Download Von Willebrand factor and thrombosis

Ann Hematol
DOI 10.1007/s00277-006-0085-5
REVIEW ARTICLE
Massimo Franchini . Giuseppe Lippi
Von Willebrand factor and thrombosis
Received: 29 December 2005 / Accepted: 29 December 2005
# Springer-Verlag 2006
Abstract There is increasing evidence that von Willebrand
factor (VWF), an adhesive multimeric protein that has an
important function in primary hemostasis and as a carrier of
factor VIII, has a pivotal role in thrombogenesis. In fact,
while the presence in plasma of unusually large VWF
multimers due to a congenital or acquired deficiency of a
VWF-cleaving metalloprotease has been implicated in the
pathogenesis of thrombotic thrombocytopenic purpura
(TTP), high plasma levels of VWF have been associated
with a slightly increased risk of arterial thrombosis. With
regard to the association between VWF and venous
thrombosis, clear conclusions cannot yet be drawn from
the conflicting published data. Patients with von Willebrand
disease, an inherited hemorrhagic disorder, may also
paradoxically experience thrombotic events as a result of
interactions among multiple prothrombotic risk factors.
After a description of the structure and physiology of VWF,
all these aspects are discussed in the present review.
Keywords von Willebrand factor . Thrombosis .
Thrombotic thrombocytopenic purpura . von Willebrand
disease
lets, endothelial cells, and the subendothelium. It supports
primary hemostasis and serves as a carrier for factor VIII
(FVIII), protecting this coagulation factor from proteolysis
by the activated protein C system [1, 2]. While an inherited
deficiency or abnormality of VWF is associated with a
bleeding disorder named von Willebrand disease (VWD),
high plasma concentrations of VWF have been associated
with an increased risk of thrombosis [3]. However, paradoxically, thrombotic complications may also occur in
VWD patients [4]. Other thrombotic events in which VWF
is involved have also been described. In fact, a congenital or
acquired deficiency of the VWF-cleaving metalloprotease
ADAMTS-13, the major regulator of the size of VWF in
plasma, causes the presence of unusually large multimers of
VWF and thus, massive intravascular formation of plateletrich thrombi in patients with thrombotic thrombocytopenic
purpura (TTP) [5]. All these thrombotic events are discussed
in this review. Data were identified by searches of the
published literature, including PubMed (without time limits)
and references from reviews.
Structure and function of von Willebrand factor
Introduction
Von Willebrand factor (VWF), the largest human plasma
protein, is an adhesive multimeric protein present in plateM. Franchini (*)
Servizio di Immunoematologia e Trasfusione,
Ospedale Policlinico, Azienda Ospedaliera di Verona,
Piazzale L. Scuro, 10,
37134 Verona, Italy
e-mail: [email protected]
Tel.: +39-45-8073610
Fax: +39-45-8073612
G. Lippi
Istituto di Chimica e Microscopia Clinica,
Dipartimento di Scienze Biomediche e Morfologiche,
Università di Verona,
Verona, Italy
Von Willebrand factor is a large multimeric glycoprotein
synthesized by endothelial cells and megakaryocytes. It
mediates the adhesion of platelets to sites of vascular lesions
and being the carrier for FVIII, is required for normal survival
of this coagulation factor in the circulation [6]. The gene
coding for VWF is large, being composed of 178 kb; it is
located on the short arm of chromosome 12 and contains 52
exons. The primary product of the VWF gene is a 2,813
amino acid protein made of a signal peptide of 22 amino acids
(also called a pre-peptide), a large pro-peptide of 741 amino
acids and a mature VWF molecule of 270 kDa containing
2,050 amino acids [7, 8]. The pro-peptide and mature subunit
constitute the pro-VWF monomer, composed of four types of
repeated domains (D1, D2, D′, D3, A1, A2, A3, D4, B, C1,
C2 from the N- to C-terminal region) of cDNA which are
responsible for the different binding functions of the molecule
(see Fig. 1). The building block of VWF multimers is a dimer
Fig. 1 Schematic representation
of the mature von Willebrand
factor subunit, including the
various domains responsible for
the different binding functions
of the molecule
formed in the endoplasmic reticulum and made up of two
single-chain pro-VWF molecules, joined through disulphide
bonds within their C-terminal region. The pro-VWF dimers
are then transported to the Golgi apparatus where they are
polymerized into very large molecules, with molecular
weights of up to 20,000 kDa, through disulphide bonds
connecting the two N-terminal ends of each dimer [9]. The
newly synthesized VWF is either secreted constitutively or is
targeted to storage granules, the Weibel–Palade bodies in
endothelial cells or α-granules in megakaryocytes [10]. These
storage granules contain the larger, more hemostatic forms of
VWF that are released upon stimulation by agonists such as
thrombin, epinephrine, and fibrin. The storage granules also
contain ultralarge multimers (ULVWF), which are not usually
found in the circulation [11]. Indeed, a specific plasma
protease, known as ADAMTS-13 (a disintegrin and
metalloprotease, with thrombospondin-1-like domains), acts
on VWF multimers secreted from endothelial cells, rapidly
cleaving the VWF subunit on the endothelial surface between
the amino acids residues Tyr1605 and Met1606 in the A2
domain, thus, reducing the size of plasma VWF and creating
the full spectrum of circulating VWF species, ranging from
the single dimer to about 20 dimers in each VWF multimer
[9, 12]. Besides being found in endothelial cells, megakaryocytes and platelets, VWF is also present in the subendothelial matrix, where it is bound, through specific regions in
its A1 and A3 domains, to different types of collagen.
VWF has two major functions in hemostasis [6, 13]. First,
it is essential for platelet-subendothelium adhesion and
platelet-to-platelet interactions and also causes platelet aggregation in vessels in which rapid blood flow results in elevated
shear stress. Adhesion is promoted by the interaction of a
region of the A1 domain of VWF with platelet-receptor
glycoprotein Ibα (GpIbα) on the platelet membrane. It is
thought that high shear stress activates the A1 domain of the
VWF bound to collagen (through the A3 domain) by
stretching VWF multimers into their filamentous form [14].
Furthermore, GPIbα and VWF are also necessary for plateletto-platelet interactions [15]. The interaction between GPIbα
and VWF can be mimicked in platelet-rich plasma by
addition of the antibiotic ristocetin, which promotes binding
of VWF to GPIbα of fresh or formalin-fixed platelets. The
Arg-Gly-Asp (RGD) sequence within the VWF C1 domain
can bind to activated integrin αIIbβ3 (GPIIb-IIIa) on
activated platelets, leading to the subsequent steps of platelet
spreading and aggregation. Both these binding activities of
VWF are highly expressed by the largest VWF multimers.
The second major function of VWF in hemostasis is as the
specific carrier of FVIII in plasma [16]. Each VWF monomer
has two binding domains (D′ and D3 domains) which can
non-covalently bind one FVIII molecule, thus, protecting the
coagulation factor from proteolytic degradation, prolonging
its half-life in the circulation and efficiently localizing it at the
site of vascular injury.
Von Willebrand factor as a risk factor for arterial
and venous thrombosis
Particularly at high shear forces, which are physiologic in
the arterioles and also occur in pathologic conditions at sites
of severe stenosis of large arteries caused by the formation
of atherosclerotic plaques, VWF supports the initial adhesion of platelets by functioning as a ligand between platelet
membrane glycoproteins and the subendothelium and plays
an essential role in platelet aggregation [1, 17, 18]. The high
shear forces increase VWF secretion by vascular endothelium, thus, stimulating platelet adhesion and aggregation at
the site of damaged arterial walls and leading to thrombus
formation. However, plasma VWF levels depend on various
factors including the individual’s genetic background,
chronic conditions, and transient events. With regard to
the genetic factors determining VWF levels, individuals
with a non-O blood group, females, and black races have
higher VWF levels (and consequently higher FVIII levels)
than do individuals with blood group O, males, and white
people [19, 20]. Conditions causing chronically raised levels
of VWF include older age, obesity, diabetes, chronic
inflammation, cancer, liver, and renal diseases. Conditions
causing a transient rise in VWF levels include pregnancy,
surgery, exercise, and agents such as epinephrine, vasopressin, and desmopressin [3, 21].
Since the early 1990s many attempts have been made to
elucidate whether high plasma concentrations of VWF are
associated with an increased risk of thrombosis [3]. Several
prospective studies on the role of VWF in arterial and venous
thrombosis have been performed in healthy individuals and
patients with cardiovascular diseases. The results of these
studies are presented in the next two sections.
Von Willebrand factor and arterial thrombosis
Among the prospective clinical studies published on the role
of VWF in coronary heart disease and stroke, the Northwick
Park Heart Study [22] examined the relation of FVIII, VWF,
and ABO blood groups with the incidence of ischemic heart
disease in 1,393 healthy men aged between 40 and 64 years
who experienced 178 first major episodes of ischemic heart
disease during an average follow-up of 16.1 years. After
adjustment for ABO blood groups, a multivariate analysis
showed that higher levels of VWF and FVIII were
associated with fatal ischemic heart disease.
In 1995, Thompson and colleagues reported the results
from the multicenter, prospective European Concerted
Action on Thrombosis (ECAT) Study [23], which was
conducted on 3,043 patients with angina pectoris followed
for 2 years. Selected hemostatic factors of the coagulation
and fibrinolytic systems were analyzed in relation to the
development of myocardial infarction or sudden coronary
death, and after adjustment for many confounding factors
(age, sex, blood group, diabetes, hypertension, smoking,
etc.), only VWF and tissue plasminogen activator were
found to be independent predictors of subsequent acute
coronary events.
The Atherosclerosis Risk In Communities (ARIC) study
recruited 14,477 adults, aged between 45 and 64 years,
who were initially free of coronary heart disease [24], and
monitored them over a mean period of 5 years for the
occurrence of new onset coronary heart disease. Among the
various plasma hemostatic factors measured, fibrinogen,
FVIII, and VWF were associated with an increased risk of
ischemic heart disease, but in a multivariate analysis that
included classical cardiovascular risk factors, this relationship was attenuated for fibrinogen and disappeared for
VWF and FVIII. In a subsequent update, the same study
[25] did, however, show a significantly higher risk of
stroke in individuals with high VWF and FVIII levels.
Like the previous study, the Edinburgh Artery Study [26],
conducted on 1,592 individuals who were free of coronary
heart disease and were monitored for 5 years, failed to find
an association between VWF levels and ischemic heart
disease. Other investigators, in the Caerphilly Heart Study
[27], studied 1,997 men aged 49–65 years for 5 years and
found a positive association between FVIII, VWF, and
ischemic heart disease. However, VWF and FVIII levels
were mutually dependent, as the statistical significance of
the relative risk for ischemic heart disease was lost in
multivariate analysis after adjustment for each other.
Jansson and colleagues [28] followed a cohort of 123
survivors of myocardial infarction for up to 10 years and
found that VWF and tissue plasminogen activator levels
were independent predictors of cardiovascular mortality.
In a prospective study conducted by Whincup and
colleagues [29] on 625 male patients with major coronary
events and 1,266 male controls followed up for 16 years for
fatal coronary heart disease and non-fatal myocardial
infarction, VWF values in the upper tertile were associated
with a higher rate of incident coronary heart disease compared to values in the lower tertile (odds ratio, 1.83; 95%
confidence interval, 1.43 to 2.35). The same authors also
conducted a meta-analysis on all the relevant populationbased prospective studies published by that time and found a
similar combined odds ratio of 1.5 (95% confidence
interval, 1.1 to 2.0). However, among the studies included
in this analysis, the predictive ability of VWF depended
strongly on the variables controlled for, in particular,
markers of inflammation. Thus, the prognostic relevance
of VWF, which is an acute-phase reactant, could simply be
as a marker of the inflammatory process, which is known to
play a major role in coronary heart disease, rather than an as
independent risk factor.
This issue had been raised by the aforementioned ECAT
study [23] which showed in subjects with angina pectoris
that the independent relative risk of cardiovascular mortality
associated with VWF disappeared after adjustment for
variables related to inflammation, i.e., C-reactive protein
and fibrinogen. In contrast, the Hoorn Study [30], which
investigated a cohort of 631 middle-aged diabetic and nondiabetic individuals followed for 5 years, found that
increased levels of VWF and C-reactive protein were
independently associated with cardiovascular and all-cause
mortality in both groups.
The Prospective Epidemiological Study of Myocardial
Infarction (PRIME) examined the association of VWF and
coronary heart disease (CHD) in 9,758 healthy men aged
50–59 years old who were followed up for 5 years [31].
Individuals with VWF levels in the upper quartile had a
threefold higher risk of ischemic heart disease compared to
those with levels in the lowest quartile. Moreover, adjustment for inflammatory markers (C-reactive protein, interleukin-6, and fibrinogen) did not alter the value of VWF as
an independent risk factor for coronary heart disease.
Recently, in order to investigate the association between
the genetic variability of VWF and the risk of coronary
artery disease, the Rotterdam Study prospectively examined
the association of the −1,793 C/G polymorphism in the
VWF gene with coronary heart disease in 1,088 subjects
with and without advanced atherosclerosis [32]. The study
concluded that this VWF gene polymorphism was associated with an increased risk of coronary heart disease but
only in individuals with advanced atherosclerosis. The
largest prospective studies of VWF and coronary heart
disease are reported in Table 1.
Although these epidemiologic studies differ profoundly
from each other in terms of design, patient populations
enrolled, and end-points evaluated, collectively, they do
provide some evidence that high VWF levels are associated
with a moderately increased risk of arterial thrombosis
[29]. However, a recent study documented that ultrasonographically measured intima–media thickness in atherosclerotic plaques in the carotid and femoral arteries of
patients with severe VWD was not different from that in
healthy controls [33]. The fact that patients with severe
VWD are not protected against atherosclerosis, together
with similar findings in animal models, suggests that VWF
does not play a role in the atherosclerotic process but only
in occlusive arterial thrombosis.
Von Willebrand factor and venous thrombosis
Fewer studies have been published with regard to the
relationship between plasma VWF levels and venous
thrombosis [3]. The belief, derived from a few studies
conducted in the 1980s [34, 35], that VWF may represent a
Table 1 Prospective studies of von Willebrand factor and coronary heart disease
Study (reference)
Year No. of subjects Risk ratio (95% confidence interval)*
NPHS (19)
1994 1,393
ECAT Study (20)
1995 3,043
ARIC Study (21)
1997 14,477
Edinburgh Heart Study (23) 1997 1,592
Caerphilly Heart Study (24) 1999 1,997
Hoorn Study (27)
1999
631
Whincup et al. (26)
2002 1,891
PRIME Study (28)
2004 9,758
Rotterdam Study (29)
2004 1,088
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
NPHS Northwick Park Heart Study, ECAT European Concerted Action on Thrombosis, ARIC Atherosclerosis Risk in Communities, PRIME
Prospective Epidemiological Study of Myocardial Infarction
*The risk ratios and 95% confidence intervals reported are adjusted for the other hemostatic and classical vascular risk factors analyzed in
the various studies
risk factor for venous thrombosis was challenged by the
results of the Leiden Thrombophilia Study [36], in which
VWF was not associated with an increased risk of venous
thrombosis. In fact, although the odds ratio for venous
thrombosis in patients with VWF levels above 150 IU/dl
compared to those with levels lower than 100 IU/dl was 3.0
(95% confidence interval, 1.8 to 4.9) in the univariate
analysis, when the results were adjusted for blood group and
FVIII in the multivariate analysis, the odds ratio was 1.2
(95% confidence interval, 0.6 to 2.1), suggesting that the
effect of VWF on the risk of venous thrombosis was fully
explained by FVIII levels.
In contrast, the Longitudinal Investigation of Thromboembolism Etiology (LITE) study [37], which followed
19,237 healthy individuals older than 45 years for a mean
period of 7.8 years, showed that VWF and FVIII were
independently associated with venous thromboembolism in
a dose-dependent manner. Another study on a small series of
patients found a positive association between VWF and
deep vein thrombosis, but it was not established whether the
levels were raised prior to the thrombosis or were merely
due to a secondary reaction (FVIII levels were not
measured) [38]. Finally, based on the fact that VWF as a
carrier of FVIII is an important determinant of FVIII levels,
other researchers have investigated whether genetic variations in the FVIII and VWF genes could influence FVIII
levels. However, none of the several polymorphisms in the
VWF and FVIII genes analyzed was found to be associated
with VWF, FVIII levels or venous thrombotic risk [39].
Thus, while the analysis of the above data documents that
FVIII is associated with an increased risk of venous
thrombosis, less information is available with regard to
VWF and venous thrombosis, making such an association
uncertain.
Von Willebrand factor and thrombotic
thrombocytopenic purpura
Since the first description of TTP in 1924, numerous
hypotheses on the etiology and pathogenesis of this
condition have been proposed. In particular, abnormalities
of plasma VWF have been recognized to be associated with
TTP for more than 20 years [40]. In fact in 1985, Asada and
colleagues used immunohistochemical techniques to show
that intravascular thrombi and subendothelial hyaline
deposits in TTP react positively for VWF antigen and
negatively for fibrin [41]. As reported above, both
endothelial cells and megakaryocytes produce multimers
of VWF that are larger (ULVWF) and have stronger
affinity for platelet glycoprotein receptors than the VWF
normally present in the plasma. In vivo, when a vascular
lesion occurs in areas of blood flow, ULVWF multimers
secreted from endothelial cells adhere to subendothelial
collagen and become extended under the high shear stress
forces, thus, localizing the platelets, bound to VWF
through the GPIb-IX-V complex, to the site of the injury
and arresting the bleeding. Newly secreted ULVWF multimers are immediately cleaved on the endothelial surface
into smaller multimers by the metalloprotease ADAMTS13, which is produced predominantly in the liver and
prevents the accumulation of pathogenic ULWVF multi-
mers, thus, protecting against uncontrolled platelet adhesion [5, 13, 42, 43]. Although a VWF-cleaving protease
was hypothesized to be the cause of TTP in 1982 by Moake
and colleagues [44], its existence was demonstrated only in
1996 independently by Furlan [45] and Tsai [46]. These
two groups subsequently published evidence that the
activity of this protease was consistently and severely
reduced in patients with TTP, either because of a congenital
deficiency or an acquired deficiency caused by an autoantibody [47–49]. In fact, in two retrospective studies on a
large number of patients with acute TTP [48, 49], these
researchers showed that most patients had severely
deficient VWF-cleaving protease activity, which in the
majority of cases of acute sporadic TTP was caused by
circulating IgG autoantibodies inhibiting the VWF-cleaving protease activity. In most patients with acute acquired
idiopathic TTP who achieved a remission, the VWFcleaving protease activity normalized and the inhibiting
autoantibodies disappeared. In contrast, patients with a
hereditary form of TTP remained severely deficient in
VWF-cleaving protease activity, even in remission, and
their plasma contained no inhibitory autoantibodies. These
results were confirmed by further studies. In particular,
Veyradier and colleagues [50], in a large study on 111
patients with thrombotic microangiopathy, found that
VWF-cleaving protease activity was deficient in the
idiopathic form of the microangiopathy and in most
subsets of TTP and that an inhibitor to metalloprotease
could be detected in about half of the TTP patients. In
2001, VWF-cleaving protease was purified from normal
plasma and was characterized as a member of the so-called
ADAMTS family of proteases [51–54]. In the same year,
through a genomic analysis of patients with hereditary TTP
and their relatives, Levy and colleagues [55] detected the
gene responsible, ADAMTS13, on chromosome 9q34. The
authors identified several mutations of this gene as being
presumably responsible for the severely deficient
ADAMTS13 activity and disease in homozygous or
compound heterozygous carriers of mutated alleles,
whereas, family members with a heterozygous ADAMTS13
mutation had approximately 50% protease activity and
were clinically asymptomatic. Various groups of researchers have since reported many new mutations throughout the
ADAMTS13 gene and to date, more than 40 missense and
nonsense mutations have been identified [5].
Von Willebrand disease and thrombosis
It is easy to appreciate from the foregoing that VWF plays
an important role in thrombogenesis. It is, however,
decidedly less intuitive to imagine thrombotic complications
of VWD, a disease that is expected to be associated with a
clinical picture of bleeding manifestations [4]. However, in
some cases, the coexistence of acquired and/or inherited
prothrombotic risk factors may overcome the bleeding
tendency and lead to the development of thrombotic
complications [56–60]. These thrombotic events, which
occur only rarely in VWD patients [61], may be associated
or not with the infusion of FVIII/VWF concentrates; events
associated with such infusions are more frequently venous,
whereas, events not related to infusions are more frequently
arterial.
However, before discussing these issues more fully, it is
worth focusing briefly on a particular subtype of VWD—
type 2B—as the recent elucidation of the physiopathological
mechanisms of this subtype has led to a better understanding
of the relationship between VWF and thrombosis [62].
Why do patients with type 2B WVD suffer
from bleeding rather than thrombosis?
Although it may seem paradoxical that patients with VWD
can develop thrombotic complications, it is equally paradoxical that the 2B subtype of VWD is characterized by
bleeding rather than thrombotic events. In fact, the VWF in
type 2B VWD is structurally abnormal causing enhanced
binding to the platelet glycoprotein Ib (GPIb) receptor. As a
consequence of this functional alteration, the concentration
of the largest VWF multimers in plasma decreases, and the
platelet count may be episodically (e.g., after desmopressin
infusion or after surgery) decreased as a result of
microaggregation [61]. Although it may be surprising
that the presence of a hyperfunctional adhesive molecule in
the blood causes a bleeding tendency instead of thrombosis, this is only apparently paradoxical and can be
explained starting from the physiology of VWF [62].
Under normal conditions, large VWF multimers circulate
in the blood in an inactive form in which the A1 domains
(where the GPIbα binding site is located) are protected
from interactions with platelet GPIb. Interactions between
platelets, mediated by the VWF–GPIbα bond, occur in
blood but only rarely and are reversible [63]. This situation
is radically different at the site of a wound, where VWF
multimers bind through A3 domains to the exposed
collagen of the extracellular matrix and become extended
and immobilized, thus, exposing the A1 domains. The
consequent adhesion of platelets to the immobilized VWF
is initially transient but becomes irreversible once
additional bonds with other matrix components have
been established [63]. The mutations in type 2B VWD
enhance the binding of the VWF A1 domain with platelet
GP1b, thus, promoting a more stable interaction with
circulating platelets [64]. Thus, the occupancy of platelet
GP1b receptors in the circulation makes the interaction of
platelets with VWF at a wound site, where it is needed for
normal hemostasis, less efficient [62]. Moreover, in parallel
with VWF-dependent platelet aggregation in the circulation, ADAMTS13-dependent proteolysis of VWF subunits
is markedly increased, and the functionally important large
VWF multimers are removed from plasma. Thus, there is in
fact, a good explanation for how a gain-of-function
mutation that increases VWF–GPIb binding, and might
be expected to cause microvascular thrombosis, is actually
associated with a loss-of-function phenotype causing a
bleeding tendency [62].
Thrombotic complications in VWD patients
after infusion of clotting factor concentrates
Most reports of thrombotic complications in VWD patients
concern those after infusion of coagulation factor concentrates. In fact, cases of thrombosis in VWD patients after
administration of various FVIII/VWF concentrates have
been reported [64–67], and nowadays, an evaluation of postinfusion thombotic complications is included in the reported
safety profile of every factor concentrate product [66, 67].
Thrombosis in this setting may be attributed to various
factors, the most important being high post-treatment levels
of FVIII (>150 UI/dl), an established risk factor for venous
thromboembolism [68], reached when FVIII/VWF concentrates are administered at short intervals. In fact, in this
setting, exogenous FVIII infused with the concentrate adds to
the endogenously synthesized FVIII which is stabilized by
the infused VWF [64]. Makris and colleagues [65] described
four cases of venous thromboembolism after treatment with
the intermediate purity FVIII concentrate Haemate P but all
of them had additional risk factors (older age, surgery,
estrogen intake). Mannucci reported the case of a patient with
type 3 VWD who developed a non-fatal pulmonary
embolism 12 days after hip replacement surgery. A postoperative check of coagulation parameters documented very
high FVIII levels (up to 400%) [69]. Recently, the same
author [64] carried out a questionnaire survey on the
occurrence of venous thromboembolism in patients with
VWD treated with FVIII/VWF concentrates in the last
10 years in 52 hemophilia centers and found a low incidence
of thromboembolic events (seven cases in 12,640 treatments
over 10 years), although higher than that observed in patients
with hemophilia A (two cases in 141,250 treatments). On the
basis of these results, the author suggested that FVIII plasma
levels should be measured daily in VWD patients treated
with FVIII/VWF concentrates to avoid excessive levels of
the clotting factor, and that thromboprophylaxis should be
given to those patients undergoing major surgical procedures, especially if other risk factors for venous thromboembolism are present (i.e., old age, previous thrombosis,
presence of prothrombotic gene mutations, orthopedic
surgery, obesity, immobility, hormone replacement therapy).
Moreover, both authors (Makris and Mannucci) outlined
the importance of using the FVIII/VWF concentrate with
the highest ratio between VWF:RCof and FVIII:C, to
correct the VWF defect without increasing FVIII:C
plasma levels excessively. Two venous thrombotic
complications were recorded in a multicenter, prospective
study evaluating a high purity FVIII/VWF concentrate in
81 patients with VWD [67]. Finally, a myocardial infarct
after administration of recombinant activated factor VII
was described in a patient with type 2A VWD [70].
Thrombotic complications in VWD patients
not associated with clotting factor concentrate use
Rare cases of thrombotic events not associated with the
infusion of clotting factor concentrates have been reported in
patients with VWD. The largest series was published in
1982 by Goodnough and colleagues who, reviewing
personal and literature data, reported 23 cases of myocardial
infarction or arterial thrombosis in VWD patients [71]. In
1989, Dulhoste and colleagues reported the cases of three
patients with VWD (two mild and one severe) who
developed atherosclerotic lesions and thrombosis [72].
More recently, Fragasso, et al. [63] reported an acute
myocardial infarct occurring in a 61-year old man with type
1 VWD, successfully treated with a thrombolytic agent
(recombinant tissue plasminogen activator). Other studies
have reported thrombosis in VWD patients with concomitant inherited prothrombotic risk factors. This association
was first described in 1986 by Girolami, et al., who noted
that the concomitant presence of VWD in a patient with
antithrombin deficiency could have a protective action
against thrombotic manifestations [73]. Bowen, et al. [60]
described a patient with type III VWD and concomitant
protein C and antithrombin deficiencies who experienced
deep venous thrombosis and pulmonary embolism.
Although two additional cases have recently been reported
by us [61, 62], the association between VWD and inherited
prothrombotic risk factors remains a controversial issue
which requires further studies on large populations of
patients to confirm or refute these preliminary findings.
Moreover, as the presence of prothrombotic factors may
modulate the clinical phenotype of severe hemophilia [74],
some authors have found that the severity of bleeding
symptoms in type 1 VWD depends on functional defects in
platelet aggregation [75] or DNA polymorphisms in the
platelet membrane proteins integrin α2, αIIb and GPVI [76].
Finally, although only a few cases of myocardial
infarction have been described in patients with congenital
or acquired bleeding conditions treated with desmopressin
[77–80], this drug should be used cautiously in elderly
VWD patients with atherosclerotic disease [6].
Conclusions
Greater understanding of the structure and function of VWF
and the mechanisms that underlie its interactions with
vascular and platelet surfaces can aid the elucidation of
important aspects of normal hemostasis and pathological
processes leading to thrombosis.
The prospective studies so far published provide some
evidences of an involvement, although at a moderate level, of
VWF in the process of arterial thrombosis. However, further
investigations are warranted to assess the exact role of VWF
in the spectrum of multiple thrombotic risk factors.
Finally, literature data show that thrombotic complications
of VWD are rare and are often, if not always, associated with
multiple acquired and/or inherited prothrombotic risk factors.
The thrombotic event occurs when these risk factors balance
or even outweigh the bleeding tendency of the disease.
Future studies should be aimed at identifying these risk
factors as precisely as possible to be able to prevent the
development of thrombotic episodes in VWD patients in
particular situations, such as major surgery.
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