant). Nevertheless, the relation-
that the regulation of VWF has not been considered ship between the blood type system and the activity
a target for medical therapy to prevent cardiovascular of VWF still presents a challenge for the clinical
thrombosis. diagnosis of VWD. Individuals with blood type O
In vivo, VWF is synthesized by the vascular endo- generally have a 25% lower activity of VWF in plasma
thelium and megakaryocytes. During biosynthesis, when compared with those with type A, B, or AB. Of
the protein is assembled into larger multimeric forms relevance, people with blood type O have also been
that range between 2 and 40 subunits, the largest of reported to experience a lower frequency of throm-
which are referred to as ultramultimers. There is a bosis, whereas individuals with blood type A, B, or AB
direct proportionality between the number of sub- have a nearly 3-fold increased risk of venous throm-
units in a multimeric molecule of VWF and its ability bosis compared with individuals with blood type O.

From the Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ in-
stitutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit
the Author Center.

Manuscript received March 16, 2021; revised manuscript received May 5, 2021, accepted May 5, 2021.

ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2021.05.003

596 Shalmi and Goetze JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 6, NO. 7, 2021

Von Willebrand Factor in Thrombosis JULY 2021:595–597

F I G U R E 1 Interaction of Von Willebrand Factor, Platelets, and ADAMTS-13

(Left) The normal binding of von Willebrand factor (VWF) and platelets, and the function of ADAMTS-13. (Right) A hypothetical drug blocking
the binding of platelets to VWF, and an effect of an exogenous ADAMTS-13 on VWF.

Though it is unclear whether reduced activity of VWF 67% fewer cases compared with the second. Similar
is the sole cause of the lower risk of thrombosis in values were found for cardiovascular disease and
people with blood type O, a partial relationship be- ischemic stroke (3). Another largescale study analyzed
tween the variables seems relevant to consider. In a group of 355 VWD patients from a 25-year period and
support of such an argument, higher VWF levels in found a notable decrease in the risk of arterial throm-
plasma have been found to be an independent pre- bosis (4). Several smaller studies suggest that both
dictor of thrombosis. An effect of blood type and venous and arterial thromboses occur less frequently
platelet function may, however, also play a role in the in patients with VWD compared with healthy control
cardiovascular phenotype of individuals with blood subjects (5,6). However, the possibility that the vari-
type O (1). Finally, a few reports have suggested that able and generally underdiagnosed nature of VWD in
a reduced level of ADAMTS-13, the key enzyme the general population means that its relationship to
involved in cleaving/inactivating the ultralarge VWF thrombosis can only be fully understood in larger-scale
forms, represents an independent risk factor for studies, is important to consider in regard to the con-
coronary thrombosis (2). clusions of small-scale studies. Furthermore, some
Following the current data on blood type, VWF, and individuals have acquired or inherited prothrombotic
risk of thrombosis, it seems reasonable to hypothesize factors that cause a considerably increased risk of
that a lower activity of VWF will reduce the risk of thrombosis. An inherent thrombophilia could, in the-
thrombosis. A largescale Dutch study analyzed the ory, be offset if the individual also had VWD. This rai-
relationship between VWD and the risk of arterial ses the question of whether lowering the activity VWF
thrombosis. The study found that between 635 Dutch could be the basis for future medicine designed to
individuals with VWD and 2 reference groups adjusted prevent thrombosis.
for age, sex, and body weight, the group with VWD Thrombosis in the coronary arteries is the most
experienced 39% fewer cases of arterial thrombotic common cause of sudden cardiac death. Although
events compared with the first reference group, and there are many modalities for preventing thrombosis,
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 6, NO. 7, 2021 Shalmi and Goetze 597
JULY 2021:595–597 Von Willebrand Factor in Thrombosis

anticoagulation therapy still comes with an increased be in relation to the asialoglycoprotein receptor in the
risk of bleeding, including cerebral hemorrhage. As liver. Selective inhibition of the VWF pathway in an-
such, there is still a need for new drugs to prevent imal models has also been found to prevent platelet
thrombosis without increasing bleeding tendency. aggregation for both venous and arterial thrombosis.
Lowering the concentration of VWF in circulation In conclusion, there is now evidence to suggest
would be such a possibility. This could be achieved that a decrease in the activity of VWF, as seen in
with a drug targeted to either inhibit the secretory patients with VWD type 1 or people with blood type
pathway of VWF or to activate the general degrada- O, is associated with a reduction of the risk of
tion of the protein. In this context, the safest way thrombosis. The potential of VWF to be a new
here would probably be to target clearance rather antithrombotic target in the future prevention of
than total protein expression, as the risk of bleeding arterial thrombosis deserves more attention in
could rapidly outweigh the antithrombotic conse- translational science. For now, we urge for clinical
quences. Given that VWF also has a role as carrier studies on the VWF phenotype and the risk of
protein for coagulation factor VIII, this could also be a arterial thrombosis, particularly in cardiological
potential target by mimicking some aspects of he- settings where both venous and arterial thromboses
mophilia A. Finally, the binding capacity of VWF to are still far from conditions with a safe and efficient
either fibrinogen or collagen could represent a mo- therapy option.
lecular target for intervention.
Reducing the amount of large VWF multimers in FUNDING SUPPORT AND AUTHOR DISCLOSURES
plasma by increasing the circulating levels of
ADAMTS-13 may be another option. Though the total The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
amount of VWF would go unchanged, a reduction in
large VWF multimers would lower platelet aggrega-
tion. This reduction could be achieved either through ADDRESS FOR CORRESPONDENCE: Dr Jens P. Goe-
the administration of recombinant ADAMTS-13, or by tze, Department of Clinical Biochemistry, Rig-
interrupting the clearance pathway of the protein. shospitalet, University of Copenhagen, Blegdamsvej
Though the process in which ADAMTS-13 is cleared 9, DK-2100, Copenhagen, Denmark. E-mail: JPG@
in vivo has not been fully mapped, it is suspected to dadlnet.dk.

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