Available via license: CC BY 4.0
Content may be subject to copyright.
International Journal of
Molecular Sciences
Review
Shear Stress-Induced Activation of von Willebrand
Factor and Cardiovascular Pathology
Sergey Okhota 1, Ivan Melnikov 1,2 , Yuliya Avtaeva 1, Sergey Kozlov 1
and Zufar Gabbasov 1, *
1National Medical Research Centre of Cardiology of the Ministry of Health of the Russian Federation,
15A, 3-rd Cherepkovskaya Street, 121552 Moscow, Russia; ae2007@mail.ru (S.O.); ivsgml@gmail.com (I.M.);
julia_94fs@mail.ru (Y.A.); bestofall@inbox.ru (S.K.)
2State Research Center of the Russian Federation—Institute of Biomedical Problems of Russian Academy
of Sciences, 76A, Khoroshevskoye Shosse, 123007 Moscow, Russia
*Correspondence: zufargabbasov@yandex.ru; Tel.: +7-(495)-414-62-79; Fax: +7-(495)-414-69-23
Received: 19 September 2020; Accepted: 20 October 2020; Published: 21 October 2020
Abstract:
The von Willebrand factor (vWF) is a plasma protein that mediates platelet adhesion
and leukocyte recruitment to vascular injury sites and carries coagulation factor VIII, a building
block of the intrinsic pathway of coagulation. The presence of ultra-large multimers of vWF in the
bloodstream is associated with spontaneous thrombosis, whereas its deficiency leads to bleeding.
In cardiovascular pathology, the progression of the heart valve disease results in vWF deficiency
and cryptogenic gastrointestinal bleeding. The association between higher plasma levels of vWF
and thrombotic complications of coronary artery disease was described. Of note, it is not the
plasma levels that are crucial for vWF hemostatic activity, but vWF activation, triggered by a
rise in shear rates. vWF becomes highly reactive with platelets upon unfolding into a stretched
conformation, at shear rates above the critical value (more than 5000 s
−1
), which might occur at
sites of arterial stenosis and injury. The activation of vWF and its counterbalance by ADAMTS-13,
the vWF-cleaving protease, might contribute to complications of cardiovascular diseases. In this
review, we discuss vWF involvement in complications of cardiovascular diseases and possible
diagnostic and treatment approaches.
Keywords:
von Willebrand factor; ADAMTS-13; atherosclerosis; atherothrombosis; coronary artery
disease; Heyde’s syndrome
1. Introduction
The von Willebrand Factor (vWF) is a large multimeric glycoprotein, present in blood plasma,
endothelial cells, megakaryocytes, and platelets. It plays a major role in hemostasis, mediating platelet
adhesion to vascular injury sites. It also binds and protects coagulation factor VIII (FVIII) from
degradation [
1
]. Recent studies showed that vWF is also involved in inflammation, linking thrombosis
and inflammation. Inflammation can provoke thrombosis through the vWF-dependent pathway,
which includes endothelial activation, the secretion of vWF into the bloodstream, vWF activation and
interaction with platelets, and subsequent platelet adhesion to a vessel wall [
2
–
4
]. vWF multimers and
platelets, adhered to injured and activated endothelium, might serve as sites of leukocyte recruitment.
Altogether, this predisposes to the propagation of the inflammatory process. vWF is considered
a risk factor of arterial thrombosis and might contribute to the development of adverse events in
atherosclerosis and other cardiovascular diseases [5–8].
Int. J. Mol. Sci. 2020,21, 7804; doi:10.3390/ijms21207804 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020,21, 7804 2 of 18
2. Structure and Functions of VWF in Bloodstream
vWF is mainly produced in endothelial cells and stored in Weibel–Palade bodies—the storage
granules of endothelium, consisting of densely packed vWF multimers and P-selectin [
9
]. A small
amount of total vWF is produced in megakaryocytes and stored in the
α
-granules of platelets. The mature
vWF monomeric molecules form dimers through C-terminal disulphide bonds. Dimers compose the
basic vWF repeating structure, with a molecular mass of approximately 500 kDa [
10
]. Dimers are then
polymerized into ultra-large multimers through N-terminal disulphide bonds, with the size of stored
multimers ranging from 20 to 100 dimers [11].
vWF is constantly secreted from the Weibel–Palade bodies of endothelial cells into the bloodstream,
and from the
α
-granules of platelets upon activation. The pool of circulating vWF consists of
multimers of various sizes, ranging from a few dimers to high-molecular weight multimers (HMWM),
which contain 11–20 dimers. The former basically serve as FVIII carriers, while the latter present
the main hemostatically active force of vWF [
11
]. The more dimers that are in a vWF molecule,
the more hemostatically active it is. Upon secretion, large vWF multimers come into contact with
metalloproteinase ADAMTS-13, the vWF-cleaving protease. ADAMTS-13 regulates the size of
circulating vWF through proteolytic cleavage of its multimers [12].
vWF contains a variety of domains, which define the characteristics of the molecule: A1, A2, A3;
D assemblies: D1, D2, D’D3, D4; and the C-terminal cysteine knot (CTCK) (Figure 1) [
13
]. The A1
domain binds mainly glycoprotein (GP) Ib receptors of platelets (the only receptor on non-activated
platelets that has pronounced affinity to vWF), and to a lesser extent, collagen types I, IV, VI, and heparin.
The A2 domain presents a binding cite for ADAMTS-13. The main collagen binding sites are located
on the A3 domain. The C1 domain can interact with activated platelets through the binding of
the IIb/IIIa receptors. The D’D3 assembly carries FVIII. The CTCK domain dimerizes vWF. All D
assemblies are involved in the assembly and disulfide linkage of vWF dimers into long tubules of
the Weibel–Palade bodies. [
9
,
13
]. vWF binds leukocytes through the interaction of the A1 domain
with P-selectin glycoprotein ligand-1 (PSGL-1), the D’D3, and the A1, A2, and A3 domains with
β2-integrins [14].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 18
2. Structure and Functions of VWF in Bloodstream
vWF is mainly produced in endothelial cells and stored in Weibel–Palade bodies—the storage
granules of endothelium, consisting of densely packed vWF multimers and P-selectin [9]. A small
amount of total vWF is produced in megakaryocytes and stored in the α-granules of platelets. The
mature vWF monomeric molecules form dimers through C-terminal disulphide bonds. Dimers
compose the basic vWF repeating structure, with a molecular mass of approximately 500 kDa [10].
Dimers are then polymerized into ultra-large multimers through N-terminal disulphide bonds, with
the size of stored multimers ranging from 20 to 100 dimers [11].
vWF is constantly secreted from the Weibel–Palade bodies of endothelial cells into the
bloodstream, and from the α-granules of platelets upon activation. The pool of circulating vWF
consists of multimers of various sizes, ranging from a few dimers to high-molecular weight
multimers (HMWM), which contain 11–20 dimers. The former basically serve as FVIII carriers, while
the latter present the main hemostatically active force of vWF [11]. The more dimers that are in a vWF
molecule, the more hemostatically active it is. Upon secretion, large vWF multimers come into contact
with metalloproteinase ADAMTS-13, the vWF-cleaving protease. ADAMTS-13 regulates the size of
circulating vWF through proteolytic cleavage of its multimers [12].
vWF contains a variety of domains, which define the characteristics of the molecule: A1, A2, A3;
D assemblies: D1, D2, D’D3, D4; and the C-terminal cysteine knot (CTCK) (Figure 1) [13]. The A1
domain binds mainly glycoprotein (GP) Ib receptors of platelets (the only receptor on non-activated
platelets that has pronounced affinity to vWF), and to a lesser extent, collagen types I, IV, VI, and
heparin. The A2 domain presents a binding cite for ADAMTS-13. The main collagen binding sites are
located on the A3 domain. The C1 domain can interact with activated platelets through the binding
of the IIb/IIIa receptors. The D’D3 assembly carries FVIII. The CTCK domain dimerizes vWF. All D
assemblies are involved in the assembly and disulfide linkage of vWF dimers into long tubules of the
Weibel–Palade bodies. [9,13]. vWF binds leukocytes through the interaction of the A1 domain with
P-selectin glycoprotein ligand-1 (PSGL-1), the D’D3, and the A1, A2, and A3 domains with β2-
integrins [14].
Figure 1. (A) A schematic representation of a von Willebrand factor thread; and (B) a von Willebrand
factor dimer. The binding sites for ADAMTS-13, platelets, leukocytes, collagen, and heparin are
indicated.
vWF exists in the bloodstream in one of two conformations—globular and unfolded [15]. vWF
conformation depends on the shear rate of blood flow in vessels. The shear rate is the rate of change
of velocity, at which one layer of fluid passes over another, and is measured in inverse, or reciprocal,
seconds (s−1). This parameter is used to estimate flow of liquids in tubes, which is important for the
Figure 1.
(
A
) A schematic representation of a von Willebrand factor thread; and (
B
) a von Willebrand factor
dimer. The binding sites for ADAMTS-13, platelets, leukocytes, collagen, and heparin are indicated.
vWF exists in the bloodstream in one of two conformations—globular and unfolded [
15
].
vWF conformation depends on the shear rate of blood flow in vessels. The shear rate is the rate
of change of velocity, at which one layer of fluid passes over another, and is measured in inverse,
Int. J. Mol. Sci. 2020,21, 7804 3 of 18
or reciprocal, seconds (s
−1
). This parameter is used to estimate flow of liquids in tubes, which is
important for the understanding of vWF activation. Under conditions of low shear rates (e.g., in veins,
where shear rates are 15–200 s
−1
, or in large arteries, where they are 300–800 s
−1
), vWF remains in a
globular shape, which hides the binding sites, and does not interact with the circulating platelets [
16
].
In the case of vessel injury and under high shear rates (e.g., in intact small arteries and arterioles, shear
rates are 450–1600 s
−1
, but at sites of advanced atherosclerosis, shear rates might reach up to 11,000 s
−1
and even higher), the vWF shape unfolds, and opens binding sites, in particular for glycoprotein (GP)
Ib receptors of platelets.
A threshold value of shear rate, critical for unfolding and the activation of vWF, is estimated at
5000 s
−1
[
15
]. Uniform shear rates occur in straight channels, but in pathological conditions in stenotic
or injured vessels, elongational flows occur, where the molecules are subjected to shear gradients.
The vasoconstriction of injured vessels and stenoses of arterial lumen by atherosclerotic plaques
create two zones of elongational flow. Flow and shear rate accelerate at the inflow and decelerate
at the outflow of a lesion. At the inflow, elongation occurs parallel to the flow direction. At the
outflow, elongation occurs perpendicular to the flow direction because the streamlines diverge. As the
adjacent shear layers have different velocities, large molecules, such as vWF multimers, are subjected
to the rotational and elongational components of the flow. In the straight sections of a blood vessel,
the rotational and elongational components are balanced. However, at the inflow and the outflow of a
lesion, the equilibrium is disturbed. At sites of vasoconstriction and stenoses, thrombus formation is
observed at the outflow zone of a lesion (Figure 2) [
9
]. Elongation flows are predicted to unfold vWF at
rates of two orders of magnitude below the corresponding pure shear rate values [
17
]. vWF-dependent
thrombus formation was observed at the outflow region of an
in vitro
model of stenosis at the inflow
shear rates of 600, 1000, and 2000 s−1[18].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 18
understanding of vWF activation. Under conditions of low shear rates (e.g., in veins, where shear
rates are 15–200 s−1, or in large arteries, where they are 300–800 s−1), vWF remains in a globular shape,
which hides the binding sites, and does not interact with the circulating platelets [16]. In the case of
vessel injury and under high shear rates (e.g., in intact small arteries and arterioles, shear rates are
450–1600 s−1, but at sites of advanced atherosclerosis, shear rates might reach up to 11,000 s−1 and even
higher), the vWF shape unfolds, and opens binding sites, in particular for glycoprotein (GP) Ib
receptors of platelets.
A threshold value of shear rate, critical for unfolding and the activation of vWF, is estimated at
5000 s−1 [15]. Uniform shear rates occur in straight channels, but in pathological conditions in stenotic
or injured vessels, elongational flows occur, where the molecules are subjected to shear gradients.
The vasoconstriction of injured vessels and stenoses of arterial lumen by atherosclerotic plaques
create two zones of elongational flow. Flow and shear rate accelerate at the inflow and decelerate at
the outflow of a lesion. At the inflow, elongation occurs parallel to the flow direction. At the outflow,
elongation occurs perpendicular to the flow direction because the streamlines diverge. As the
adjacent shear layers have different velocities, large molecules, such as vWF multimers, are subjected
to the rotational and elongational components of the flow. In the straight sections of a blood vessel,
the rotational and elongational components are balanced. However, at the inflow and the outflow of
a lesion, the equilibrium is disturbed. At sites of vasoconstriction and stenoses, thrombus formation
is observed at the outflow zone of a lesion (Figure 2) [9]. Elongation flows are predicted to unfold
vWF at rates of two orders of magnitude below the corresponding pure shear rate values [17]. vWF-
dependent thrombus formation was observed at the outflow region of an in vitro model of stenosis
at the inflow shear rates of 600, 1000, and 2000 s−1 [18].
Figure 2. Shear rate-induced activation of the von Willebrand factor at the site of atherosclerotic
narrowing of a vessel.
Unfolded by high shear rates, the vWF threads can self-associate and form long strands and
web-like structures, further stimulating platelet adhesion [19]. The ability of unfolded vWF to self-
associate under high-shear rates was studied in vitro in endothelialized microvessels. Smaller vessels,
Figure 2.
Shear rate-induced activation of the von Willebrand factor at the site of atherosclerotic
narrowing of a vessel.
Int. J. Mol. Sci. 2020,21, 7804 4 of 18
Unfolded by high shear rates, the vWF threads can self-associate and form long strands and web-like
structures, further stimulating platelet adhesion [
19
]. The ability of unfolded vWF to self-associate
under high-shear rates was studied
in vitro
in endothelialized microvessels. Smaller vessels, turns,
bifurcations, flow acceleration predisposed to thickening, and elongation of vWF strands. In regions
with complex flow, the vWF strands tended to form web-like structures. At the same time, at sites of
low shear rates, the vWF remained in a globular conformation and no vWF strands were visible [
19
].
Schneider et al. also reported spider web-like network formation by vWF, under high shear rates [
15
].
Zhang et al., demonstrated that vWF association was dependent on the A2 domain under shear rate of
9600 s
−1
. Hence, the A2 domain might have an overlapping role, both in proteolysis and self-association
of vWF [20].
The role of platelet vWF in hemostasis is not clearly established, and the studies here are
quite sparse. A study on the vWF-knockout mice showed that replenishing of vWF in platelets after
bone marrow transplantation from wild-type mice, resulted in partial correction of bleeding time and
reduction of blood loss volume [
21
]. Recently, a study showed that chimeric mice with only platelet
vWF had a bleeding time comparable to that of the vWF-knockout mice [
22
]. Platelet vWF did not
contribute to thrombus formation in a model of carotid artery injury. On the other hand, after ischemic
brain injury, the mice with only platelet vWF and without plasma vWF, had a cerebral infarction size
similar to the wild-type mice. Platelet vWF mediated ischemic brain injury in a GPIb-dependent
mechanism and significantly contributed to intracerebral thrombosis formation [22].
Upon the unfolding of vWF multimers, FVIII is exposed on D’D3 domains [
1
]. FVIII participates
immediately in the intrinsic coagulation pathway, interacting with factor IXa as a cofactor to form the
intrinsic tenase (enzyme complex that cleaves inactive coagulation factor X into active Xa). FVIII is
essential for normal hemostasis—its deficiency leads to hemophilia A. vWF acts as a carrier of
FVIII in circulation. In the absence of vWF, FVIII is unstable and exposed to rapid degradation.
vWF significantly elongates its half-life and protects FVIII from proteolysis, eventually delivering it to
sites of vessel injury [1].
Unraveling, vWF faces its antagonist, ADAMTS-13 [
9
]. It is a member of the ADAMTS
(A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats) family of proteolytic
enzymes. ADAMTS-13 was first isolated in 2001, though the presence of Ca
2+
-dependent vWF-cleaving
protease was predicted earlier [
23
]. Human ADAMTS-13 mRNA and protein synthesis is localized
exclusively to hepatic stellate cells [
24
]. The plasma levels of ADAMTS-13 show negative correlation
with the plasma levels of vWF [
25
]. In the absence of vWF in the bloodstream, i.e., in patients with von
Willebrand disease (vWD) type 3, the plasma levels of ADAMTS-13 are 30% higher than in healthy
volunteers. On the contrary, after the administration of 1-deamino-8-D-arginine vasopressin (DDAVP),
which stimulates the release of vWF from endothelial Weibel–Palade bodies, the plasma levels of
ADAMTS-13 showed a 20% reduction in healthy volunteers [
25
]. The negative correlation is likely to
occur because of consumption in the cleavage of vWF. ADAMTS-13 circulates in the bloodstream as
an active enzyme, but vWF in the globular conformation remains resistant to proteolysis. Once vWF
unfolds, it exposes the binding sites for ADAMTS-13 on the A2 domain. The ensuing interaction
with ADAMTS-13 leads to the cleavage of vWF multimers between tyrosine in the 1605 position and
methionine in the 1606 position, which shortens the multimers and decreases the hemostatic activity of
vWF [16,26].
The growing evidence shows that vWF is an important mediator of vascular inflammation [
27
].
A murine model of acute peritonitis showed that vWF plays an important role in leukocyte
recruitment and extravasation into the site of inflammation. Notably, leukocyte extravasation
requires vWF-platelet binding, as inhibition of the platelet GPIb receptors prevented vWF-mediated
leukocyte extravasation [
28
]. A murine model of immune complex-mediated vasculitis and irritant
contact dermatitis showed that the interference with vWF activity with vWF-blocking antibody
led to a substantial decrease in vWF-mediated leukocyte recruitment and reduction of cutaneous
inflammatory response. In this study, the vWF-blocking antibody did not interfere with the GPIb
Int. J. Mol. Sci. 2020,21, 7804 5 of 18
domain [
29
]. Another murine model with the same pathology but with the use of the antibody targeting
the A1 domain showed comparable results [
30
]. A study comparing features of acute inflammation
after focal cerebral ischemia in vWF-deficient and ADAMTS-13-deficient mice, showed that the
vWF-deficient mice had a smaller injury size, reduced cytokine release and neutrophil infiltration of
the injury site, compared to the ADAMTS-13-deficient mice [
31
]. A myocardial ischemia/reperfusion
study in ADAMTS-13-knockout mice showed that infusion of recombinant ADAMTS-13 substantially
reduced myocardial apoptosis, troponin-I release, and resulted in a 9-fold reduction in the number of
neutrophils infiltrating the ischemic zone [32].
3. Diagnostic Tests for the von Willebrand Factor Deficiency and Dysfunction
Studies of acquired von Willebrand syndrome in aortic stenosis and obstructive hypertrophic
cardiomyopathy revealed that, despite the clinical manifestation of bleeding, plasma levels of vWF
and ristocetin cofactor assay remained at normal values [
33
]. The plasma levels of vWF show mass
concentration of all vWF multimers, from dimers to HMWM. The proteolyzed HMWM of vWF are
cleaved into smaller multimers and dimers. This significantly affects the hemostatic function of vWF,
but not its mass concentration. Thus, measuring the plasma levels of vWF shows the amount of protein
in the plasma, but not its functional status. The plasma levels of vWF depend on the blood group
of a person [
34
]. Variations of the plasma levels of vWF between blood groups might complicate
distinguishing healthy persons with low vWF from mild cases of vWD [
35
]. Unlike oligosaccharides of
other plasma glycoproteins, the vWF structure includes oligosaccharides of the ABO blood groups.
Persons in the O blood group have significantly lower levels of vWF than persons in other blood
groups [
36
]. A study, comprising 1117 blood donors showed that the plasma levels of vWF were the
lowest in the O blood group (74.8 IU/dL), higher in the A blood group (105.9 IU/dL), even higher in the
B blood group (116.9 IU/dL), and the highest in the AB blood group (123.3 IU/dL) [
37
]. In ristocetin
cofactor assay, ristocetin was used to bind the GPIb receptors of platelets to the A1 domain of
vWF [
38
]. The assay was performed under very low shear rate conditions, when the vWF multimers
remained folded. Thus, the assay reflected the presence of vWF in a sample per se, but not the
physiological hemostatic function of vWF. It also had a low sensitivity to the loss of HMWM of vWF.
Hence, it was useful in the diagnosis of vWD, especially in the case of severe vWF deficiency (
e.g., in type
3 vWD, in which vWF was almost or completely absent in the blood), but provided little diagnostic
information concerning the actual hemostatic function of vWF. Significant interlaboratory variations
in test results existed for both of these assays [
38
]. vWF multimer analysis by the electrophoresis
of vWF on agarose gels remained the main assay of qualitative deficiency of vWF [
10
]. The assay
had excellent sensitivity for the loss of HMWM of vWF. The inclusion of the luminescent methods
gave it the power to detect the presence of vWF in samples with a concentration of less than 1 IU/dL.
This allowed differentiation between homozygous type 2 and type 3 vWD. vWF multimer analysis
is crucially important for subtyping of type 2 vWD [
10
]. It is also very useful in diagnostic of
HMWM of vWF deficiency in acquired von Willebrand syndrome, due to the heart valve disease [
39
].
However, the assay placed high demands on the technical competence of the laboratory personnel
and was unsuitable for standardization [
35
]. Therefore, its introduction to routine diagnostics in
cardiovascular disease is challenging. vWF collagen binding assay might be used as a substitution
for the detection of HMWM of vWF [
40
]. Thus, the broad panel of tests is needed to diagnose vWD
and its type. To simplify testing (e.g., in screening for bleeding disorders or in the emergency setting),
a screening tool that can quickly exclude platelet defects and vWD was introduced. The Platelet
Function Analyzer-100 (PFA-100) is an easy to use device, which utilizes whole blood and requires
only 5 min to complete a test [
41
]. Currently, this is the only commercially available system that
evaluates primary hemostasis under high shear rate conditions. PFA-100 pumps a whole blood sample
through a narrow orifice in a membrane, covered with collagen and platelet activator agents, such as
adenosine diphosphate (ADP) or epinephrine. The system measures time from the start of a sample
pumping to the closure of the orifice (the closure time). The shear rates in the orifice might reach
Int. J. Mol. Sci. 2020,21, 7804 6 of 18
5000–6000 s
−1
, which is sufficient to activate vWF. However, PFA-100 possesses a drawback concerning
vWF activation. The system is designed to assess primary hemostasis, not exclusively vWF hemostatic
function. The closure time is dependent on interactions between platelets and other blood cells,
not vWF activation alone. Its sensitivity varies, depending on the severity of vWF deficiency and
platelet defects, from moderate in mild cases to 100% sensitivity in the case of complete absence of
vWF in blood [
41
,
42
]. Thus, currently there is no widely available assay that exclusively measures
vWF shear rate-dependent hemostatic function. Experimental assays and devices, such as microfluidic
chambers, are created by some research laboratories to study different aspects of hemostasis, including
vWF functions. However, these devices are cumbersome and not standardized. Therefore, currently,
these devices fall short of satisfying clinical demands [43].
4. Diseases, Associated with von Willebrand Factor and ADAMTS-13 Dysfunction
vWF plays a major role in coagulation, and its deficiency or dysfunction predisposes one to
bleeding. A genetic disorder, caused by partial or total deficiency or structural aberrations of vWF
molecules, is called vWD [
35
]. This is one of the most widespread hemostasis disorders with an
incidence of around 1:100 persons. It is characterized by nasal and gingival bleeding, hemarthrosis,
muscular and subcutaneous hematomas, menorrhagia, and prolonged bleeding in traumas.
Desmopressin, which stimulates the release of vWF from endothelium, is the main medication
for the mild forms of vWD. In severe cases, the only choice is regular vWF-rich plasma transfusions [
11
].
Acquired von Willebrand syndrome is a rare disorder that occurs due to lymphoproliferative
(e.g., chronic lymphocytic leukemia), myeloproliferative (e.g., thrombocythemia), cardiovascular
(e.g., aortic stenosis) and immunological disorders (e.g., hypothyroidism), which provoke the qualitative
and quantitative deficiency of vWF [44].
On the contrary, increased concentrations of ultra-large multimers of vWF lead to thrombotic
thrombocytopenic purpura (TTP), which develops due to a deficiency of ADAMTS-13 [
45
].
ADAMTS-13 deficiency causes an unrestricted presence of ultra-large multimers of vWF in the
bloodstream, which might spontaneously interact with platelets and provoke thrombosis in multiple
small vessels. This results in thrombocytopenia with purpura, hemolytic anemia, and multiple organ
damage, due to microvascular thrombosis—acute renal, heart and neurological damage, mental
derangement, and fever. TTP can develop either due to genetic anomalies (congenital TTP) or
production of autoantibodies to ADAMTS-13 (acquired TTP), which interfere with its function or
enhance clearance. The determination of the ADAMTS-13 function is essential in TTP diagnosis.
TTP usually manifests when the ADAMTS-13 levels fall below 10%, which is below the detection
limit of many assays. As soon as ADAMTS-13 activity becomes detectable (i.e., higher than 10%),
TTP symptoms resolve. Differentiation between congenital and acquired TTP is vitally important, as
treatment of these life-threatening conditions significantly differ. The diagnosis of congenital TTP
is built on the detection of pronounced fall in ADAMTS-13 activity, ruling out autoantibodies to
ADAMTS-13, and analyzing the ADAMTS-13 gene. The diagnosis of acquired TTP requires the lack of
ADAMTS-13 activity and the detection of autoantibodies to ADAMTS-13. Patients with congenital
TTP respond well to the plasma exchange therapy, which improves survival rates from 10% to 80–90%.
During the plasma exchange, ultra-large multimers of vWF, immune complexes, and autoantibodies are
removed. Infusions of donor plasma with normal content of ADAMTS-13 are also effective, and used
in combination with the plasma exchange therapy. Patients with acquired TTP respond to normal
plasma infusions poorly. Suppression of autoantibody production with corticosteroids, destruction of
CD20-posititve B-lymphocytes with rituximab, or the use of other immunosuppressive agents is
considered to be effective in acquired TTP. Splenectomy is effective, but reserved for refractory cases of
acquired TTP [
46
]. Recently, caplacizumab, an immunoglobulin fragment that targets the A1 domain
of vWF, and prevents its interaction with platelet GPIb receptors, was introduced in addition to plasma
exchange therapy [47].
Int. J. Mol. Sci. 2020,21, 7804 7 of 18
5. Acquired von Willebrand Syndrome in Heart Valve Disease and Hypertrophic Cardiomyopathy
The association between aortic stenosis and cryptogenic gastrointestinal bleeding was first
described in 1958 in a letter by E.C. Heyde [
48
]. In 1992, Warkentin et al. were the first to suggest
a link between the loss of HMWM of vWF that develops due to aortic stenosis or hypertrophic
cardiomyopathy and bleeding from gastrointestinal angiodysplasia [
49
]. In 2002, Warkentin et al.,
was also the first to provide a rationale for this association [
50
]. They reported two cases of severe
aortic stenosis with concomitant gastrointestinal bleeding that ceased after successful replacement of
the aortic valve. Notably, prior to the platelet count operation, activated partial-thromboplastin time,
the plasma level of FVIII, the plasma levels of vWF, and the ristocetin cofactor assay values were normal,
whereas the loss of HMWM of vWF was severe. After the valve replacement, the percentage of HMWM
recovered and remained normal during a 10-year follow up [
50
]. Acquired von Willebrand syndrome
in cardiovascular disease develops due to aortic stenosis, left ventricle outflow tract obstruction in
hypertrophic cardiomyopathy, and aortic and mitral regurgitation [
8
]. In severe aortic stenosis, a
steep increase in shear rates in the aortic orifice and left ventricular outflow tract occur. HMWM of
vWF, which pass through the narrowing aortic valve, undergo activation and subsequent proteolysis
by ADAMTS-13. Additionally, lower pulse pressure, which is observed in aortic stenosis, contributes to
the decreased secretion of HMWM of vWF from the endothelium [
8
]. In severe aortic stenosis,
HMWM of vWF might decline to approximately 1/2 of the normal levels [
51
]. Panzer et al., reported
a study of 47 patients with severe aortic stenosis, who were subjected to aortic valve replacement.
HMWM of vWF were depleted in all patients before valve replacement and became normal in most
patients. PFA-100 closure time in collagen-ADP cartridges were significantly prolonged at the baseline,
and normalized after the treatment. Using the cone and plate analyzer, the authors showed that
the loss of HMWM of vWF affects platelet adhesion and, to a larger extent, ADP-induced platelet
aggregation [
52
]. The quantitative deficiency of HMWM of vWF leads to the acquired von Willebrand
syndrome type 2A. Its clinical manifestation in patients with heart valve disease is called Heyde’s
syndrome [
53
]. It is characterized by cryptogenic gastrointestinal bleedings from submucous arterial
malformations, developing together with the progression of aortic stenosis and its cardiovascular
symptoms (such as fatigue and angina). Bleeding from arterial malformations is thought to be provoked
by increased shear rates, due to the complex structure of vessels, which cause further consumption of
vWF [
53
]. Patients with severe aortic stenosis also report skin and mucosal bleeding. In a study of
50 patients with aortic stenosis, skin or mucosal bleeding was reported by 21% of participants [
33
].
Primary hemostasis, measured by PFA-100 was significantly prolonged; the percentage of HMWM and
the collagen-binding activity of vWF were reduced in patients with severe aortic stenosis. The plasma
levels of vWF were normal in all patients. One day after surgical treatment, PFA-100 values and
the percentage of HMWM of vWF were completely corrected; however, after 6 months, these values
deteriorated, primarily in patients with prosthesis mismatch [
33
]. In two other studies of 183 and
21 patients with severe aortic stenosis, undergoing valve replacement, the same pattern was observed.
PFA-100 closure time was prolonged and the HMWM of vWF reduced at the baseline; they normalized
after successful valve replacement [
51
,
54
]. The volume of blood that is affected by high shear rates
is a crucial component in the development of Heyde’s syndrome, in which the whole volume of
circulating blood is affected. For example, in patients with severe coronary or peripheral atherosclerosis,
vWF deficiency does not occur because blood volume is affected only partially. The treatment of aortic
stenosis with valve replacement results in fast recovery and the cessation of bleeding. The normalization
of shear rates and pulse pressure leads to an increase in the plasma level of functional HMWM of vWF
within hours [
55
]. A prospective study with an 18-month follow-up of patients treated with aortic
valve replacement, and several other studies with follow-up from 2 weeks up to 6 months, showed that,
after recovery, the plasma levels of HMWM of vWF did not drop again [
51
]. However, if significant
aortic regurgitation and paravalvular leak develop after aortic valve replacement, the plasma levels
of HMWM of vWF might not recover [
54
]. A similar development pathway of the acquired von
Willebrand syndrome was also reported in patients with aortic or mitral valve regurgitation [56,57].
Int. J. Mol. Sci. 2020,21, 7804 8 of 18
In obstructive hypertrophic cardiomyopathy, the obstructed left ventricle outflow tract
predisposes the proteolysis of HMWM of vWF in a manner similar to aortic stenosis. A study by
Blackshear et al., included five patients with symptomatic obstructive hypertrophic cardiomyopathy [
58
].
Spontaneous gastrointestinal, mucosal, or excessive postsurgical bleeding was observed in all patients.
The plasma levels of vWF and ristocetin cofactor assay values were within normal limits, whereas
electrophoresis revealed loss of HMWM and excess of low-molecular weight multimers of vWF.
After surgical septal myectomy, bleeding resolved, and HMWM were restored to normal levels in all
patients [
58
]. In another study of 28 patients with obstructive hypertrophic cardiomyopathy, plasma
levels of vWF were normal in all patients [
59
]. PFA-100 closure time was significantly prolonged in all
but one patient. Additionally, all patients had a substantial reduction in HMWM of vWF. A strong
correlation of closure time in the PFA-100 tests and reduction in HMWM of vWF with peak gradients,
measured by ultrasonography, was observed. The mean peak gradient, sufficient for the impairment
of vWF function and the reduction in HMWM, was estimated at 15 mm Hg [59].
The use of left ventricle assist devices (LVADs) might also lead to acquired von Willebrand
syndrome [
60
]. LVADs provide circulatory support for patients with end-stage heart failure, either
as a bridge or destination therapy. vWF might immobilize on the biomaterial surfaces of LVAD and
undergo cleavage at sites of high shear rates, which might occur in the LVAD system. This might
lead to the development of LVAD-associated complications, such as pump thrombosis and bleeding;
in particular, gastrointestinal bleeding from arteriovenous malformations [60].
6. von Willebrand Factor and Coronary Artery Disease
The relevance of vWF in platelet adhesion and thrombus formation under high shear rates
was shown in a study on pigs [
61
]. In this study, 8 healthy pigs and 6 pigs with vWD were
fed a high-cholesterol diet for 24 weeks with the assessment of coronary arteries for the presence
of atherosclerosis. The diet led to severe hypercholesterolemia (7–39 mMol/L). Coronary atherosclerosis
developed in both groups and was detected by histology in all but one healthy and all vWD pigs.
Left anterior descending coronary and carotid arteries were clamped to produce stenotic segments,
which were then injured. Occlusive thrombosis occurred in all stenotic segments in phenotypically
normal pigs, while it did not occur in the vWD pigs [61].
A study on mice showed the influence of ADAMTS-13 and vWF deficiency on a myocardial
infarction (MI), induced by the ligation of the left anterior descending coronary artery [
62
]. The infarct
size was significantly larger in homozygous ADAMTS-13-deficient mice (22.2
±
1.1%), compared to
heterozygous ADAMTS-13-deficient mice (17.3
±
0.8%) and wild-type mice (16.9
±
1.2%), which suggests
that a level of approximately 50% of ADAMTS-13 in plasma is sufficient to prevent aggravated MI.
The infarct size was markedly reduced in the vWF-deficient mice (7.3
±
0.7%), compared to the
wild-type mice (18.6
±
1.3%). A group comprising ADAMTS-13 deficient and wild-type mice was
treated with a polyclonal antibody to vWF. In this group, the infarct size in the wild-type and in the
ADAMTS-13-deficient mice (8.5
±
0.7% and 8.2
±
1.3%, respectively) was significantly smaller than in
the control wild-type mice treated with a nonspecific antibody (17.48 ±0.7%) [62].
CAD in patients with vWD was observed less frequently. In a register study comprising 7556 cases
related to vWD and 19,918,970 cases unrelated to vWD, CAD was less common in patients with vWD
(15.0%) than in patients without vWD (26.0%). After multivariable logistic regression analysis with
adjustment for the main risk factors of CAD, the probability of CAD in patients with vWD remained
lower than in patients without it (OR 0.85; 95% CI 0.79–0.92) [63].
The plasma levels of vWF differ in healthy persons and patients with CAD. In 110 patients with a
mean age of 58
±
20 years with CAD, the plasma level of vWF was 141.78
±
20.53 IU/dL, whereas in a
control group of healthy volunteers it was 111.95
±
17.15 IU/dL [
64
]. A prospective multicenter study
comprising 3043 patients with stable angina or previous MI, showed that the higher plasma levels of
vWF correlated with an 8.5% increase in the rate of MI and sudden cardiac death [
65
]. A meta-analysis
of the prospective Reykjavik study, comprising 1925 persons who had primary nonfatal MI or died
Int. J. Mol. Sci. 2020,21, 7804 9 of 18
of CAD during a follow-up (median 19.4 years), and 3616 controls, showed that the baseline plasma
levels of vWF were higher in patients with CAD than in the control group [
66
]. The ENTIRE-TIMI 23
study, comprising 314 patients with ST-elevation myocardial infarction (STEMI) in whom the plasma
levels of vWF were measured before and 48–72 h after fibrinolysis, showed that an increase in vWF
levels after fibrinolysis was associated with the higher mortality and MI rate in 30 days (
11.2% vs. 4.1%
,
respectively) [
67
]. In 123 patients who had MI before the age of 70, plasma levels of vWF were measured
3 months after MI. A 4.9-year follow up showed that higher concentrations of vWF were independently
associated with recurrent MI and mortality [68].
A study, comprising 1026 patients with confirmed first STEMI and 652 healthy controls, showed
that the plasma levels of vWF were nearly 1.5-fold higher in patients with STEMI, than in healthy
controls (median 378.2 vs. 264.4 ng/mL, respectively). The plasma levels of ADAMTS-13 were lower in
patients with STEMI, than in the healthy controls (median 90% vs. 97%, respectively) [
69
]. In another
study, the plasma levels of vWF in 41 patient of mean age 68
±
23 years, hospitalized within 72 h
after the onset of MI, were significantly higher (2151
±
97 mU/mL) than in 33 patients with stable
angina and 90% narrowing of a major coronary artery (1445
±
93 mU/mL), who had angina attack
within 4 weeks before the study, or 30 patients with chest pain syndrome without hemodynamically
significant stenosis or coronary spasm (1425
±
76 mU/mL), in whom the vWF levels did not differ
significantly [
70
]. On the other hand, the plasma levels of ADAMTS-13 were significantly lower in
patients with acute MI (
799 ±29 mU/mL
) than in patients with stable angina (996
±
31 mU/mL) or
patients without hemodynamically significant stenosis or vasospasm (967
±
31 mU/mL). The enzymatic
activity of ADAMTS-13 was also lower in patients with acute MI (768
±
27 mU/mL) than in patients
with stable angina (893
±
27 mU/mL) or patients without hemodynamically significant stenosis or
vasospasm (936
±
29 mU/mL). [
70
]. In the GLAMIS study of 466 patients of mean age 55.1
±
7.45 years
with acute MI and 484 healthy controls, no correlation between ADAMTS-13 and vWF levels was found
in the healthy controls [
71
]. On the other hand, the plasma levels of vWF correlated positively and
the plasma levels of ADAMTS-13 correlated negatively with the risk of MI. After adjustment for the
main cardiovascular risk factors, each 60 IU/dL increase in plasma levels of vWF was expected to raise
the risk of MI by about 35%. Each 33% increase in the plasma levels of ADAMTS-13 was expected to
decrease the risk of MI by about 27% [
71
]. The SMILE study, which included 650 men, 18–70-years-old,
with stable CAD, who had an MI event at least 6 months before the study, and 646 healthy men,
revealed no clear association between ADAMTS-13 and the vWF plasma levels, measured more than
6 months after the onset of MI [
72
]. There was also no significant difference between the ADAMTS-13
levels in men with stable CAD and the healthy controls (mean levels 101% and 100%, respectively).
Neither were the plasma levels of vWF different between the groups (mean 138% in the CAD group
and 135% in controls) [
72
]. The prospective PRIME study, comprising nearly 10,000 healthy men,
among whom 296 developed CAD during the 5 years of follow-up (158 persons with MI and 142 with
stable and unstable angina), showed that the baseline plasma levels of vWF were significantly higher in
men who developed MI (129.2
±
53.1 IU/dL) compared to the healthy controls (115.9
±
41.8 IU/dL) [
73
].
The relative risk of MI development was 3.34 in patients with plasma levels of vWF in the 4th quartile,
compared to 1.0 in persons with vWF plasma levels in the 1st quartile. Stable and unstable angina
incidence did not correlate with the plasma levels of vWF [73].
A study on rats attempted to determine time span for vWF plasma level recovery after STEMI [
74
].
The study comprised 57 male rats subjected to ligation of the left anterior descending artery, 2 mm
away from bifurcation, which provoked ECG-verified STEMI and myocardial fibrosis, on histological
examination. Rats were randomized into four groups—in the first, blood was taken from the coronary
sinus and the inferior vena cava, 1 h after the onset of MI; in the second, 24 h after MI; in the third,
7 days after MI; the fourth was used as a control. The plasma levels of vWF, obtained from the coronary
sinus, increased 1.31-fold after 1 h, and 0.88-fold, 24 h later. They decreased to normal levels on the
seventh day. In the inferior vena cava, the plasma levels of vWF were 0.37-fold higher 1 h after the
onset of MI, 0.18-fold higher 24 h later, and decreased to normal levels on the seventh day [74].
Int. J. Mol. Sci. 2020,21, 7804 10 of 18
7. Inflammatory and Stress Stimuli as a Possible Cause of Elevation in Plasma von Willebrand
Factor in Coronary Artery Disease
There are several reasons for the increase in plasma levels of vWF in CAD and, in particular, MI.
In a 5-year follow-up of 1592 persons 55–74 years old, smoking was associated with higher levels
of vWF and a higher risk of atherosclerosis development [
75
]. In a study of 2459 patients who had
nonfatal MI or died of CAD during the 12-year follow-up, higher plasma levels of vWF were associated
with smoking and older age [76].
In another study, 73 men of age 59
±
11 years, with stable CAD and in sinus rhythm, and 35 healthy
volunteers, underwent 24-h ambulatory blood pressure monitoring [
77
]. Patients were divided into
four groups: 1—with high pulse pressure; 2—with low pulse pressure; 3—dippers; and 4—non-dippers.
The results of the study showed that all patient groups had higher plasma levels of vWF compared
to controls (mean 197
±
58 vs. 120
±
18 IU/dL, respectively). The highest plasma levels of vWF were
detected in the high pulse pressure (219
±
58 IU/dL) and non-dipper (222
±
55 IU/dL) groups [
77
]. In a
study of 178 patients, 54
±
15 years-old with arterial hypertension, who had blood pressure higher than
160/90 mmHg on two visits to a physician, and 47 normotensive healthy controls, the plasma levels of
vWF were significantly higher in the hypertensive group, than in controls (mean 113 vs. 98 IU/dL,
respectively) [78].
Another prospective study of 631 patients 50–75 years-old showed that increased vWF
plasma levels correlated with cardiovascular and all-cause mortality, in patients with and without
diabetes mellitus. The increase in plasma levels of vWF significantly correlated with older age,
higher fasting glucose levels, glycated hemoglobin, body mass index, and systolic arterial pressure [
79
].
A study of 94 patients with non-insulin-dependent diabetes mellitus showed correlation between
albuminuria and increased plasma levels of vWF [
80
]. In the ASCET study, age, smoking, and diabetes
mellitus were associated with elevated vWF in plasma [
81
]. In the ENTIRE-TIMI 23 sub-study,
the reduced success of thrombolysis (estimated by the thrombolysis in myocardial infarction (TIMI)
flow grade and the corrected TIMI frame count) positively correlated with the plasma levels of VWF.
The plasma levels of vWF in the upper quartile were associated with a higher incidence of death within
30 days, compared with the lower quartile (11.2% vs. 4.1%, respectively) [67].
Elevated plasma vWF was observed in patients with systemic inflammatory diseases. In a
study of 113 patients with systemic inflammatory diseases (40 with rheumatoid arthritis, 38 with
systemic scleroderma, 35 with systemic vasculitis), the plasma levels of VWF were significantly
elevated, compared to 80 healthy controls [
82
]. Of note, in patients with chronic systemic inflammation,
experiencing exacerbation in the form of serositis, plasma vWF levels, and ristocetin cofactor assay
values were increased, compared to healthy controls, but were unrelated to clinical manifestations of
the disease, including thrombotic complications [83].
One of the reasons for elevated plasma vWF is the polymorphism of Thr789Ala allele in the vWF
gene, which is an independent predictor of CAD development [
84
]. Additionally, the drug-induced
elevation of plasma vWF might occur due to the intake of diuretics, digoxin, heparin, and oral
anticoagulants [
64
]. On the other hand, the administration of enoxaparin decreases plasma vWF levels,
compared to heparin [67].
Plasma vWF elevation might occur due to endothelial damage. Taking into consideration that
vWF is predominantly secreted by the endothelium, elevated plasma vWF might be considered to be a
marker of endothelial dysfunction. Endothelial dysfunction plays a major role in the pathogenesis
of atherosclerosis, increasing the risk of adverse cardiovascular events [
85
]. This is demonstrated
effectively in a study of 50 patients with CAD who underwent coronary artery stenting with single
or multiple bare-metal stents (BMS), and 8 controls with CAD who underwent only diagnostic
coronary angiography [
86
]. The single stent implantation group comprised 25 persons of mean
age
59.7 ±9.44 years
, and the multiple stent implantation group comprised 25 persons of mean age
57.5 ±8.1 years
. Blood for the measurement of vWF was taken from the coronary sinus, before and after
PCI. There was no significant difference in vWF plasma levels before and after coronary angiography
Int. J. Mol. Sci. 2020,21, 7804 11 of 18
in the controls (123
±
10.8 IU/dL before, 125
±
11.6 IU/dL after). In patients with a single stent
implantation, the plasma levels of vWF rose slightly from 113.6
±
39.6 to 121.35
±
46.63 IU/dL after
stenting. In patients with multiple stent implantation, a steep rise in the plasma levels of vWF
was detected, from
112.7 ±25.16 IU/dL
to
152.78 ±41.03 IU/dL
. Thus, multiple stenting significantly
increased the plasma levels of vWF in coronary circulation [
86
]. Another study demonstrated the
different influence on vWF plasma levels of BMS and drug-eluting stents (DES) [
87
]. In total, 16 patients
with the proximal stenosis of left anterior descending artery received BMS or DES. The plasma levels
of vWF were measured in the aorta and the coronary sinus immediately before and 2 h after stenting.
The systemic plasma levels of vWF were measured at the baseline and 24 h after stenting. The baseline
plasma levels of vWF were similar in both groups. The change in plasma levels of vWF in the coronary
sinus, 2 h after stent implantation, was +20.1
±
26.9% in the BMS group,
and −5.7 ±23.02%
in the
DES group. The systemic baseline plasma levels rose from 132.8
±
58.8% to 169
±
40.7% in the BMS
group and slightly decreased from 140.6
±
84% to 136
±
39.5% in the DES group, 24 h after stent
implantation [87].
Therefore, the elevated plasma levels of vWF do not necessarily reflect a causal relationship
with the development of thrombotic complications of CAD. Rather, vWF levels rise in response to
acute inflammatory stimuli and stress. In acute inflammation, vWF levels rise and fall together with
C-reactive protein [
88
]. Different mediators of stress and inflammation influence vWF release from
endothelial cells. Thus, interleukin-6 (IL-6) in a complex with the soluble IL-6 receptor, IL-8, and tumor
necrosis factor-
α
(TNF-
α
), significantly stimulate the release of vWF from the endothelial Weibel–Palade
bodies. IL-6 interferes in vWF cleavage by ADAMTS-13 under flow, but not static, conditions [
89
].
Vasopressin, which rises in response to stress stimuli, induces the release of vWF from endothelial
Weibel–Palade bodies and substantially increases the plasma levels of vWF. Its analogue desmopressin
(DDAVP) is used in the treatment of vWD to sustain vWF plasma levels [
90
]. Thus, the rise in vWF
plasma levels in acute MI might reflect a reaction to ischemic injury and endothelial dysfunction,
rather than a causal role in MI development.
The physiology of vWF demands high shear rates for activation and proper functioning,
which future research into the role of vWF in the development of thrombotic complications of
CAD should take into consideration. Preliminary data show that the shear stress-induced activation of
vWF might play a role in the premature development of MI [91].
8. The Potential for New Treatment, Targeting von Willebrand Factor and ADAMTS-13
in Cardiovascular Diseases
Most medications, routinely used in CAD to prevent thrombotic complications, do not affect vWF
and ADAMTS-13. Only heparins were shown to bind to a site on vWF that overlapped the A1 domain,
thus impairing the GPIb-mediated platelet adhesion, measured by the ristocetin-cofactor activity [
92
].
In clinical studies, administration of enoxaparin, a low-molecular-weight heparin, was associated with
a decrease in the plasma levels of vWF, MI frequency, and death in MI [67,93].
At the turn of the century, antibodies against the A1 domain of vWF, such as AJvW-2 and
AJW200, were studied [
94
]. Despite promising preliminary results, no further studies and clinical
investigations were reported. Current vWF-specific therapeutics is under development focus on
aptamer antagonists of the A1 domain of vWF. The administration of the first-generation aptamer,
ARC1779, to healthy volunteers, resulted in the dose- and concentration-dependent inhibition of vWF
activity [
95
]. The ARC1779 antithrombotic effect was also studied on 36 patients who underwent carotid
endartherectomy. It was shown that ARC1779 inhibits vWF activity and reduces thromboembolism in
humans, but also provokes bleeding complications [
96
]. Recently, the development of novel aptamers
was reported [
97
,
98
]. The only drug targeting the A1 domain of vWF that is approved for clinical use is
ALX-0081 (caplacizumab) [
47
]. Caplacizumab is a humanized bivalent nanobody that specifically binds
to the GPIb binding site on the A1 domain of vWF. Following remarkable results of the HERCULES
trial, in which its administration resulted in a lower incidence of TTP-related death, thromboembolism
Int. J. Mol. Sci. 2020,21, 7804 12 of 18
and the recurrence of TTP [
47
], caplacizumab was approved in the European Union in 2018 and in the
USA in early 2019, to treat adults with TTP. Studies of caplacizumab safety and efficacy in patients with
CAD are sparse. The efficacy of caplacizumab was shown in ex vivo study of 9 patients with CAD
and 11 healthy controls [
99
]. Caplacizumab completely inhibited platelet adhesion and aggregation,
measured by ristocetin-cofactor assay, platelet function analyzer, and in flow chambers. The efficacy of
caplacizumab was not influenced by antithrombotic medications, which included aspirin, clopidogrel,
and heparin [
99
]. In a randomized, placebo-controlled phase Ib trial on 46 patients with stable CAD,
undergoing PCI, administration of caplacizumab was safe, and resulted in the complete inhibition of
platelet aggregation, measured by the ristocetin-cofactor assay [
100
]. In 2009, a phase II, randomized,
open-label clinical trial was initiated in 380 high-risk patients with ACS, undergoing PCI. The objective
was to compare the bleeding risk and effectiveness of caplacizumab and abciximab, a GPIIb/IIIa
inhibitor [101]. As of 2020, no results of the study are published.
Recently, in a study on mice, treatment with recombinant human ADAMTS-13 was shown to
decrease coronary vascular dysfunction and improve cardiac remodeling after left ventricular pressure
overload [
102
]. Another study on mice showed that the administration of recombinant human
ADAMTS-13 resulted in a reduction in infarct size, the neutrophil infiltration of ischemic myocardium,
and lower troponin-I release [
32
]. Currently, there are no therapeutics targeting vWF and ADAMTS-13
approved for the treatment of cardiovascular diseases.
9. Conclusions
vWF plays an important role in cardiovascular disease. The deficiency of HMWM of vWF in
valvular heart disease and obstructive hypertrophic cardiomyopathy manifests with gastrointestinal,
skin or mucosal bleeding. The bleeding might also complicate the surgical treatment of such patients.
In CAD, the involvement of vWF is more controversial. Though abundant data show that the plasma
levels of vWF are increased and ADAMTS-13 levels are decreased in CAD, especially in MI, this does
not necessarily reflect a causal relationship between elevated plasma vWF and MI. The existing data
show that vWF levels rise in response to stress and acute inflammatory stimuli, which occur in acute MI.
Rather than focusing on the measurement of plasma levels of vWF and the evaluation of vWF activity
in static or low shear rate conditions, future research should concentrate on physiologically relevant
studies of vWF functions under high shear rates. This might pave a way to new approaches to measure
vWF function, which eventually might turn vWF into a treatment target or an important tool for
diagnostics and risk assessment in cardiovascular disease.
Author Contributions:
Conceptualization, S.K.; Methodology, S.K., Z.G.; Data search and analysis, S.O., I.M., Y.A.;
Resources, Z.G.; Data Curation, S.K.; Writing—Original Draft Preparation, S.O., I.M., Y.A.; Writing—Review &
Editing, I.M., S.K., Z.G.; Visualization, Y.A.; Supervision, Z.G.; Project Administration, Z.G.; Funding Acquisition,
I.M. and Z.G. All authors have read and agreed to the published version of the manuscript.
Funding: This work was funded by Russian Science Foundation (project #16-15-10098).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Terraube, V.; O’Donnell, J.S.; Jenkins, P.V. Factor VIII and von Willebrand factor interaction: Biological,
clinical and therapeutic importance. Haemophilia 2010,16, 3–13. [CrossRef] [PubMed]
2.
Chen, J.; Chung, D.W. Inflammation, von Willebrand factor, and ADAMTS13. Blood
2018
,132, 141–147.
[CrossRef] [PubMed]
3.
Kawecki, C.; Lenting, P.J.; Denis, C.V. von Willebrand factor and inflammation. J. Thromb. Haemost.
2017
,15,
1285–1294. [CrossRef] [PubMed]
4.
Pendu, R.; Terraube, V.; Christophe, O.D.; Gahmberg, C.G.; de Groot, P.G.; Lenting, P.J.; Denis, C.V. P-selectin
glycoprotein ligand 1 and
β
2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor.
Blood 2006,108, 3746–3752. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020,21, 7804 13 of 18
5.
Fan, M.; Wang, X.; Peng, X.; Feng, S.; Zhao, J.; Liao, L.; Zhang, Y.; Hou, Y.; Liu, J. Prognostic value of plasma
von Willebrand factor levels in major adverse cardiovascular events: A systematic review and meta-analysis.
BMC Cardiovasc. Disord. 2020,20, 72. [CrossRef] [PubMed]
6.
Kovacevic, K.D.; Mayer, F.J.; Jilma, B.; Buchtele, N.; Obermayer, G.; Binder, C.J.; Blann, A.D.; Minar, E.;
Schillinger, M.; Hoke, M. Von Willebrand factor antigen levels predict major adverse cardiovascular events
in patients with carotid stenosis of the ICARAS study. Atherosclerosis
2019
,290, 31–36. [CrossRef] [PubMed]
7.
Lv, J.-X.; Kong, Q.; Ma, X. Current advances in circulating inflammatory biomarkers in atherosclerosis and
related cardio-cerebrovascular diseases. Chronic Dis. Transl. Med. 2017,3, 207–212. [CrossRef]
8.
Van Belle, E.; Vincent, F.; Rauch, A.; Casari, C.; Jeanpierre, E.; Loobuyck, V.; Rosa, M.; Delhaye, C.;
Spillemaeker, H.; Paris, C.; et al. von Willebrand Factor and Management of Heart Valve Disease. J. Am.
Coll. Cardiol. 2019,73, 1078–1088. [CrossRef]
9.
Springer, T.A. von Willebrand factor, Jedi knight of the bloodstream. Blood
2014
,124, 1412–1425. [CrossRef]
10.
Budde, U.; Pieconka, A.; Will, K.; Schneppenheim, R. Laboratory Testing for von Willebrand Disease:
Contribution of Multimer Analysis to Diagnosis and Classification. Semin. Thromb. Hemost.
2006
,32, 514–521.
[CrossRef]
11.
Stockschlaeder, M.; Schneppenheim, R.; Budde, U. Update on von Willebrand factor multimers: Focus on
high-molecular-weight multimers and their role in hemostasis. Blood Coagul. Fibrinolysis
2014
,25, 206–216.
[CrossRef]
12.
Zhang, Q.; Zhou, Y.-F.; Zhang, C.-Z.; Zhang, X.; Lu, C.; Springer, T.A. Structural specializations of A2,
a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc. Natl. Acad. Sci. USA
2009,106, 9226–9231. [CrossRef] [PubMed]
13.
Sadler, J.E. Biochemistry and Genetics of von willebrand factor. Annu. Rev. Biochem.
1998
,67, 395–424.
[CrossRef]
14.
Denorme, F.; Vanhoorelbeke, K.; De Meyer, S.F. von Willebrand Factor and Platelet Glycoprotein Ib:
A Thromboinflammatory Axis in Stroke. Front. Immunol. 2019,10, 2884. [CrossRef]
15.
Schneider, S.W.; Nuschele, S.; Wixforth, A.; Gorzelanny, C.; Alexander-Katz, A.; Netz, R.R.; Schneider, M.F.
Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc. Natl. Acad. Sci. USA
2007
,
104, 7899–7903. [CrossRef]
16.
Crawley, J.T.B.; de Groot, R.; Xiang, Y.; Luken, B.M.; Lane, D.A. Unraveling the scissile bond: How
ADAMTS13 recognizes and cleaves von Willebrand factor. Blood
2011
,118, 3212–3221. [CrossRef] [PubMed]
17.
Sing, C.E.; Alexander-Katz, A. Elongational Flow Induces the Unfolding of von Willebrand Factor at
Physiological Flow Rates. Biophys. J. 2010,98, L35–L37. [CrossRef]
18.
Westein, E.; van der Meer, A.D.; Kuijpers, M.J.E.; Frimat, J.-P.; van den Berg, A.; Heemskerk, J.W.M.
Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand
factor-dependent manner. Proc. Natl. Acad. Sci. USA 2013,110, 1357–1362. [CrossRef] [PubMed]
19.
Zheng, Y.; Chen, J.; L
ó
pez, J.A. Flow-driven assembly of VWF fibres and webs in
in vitro
microvessels.
Nat. Commun. 2015,6, 7858. [CrossRef]
20.
Zhang, C.; Kelkar, A.; Neelamegham, S. von Willebrand factor self-association is regulated by the
shear-dependent unfolding of the A2 domain. Blood Adv. 2019,3, 957–968. [CrossRef]
21.
Kanaji, S.; Fahs, S.A.; Shi, Q.; Haberichter, S.L.; Montgomery, R.R. Contribution of platelet vs. endothelial VWF
to platelet adhesion and hemostasis: Hemostatic effect of platelet VWF in murine VWD. J. Thromb. Haemost.
2012,10, 1646–1652. [CrossRef] [PubMed]
22.
Verhenne, S.; Denorme, F.; Libbrecht, S.; Vandenbulcke, A.; Pareyn, I.; Deckmyn, H.; Lambrecht, A.;
Nieswandt, B.; Kleinschnitz, C.; Vanhoorelbeke, K.; et al. Platelet-derived VWF is not essential for normal
thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood
2015
,126, 1715–1722. [CrossRef]
[PubMed]
23.
Fujikawa, K.; Suzuki, H.; McMullen, B.; Chung, D. Purification of human von Willebrand factor–cleaving
protease and its identification as a new member of the metalloproteinase family. Blood
2001
,98, 1662–1666.
[CrossRef]
24.
Uemura, M.; Tatsumi, K.; Matsumoto, M.; Fujimoto, M.; Matsuyama, T.; Ishikawa, M.; Iwamoto, T.; Mori, T.;
Wanaka, A.; Fukui, H.; et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood
2005
,106,
922–924. [CrossRef]
Int. J. Mol. Sci. 2020,21, 7804 14 of 18
25.
Mannucci, P.M.; Capoferri, C.; Canciani, M.T. Plasma levels of von Willebrand factor regulate ADAMTS-13,
its major cleaving protease. Br. J. Haematol. 2004,126, 213–218. [CrossRef]
26.
Xiang, Y.; de Groot, R.; Crawley, J.T.B.; Lane, D.A. Mechanism of von Willebrand factor scissile bond cleavage
by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13).
Proc. Natl. Acad. Sci. USA 2011,108, 11602–11607. [CrossRef]
27.
Gragnano, F.; Sperlongano, S.; Golia, E.; Natale, F.; Bianchi, R.; Crisci, M.; Fimiani, F.; Pariggiano, I.; Diana, V.;
Carbone, A.; et al. The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to
Targeted Therapy. Mediat. Inflamm. 2017,2017, 5620314. [CrossRef]
28.
Petri, B.; Broermann, A.; Li, H.; Khandoga, A.G.; Zarbock, A.; Krombach, F.; Goerge, T.; Schneider, S.W.;
Jones, C.; Nieswandt, B.; et al. von Willebrand factor promotes leukocyte extravasation. Blood
2010
,116,
4712–4719. [CrossRef] [PubMed]
29.
Hillgruber, C.; Steingräber, A.K.; Pöppelmann, B.; Denis, C.V.; Ware, J.; Vestweber, D.; Nieswandt, B.;
Schneider, S.W.; Goerge, T. Blocking von Willebrand Factor for Treatment of Cutaneous Inflammation.
J. Investig. Dermatol. 2014,134, 77–86. [CrossRef] [PubMed]
30.
Aym
é
, G.; Adam, F.; Legendre, P.; Bazaa, A.; Proulle, V.; Denis, C.V.; Christophe, O.D.; Lenting, P.J. A Novel
Single-Domain Antibody against von Willebrand Factor A1 Domain Resolves Leukocyte Recruitment and
Vascular Leakage during Inflammation—Brief Report. Arter. Thromb. Vasc. Biol.
2017
,37, 1736–1740.
[CrossRef]
31.
Khan, M.M.; Motto, D.G.; Lentz, S.R.; Chauhan, A.K. ADAMTS13 reduces VWF-mediated acute inflammation
following focal cerebral ischemia in mice: Role of ADAMTS13 and VWF in inflammatory brain injury.
J. Thromb. Haemost. 2012,10, 1665–1671. [CrossRef] [PubMed]
32.
De Meyer, S.F.; Savchenko, A.S.; Haas, M.S.; Schatzberg, D.; Carroll, M.C.; Schiviz, A.; Dietrich, B.;
Rottensteiner, H.; Scheiflinger, F.; Wagner, D.D. Protective anti-inflammatory effect of ADAMTS13 on
myocardial ischemia/reperfusion injury in mice. Blood 2012,120, 5217–5223. [CrossRef]
33.
Vincentelli, A.; Susen, S.; Le Tourneau, T.; Six, I.; Fabre, O.; Juthier, F.; Bauters, A.; Decoene, C.; Goudemand, J.;
Prat, A.; et al. Acquired von Willebrand Syndrome in Aortic Stenosis. N. Engl. J. Med.
2003
,349, 343–349.
[CrossRef] [PubMed]
34.
Sousa, N.C.; Anicchino-Bizzacchi, J.M.; Locatelli, M.F.; Castro, V.; Barjas-Castro, M.L. The relationship
between ABO groups and subgroups, factor VIII and von Willebrand factor. Haematologica
2007
,92, 236–239.
[CrossRef] [PubMed]
35. Budde, U.; Schneppenheim, R. von Willebrand Factor and von Willebrand disease. Rev. Clin. Exp. Hematol.
2001,5, 335–368. [CrossRef]
36.
Franchini, M.; Capra, F.; Targher, G.; Montagnana, M.; Lippi, G. Relationship between ABO blood group and
von Willebrand factor levels: From biology to clinical implications. Thromb. J. 2007,5, 14. [CrossRef]
37.
Gill, J.C.; Endres-Brooks, J.; Bauer, P.J.; Marks, W.J.; Montgomery, R.R. The effect of ABO blood group on the
diagnosis of von Willebrand disease. Blood 1987,69, 1691–1695. [CrossRef]
38. Smith, L.J. Laboratory Diagnosis of von Willebrand Disease. Clin. Lab. Sci. 2017,30, 65–74. [CrossRef]
39.
Budde, U.; Schneppenheim, R. Interactions of von Willebrand factor and ADAMTS13 in von Willebrand
disease and thrombotic thrombocytopenic purpura. Hamostaseologie 2014,34, 215–225. [CrossRef]
40.
Roberts, J.C.; Flood, V.H. Laboratory diagnosis of von Willebrand disease. Int. J. Lab. Hematol.
2015
,37,
11–17. [CrossRef]
41.
Favaloro, E.J. The Platelet Function Analyser (PFA)-100 and von Willebrand disease: A story well over
16 years in the making. Haemophilia 2015,21, 642–645. [CrossRef] [PubMed]
42.
Harrison, P. The role of PFA-100R testing in the investigation and management of haemostatic defects in
children and adults. Br. J. Haematol. 2005,130, 3–10. [CrossRef] [PubMed]
43.
Schoeman, R.M.; Lehmann, M.; Neeves, K.B. Flow chamber and microfluidic approaches for measuring
thrombus formation in genetic bleeding disorders. Platelets 2017,28, 463–471. [CrossRef]
44.
Federici, A.B. Acquired von Willebrand syndrome: Is it an extremely rare disorder or do we see only the tip
of the iceberg? J. Thromb. Haemost. 2008,6, 565–568. [CrossRef] [PubMed]
45.
Rizzo, C.; Rizzo, S. Thrombotic thrombocytopenic purpura: A review of the literature in the light of our
experience with plasma exchange. Blood Transfus. 2012. [CrossRef]
46.
Knöbl, P. Inherited and Acquired Thrombotic Thrombocytopenic Purpura (TTP) in Adults.
Semin. Thromb. Hemost. 2014,40, 493–502. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020,21, 7804 15 of 18
47.
Scully, M.; Cataland, S.R.; Peyvandi, F.; Coppo, P.; Knöbl, P.; Kremer Hovinga, J.A.; Metjian, A.;
de la Rubia, J.; Pavenski, K.; Callewaert, F.; et al. Caplacizumab Treatment for Acquired Thrombotic
Thrombocytopenic Purpura. N. Engl. J. Med. 2019,380, 335–346. [CrossRef]
48. Heyde, E.C. Gastrointestinal Bleeding in Aortic Stenosis. N. Engl. J. Med. 1958,259, 196. [CrossRef]
49.
Warkentin, T.; Morgan, D.G.; Moore, J.C. Aortic stenosis and bleeding gastrointestinal angiodysplasia:
Is acquired von Willebrand’s disease the link? Lancet 1992,340, 35–37. [CrossRef]
50.
Warkentin, T.E.; Moore, J.C.; Morgan, D.G. Gastrointestinal Angiodysplasia and Aortic Stenosis. N. Engl.
J. Med. 2002,347, 858–859. [CrossRef]
51.
Frank, R.D.; Lanzmich, R.; Haager, P.K.; Budde, U. Severe Aortic Valve Stenosis: Sustained Cure of Acquired
von Willebrand Syndrome after Surgical Valve Replacement. Clin. Appl. Thromb. Hemost.
2017
,23, 229–234.
[CrossRef] [PubMed]
52.
Panzer, S.; Eslam, R.B.; Schneller, A.; Kaider, A.; Koren, D.; Eichelberger, B.; Rosenhek, R.; Budde, U.;
Lang, I. Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation
in patients with aortic stenosis. Thromb. Haemost. 2010,103, 408–414. [CrossRef] [PubMed]
53.
Yasar, S.J.; Abdullah, O.; Fay, W.; Balla, S. Von Willebrand factor revisited. J. Interven. Cardiol.
2018
,31,
360–367. [CrossRef] [PubMed]
54.
Van Belle, E.; Rauch, A.; Vincent, F.; Robin, E.; Kibler, M.; Labreuche, J.; Jeanpierre, E.; Levade, M.; Hurt, C.;
Rousse, N.; et al. Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement. N. Engl.
J. Med. 2016,375, 335–344. [CrossRef] [PubMed]
55.
Solomon, C.; Budde, U.; Schneppenheim, S.; Czaja, E.; Hagl, C.; Schoechl, H.; von Depka, M.; Rahe-Meyer, N.
Acquired type 2A von Willebrand syndrome caused by aortic valve disease corrects during valve surgery.
Br. J. Anaesth. 2011,106, 494–500. [CrossRef] [PubMed]
56.
Blackshear, J.L.; Wysokinska, E.M.; Safford, R.E.; Thomas, C.S.; Shapiro, B.P.; Ung, S.; Stark, M.E.; Parikh, P.;
Johns, G.S.; Chen, D. Shear stress-associated acquired von Willebrand syndrome in patients with mitral
regurgitation. J. Thromb. Haemost. 2014,12, 1966–1974. [CrossRef]
57.
Susen, S.; Vincentelli, A.; Le Tourneau, T.; Caron, C.; Zawadzki, C.; Prat, A.; Goudemand, J.; Jude, B. Severe Aortic
and Mitral Valve Regurgitation Are Associated with von Willebrand Factor Defect. Blood
2005
,106, 1790. [CrossRef]
58.
Blackshear, J.L.; Schaff, H.V.; Ommen, S.R.; Chen, D.; Nichols, W.L. Hypertrophic Obstructive
Cardiomyopathy, Bleeding History, and Acquired von Willebrand Syndrome: Response to Septal Myectomy.
Mayo Clin. Proc. 2011,86, 219–224. [CrossRef]
59.
Le Tourneau, T.; Susen, S.; Caron, C.; Millaire, A.; Mar
é
chaux, S.; Polge, A.-S.; Vincentelli, A.; Mouquet, F.;
Ennezat, P.-V.; Lamblin, N.; et al. Functional Impairment of von Willebrand Factor in Hypertrophic
Cardiomyopathy: Relation to Rest and Exercise Obstruction. Circulation 2008,118, 1550–1557. [CrossRef]
60.
Nascimbene, A.; Neelamegham, S.; Frazier, O.H.; Moake, J.L.; Dong, J. Acquired von Willebrand syndrome
associated with left ventricular assist device. Blood 2016,127, 3133–3141. [CrossRef]
61.
Nichols, T.C.; Bellinger, D.A.; Tate, D.A.; Reddick, R.L.; Read, M.S.; Koch, G.G.; Brinkhous, K.M.; Griggs, T.R.
von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand’s disease pigs
with diet-induced hypercholesterolemia and atherosclerosis. Arteriosclerosis
1990
,10, 449–461. [CrossRef]
[PubMed]
62.
Gandhi, C.; Motto, D.G.; Jensen, M.; Lentz, S.R.; Chauhan, A.K. ADAMTS13 deficiency exacerbates
VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood
2012
,120, 5224–5230. [CrossRef]
[PubMed]
63. Seaman, C.D.; Yabes, J.; Comer, D.M.; Ragni, M.V. Does deficiency of von Willebrand factor protect against
cardiovascular disease? Analysis of a national discharge register. J. Thromb. Haemost.
2015
,13, 1999–2003.
[CrossRef] [PubMed]
64.
Xu, A.-G.; Xu, R.-M.; Lu, C.-Q.; Yao, M.-Y.; Zhao, W.; Fu, X.; Guo, J.; Xu, Q.-F.; Li, D.-D. Correlation of von
Willebrand factor gene polymorphism and coronary heart disease. Mol. Med. Rep.
2012
,6, 1107–1110.
[CrossRef]
65.
Thompson, S.G.; Kienast, J.; Pyke, S.D.M.; Haverkate, F.; van de Loo, J.C.W. Hemostatic Factors and the
Risk of Myocardial Infarction or Sudden Death in Patients with Angina Pectoris. N. Engl. J. Med.
1995
,332,
635–641. [CrossRef]
Int. J. Mol. Sci. 2020,21, 7804 16 of 18
66.
Willeit, P.; Thompson, A.; Aspelund, T.; Rumley, A.; Eiriksdottir, G.; Lowe, G.; Gudnason, V.;
Di Angelantonio, E. Hemostatic Factors and Risk of Coronary Heart Disease in General Populations:
New Prospective Study and Updated Meta-Analyses. PLoS ONE 2013,8, e55175. [CrossRef]
67.
Ray, K.K.; Morrow, D.A.; Gibson, C.M.; Murphy, S.; Antman, E.M.; Braunwald, E. Predictors of the rise in
vWF after ST elevation myocardial infarction: Implications for treatment strategies and clinical outcome.
Eur. Heart J. 2005,26, 440–446. [CrossRef]
68.
Jansson, J.H.; Nilsson, T.K.; Johnson, O. von Willebrand factor in plasma: A novel risk factor for recurrent
myocardial infarction and death. Heart 1991,66, 351–355. [CrossRef]
69.
Rutten, B.; Maseri, A.; Cianflone, D.; Laricchia,A.; Cristell, N.; Durante, A.; Spartera, M.; Ancona, F.; Limite, L.;
Hu, D.; et al. Plasma levels of active von Willebrand factor are increased in patients with first ST-segment
elevation myocardial infarction: A multicenter and multiethnic study. Eur. Heart J. Acute Cardiovasc. Care
2015,4, 64–74. [CrossRef]
70. Kaikita, K.; Soejima, K.; Matsukawa, M.; Nakagaki, T.; Ogawa, H. Reduced von Willebrand factor-cleaving
protease (ADAMTS13) activity in acute myocardial infarction. J. Thromb. Haemost.
2006
,4, 2490–2493.
[CrossRef]
71.
Crawley, J.T.B.; Lane, D.A.; Woodward,M.; Rumley, A.; Lowe, G.D.O. Evidence that high von Willebrand factor
and low ADAMTS-13 levels independently increase the risk of a non-fatal heart attack. J. Thromb. Haemost.
2008,6, 583–588. [CrossRef] [PubMed]
72.
Chion, C.K.N.K.; Doggen, C.J.M.; Crawley, J.T.B.; Lane, D.A.; Rosendaal, F.R. ADAMTS13 and von Willebrand
factor and the risk of myocardial infarction in men. Blood 2007,109, 1998–2000. [CrossRef] [PubMed]
73.
Morange, P.E.; Simon, C.; Alessi, M.C.; Luc, G.; Arveiler, D.; Ferrieres, J.; Amouyel, P.; Evans, A.; Ducimetiere, P.;
Juhan-Vague, I. Endothelial Cell Markers and the Risk of Coronary Heart Disease: The Prospective Epidemiological
Study of Myocardial Infarction (PRIME) Study. Circulation 2004,109, 1343–1348. [CrossRef]
74.
Li, Y.; Li, L.; Dong, F.; Guo, L.; Hou, Y.; Hu, H.; Yan, S.; Zhou, X.; Liao, L.; Allen, T.D.; et al. Plasma von
Willebrand factor level is transiently elevated in a rat model of acute myocardial infarction. Exp. Ther. Med.
2015,10, 1743–1749. [CrossRef]
75.
Price, J. Relationship between smoking and cardiovascular risk factors in the development of peripheral
arterial disease and coronary artery disease; Edinburgh Artery Study Edinburgh Artery Study. Eur. Heart J.
1999,20, 344–353. [CrossRef] [PubMed]
76.
Danesh, J.; Wheeler, J.G.; Hirschfield, G.M.; Eda, S.; Eiriksdottir, G.; Rumley, A.; Lowe, G.D.O.; Pepys, M.B.;
Gudnason, V. C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of
Coronary Heart Disease. N. Engl. J. Med. 2004,350, 1387–1397. [CrossRef]
77.
Lee, K.; Blann, A.; Lip, G. High pulse pressure and nondipping circadian blood pressure in patients
with coronary artery disease: Relationship to thrombogenesis and endothelial damage/dysfunction.
Am. J. Hypertens. 2005,18, 104–115. [CrossRef]
78.
Lip, G.Y.H.; Blann, A.D.; Jones, A.F.; Lip, P.L.; Beevers, D.G. Relation of Endothelium, Thrombogenesis,
and Hemorheology in Systemic Hypertension to Ethnicity and Left Ventricular Hypertrophy. Am. J. Cardiol.
1997,80, 1566–1571. [CrossRef]
79.
Jager, A.; van Hinsbergh, V.W.M.; Kostense, P.J.; Emeis, J.J.; Yudkin, J.S.; Nijpels, G.; Dekker, J.M.; Heine, R.J.;
Bouter, L.M.; Stehouwer, C.D.A. von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic
and Nondiabetic Subjects: The Hoorn Study. Arter. Thromb. Vasc. Biol 1999,19, 3071–3078. [CrossRef]
80.
Stehouwer, C.A.; Zeldenrust, G.C.; den Ottolander, G.H.; Hackeng, W.H.L.; Donker, A.J.M.; Nauta, J.J.P.
Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent
diabetes mellitus. Lancet 1992,340, 319–323. [CrossRef]
81.
Warlo, E.M.K.; Pettersen, A.-Å.R.; Arnesen, H.; Seljeflot, I. vWF/ADAMTS13 is associated with on-aspirin
residual platelet reactivity and clinical outcome in patients with stable coronary artery disease. Thromb. J.
2017,15, 28. [CrossRef] [PubMed]
82.
Blann, A.D.; Herrick, A.; Jayson, M.I.V. Altered levels of soluble adhesion molecules in rheumatoid arthritis,
vasculitis and systemic sclerosis. Rheumatology 1995,34, 814–819. [CrossRef] [PubMed]
83.
Nossent, J.C.; Raymond, W.D.; Eilertsen, G.Ø. Increased von Willebrand factor levels in patients with
systemic lupus erythematosus reflect inflammation rather than increased propensity for platelet activation.
Lupus Sci. Med. 2016,3, e000162. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020,21, 7804 17 of 18
84.
Lacquemant, C.; Gaucher, C.; Delorme, C.; Chatellier, G.; Gallois, Y.; Rodier, M.; Passa, P.; Balkau, B.;
Mazurier, C.; Marre, M.; et al. Association between high von Willebrand factor levels and the Thr789Ala
vWF gene polymorphism but not with nephropathy in type I diabetes. Kidney Int.
2000
,57, 1437–1443.
[CrossRef] [PubMed]
85.
Bonetti, P.O.; Lerman, L.O.; Lerman, A. Endothelial Dysfunction: A Marker of Atherosclerotic Risk.
ATVB 2003,23, 168–175. [CrossRef] [PubMed]
86.
Heper, G.; Murat, S.N.; Durmaz, T.; Kalkan, F. Prospective Evaluation of von Willebrand Factor Release after
Multiple and Single Stenting. Angiology 2004,55, 177–186. [CrossRef] [PubMed]
87.
Kefer, J.M.; Galanti, L.M.; Desmet, S.; Deneys, V.; Hanet, C.E. Time course of release of inflammatory markers
after coronary stenting: Comparison between bare metal stent and sirolimus-eluting stent. Coron. Artery Dis.
2005,16, 505–509. [CrossRef]
88.
Pottinger, B.E.; Read, R.C.; Paleolog, E.M.; Higgins, P.G.; Pearson, J.D. von Willebrand factor is an acute
phase reactant in man. Thromb. Res. 1989,53, 387–394. [CrossRef]
89.
Bernardo, A.; Ball, C.; Nolasco, L.; Choi, H.; Moake, J.L.; Dong, J.F. Platelets adhered to endothelial cell-bound
ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress.
J. Thromb. Haemost. 2005,3, 562–570. [CrossRef]
90.
Kaufmann, J.E.; Oksche, A.; Wollheim, C.B.; Günther, G.; Rosenthal, W.; Vischer, U.M. Vasopressin-induced
von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J. Clin. Investig.
2000
,
106, 107–116. [CrossRef]
91.
Melnikov, I.; Avtaeva, Y.; Kozlov, S.; Nozadze, D.; Gabbasov, Z. P721Shear stress induced unfolding of von
willebrand factor may be involved in the premature development of myocardial infarction. Eur. Heart J.
2019,40, ehz747.0326. [CrossRef]
92.
Sobel, M.; McNeill, P.M.; Carlson, P.L.; Kermode, J.C.; Adelman, B.; Conroy, R.; Marques, D. Heparin
inhibition of von Willebrand factor-dependent platelet function
in vitro
and
in vivo
.J. Clin. Investig.
1991
,
87, 1787–1793. [CrossRef] [PubMed]
93.
Montalescot, G.; Philippe, F.; Ankri, A.; Vicaut, E.; Bearez, E.; Poulard, J.E.; Carrie, D.; Flammang, D.;
Dutoit, A.; Carayon, A.; et al. Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable
Coronary Artery Disease: Beneficial Effects of Enoxaparin. Circulation 1998,98, 294–299. [CrossRef]
94.
Kageyama, S.; Matsushita, J.; Yamamoto, H. Effect of a humanized monoclonal antibody to von Willebrand
factor in a canine model of coronary arterial thrombosis. Eur. J. Pharmacol. 2002,443, 143–149. [CrossRef]
95.
Gilbert, J.C.; DeFeo-Fraulini, T.; Hutabarat, R.M.; Horvath, C.J.; Merlino, P.G.; Marsh, H.N.; Healy, J.M.;
BouFakhreddine, S.; Holohan, T.V.; Schaub, R.G. First-in-Human Evaluation of Anti–von Willebrand Factor
Therapeutic Aptamer ARC1779 in Healthy Volunteers. Circulation
2007
,116, 2678–2686. [CrossRef] [PubMed]
96.
Markus, H.S.; McCollum, C.; Imray, C.; Goulder, M.A.; Gilbert, J.; King, A. The von Willebrand Inhibitor
ARC1779 Reduces Cerebral Embolization after Carotid Endarterectomy: A Randomized Trial. Stroke
2011
,
42, 2149–2153. [CrossRef]
97.
Kovacevic, K.D.; Buchtele, N.; Schoergenhofer, C.; Derhaschnig, U.; Gelbenegger, G.; Brostjan, C.; Zhu, S.;
Gilbert, J.C.; Jilma, B. The aptamer BT200 effectively inhibits von Willebrand factor (VWF) dependent platelet
function after stimulated VWF release by desmopressin or endotoxin. Sci. Rep. 2020,10, 11180. [CrossRef]
98.
Sakai, K.; Someya, T.; Harada, K.; Yagi, H.; Matsui, T.; Matsumoto, M. Novel aptamer to von Willebrand
factor A1 domain (TAGX-0004) shows total inhibition of thrombus formation superior to ARC1779 and
comparable to caplacizumab. Haematologica 2019. [CrossRef]
99.
van Loon, J.E.; de Jaegere, P.P.T.; van Vliet, H.H.D.M.; de Maat, M.P.M.; de Groot, P.G.; Simoons, M.L.;
Leebeek, F.W.G. The
in vitro
effect of the new antithrombotic drug candidate ALX-0081 on blood samples of
patients undergoing percutaneous coronary intervention. Thromb. Haemost 2011,106, 165–171. [CrossRef]
100.
Bartunek, J.; Barbato, E.; Vercruysse, K.; Duby, C.; Wijns, W.; Heyndrickx, G.; Holz, J.-B. Abstract 15084: Safety
and Efficacy of Anti-von Willebrand Factor Nanobody
®
ALX-0081 in Stable Angina Patients Undergoing
Percutaneous Coronary Intervention. Circulation 2010,122, A15084.
Int. J. Mol. Sci. 2020,21, 7804 18 of 18
101.
Bartunek, J.; Barbato, E.; Heyndrickx, G.; Vanderheyden, M.; Wijns, W.; Holz, J.-B. Novel Antiplatelet Agents:
ALX-0081, a Nanobody Directed towards von Willebrand Factor. J. Cardiovasc. Trans. Res.
2013
,6, 355–363.
[CrossRef] [PubMed]
102.
Witsch, T.; Martinod, K.; Sorvillo, N.; Portier, I.; De Meyer, S.F.; Wagner, D.D. Recombinant Human
ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality after Pressure Overload Injury
in Mice. JAHA 2018,7. [CrossRef] [PubMed]
Publisher’s Note:
MDPI stays neutral with regard to jurisdictional claims in published maps and institutional
affiliations.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
