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The molecular basis ofvon Willebrand disease 243
https://t.me/med1917
identified in about 25% of the unrelated type 3 patients investigated among the Hungarian population. The nonsense variant p.Gln1311*, derived from a probable gene conversion, was
recurrent among type 3 patients from Spain (6 patients out 42)
and Portugal (5 out of 15). In both investigations, this nonsense variant was identified among Spanish Romani families.
In two large type 3 VWD cohorts from Canada and North
America the clinical, biochemical, and molecular investigations have been extended to the patients’ relatives. Although
type 3inheritance has usually been considered recessive, both
studies reported evidence for co- dominant inheritance, with
almost 50% of the obligated carriers (parents and offspring)
having both reduced VWF levels and bleeding symptoms.
Interestingly, null variants were common among these type 1
VWD patients or low VWF subjects, suggesting the role of
other modifying genes affecting VWF levels. Despite the
crucial improvement of the techniques to detect the genetic
variants, in most type 3 VWD investigations, disease- causing
variants are identified only in 80–95% of cases. The missing
variants in these patients are expected to be in the gene promoter, distant regulatory sequences, deep intronic, or due to
other modifying genes.
Type 3 VWD patients may develop alloantibodies that
neutralize VWF, making replacement therapy ineffective,
This severe complication is more often associated with the
presence of homozygous large gene deletions, although several cases have been reported due to nonsense mutations
(e.g. p.Gln1311*) and at list in one case with a missense variant (i.e. p.Asn2546Tyr). The largest type 3 VWD investigation, regarding patients from both Europe and Iran, found
anti- VWF antibodies in 8.4% of the cases, whereas neutralizing VWF inhibitors were found in 6%.
Treatment ofvon Willebrand disease
Given the dual deficiencies of VWF and FVIII in patients
with VWD, the aim of therapy is to correct both patients’
hemostasis defects: the decreased VWFadhesion and the reduced FVIII level secondary to the VWF
deficiency or dysfunction. Principally, the clinical management of patients with VWD has remained largely unchanged
over the last 30 years. The current mainstay treatment
options to stop spontaneous bleeding or to prevent bleeding
at the time of surgical procedures include desmopressin
(1- deamino- 8- - arginine vasopressin, DDAVP) and replacement therapy with plasma- derived FVIII/VWF concentrates
or recombinant (r)VWF devoid of FVIII. A number of
adjunctive treatments are available, such as platelet concentrates, synthetic fibrinolysis inhibitors, and estrogen/progestogen preparations, which can sometimes be used
alongside the main treatment or as an alternative.
dependent platelet
Desmopressin
Desmopressin is a synthetic analog of the antidiuretic hormone vasopressin. Following its administration, in healthy
volunteers, patients with mild hemophilia or VWD, it releases
VWF and FVIII from storage sites into plasma and thus transiently increases the levels of these moieties. Although VWF
is stored in platelet (α- granules) and ECs (WPBs), DDAVP
releases VWF from ECs but not from platelets. This induced
release of VWF into plasma happens by binding of desmopressin to the vasopressin V2 receptor, thereby activating
cyclic AMP- mediated signaling in vascular ECs. VWF is constitutively stored in WPBs, organelles whose generation is
strictly VWF dependent, whereas FVIII is primarily synthesized in the liver and only a selected subset of ECs (lung,
heart, intestine, skin, and pulmonary artery).
The advantage of this compound is that it is relatively inexpensive and carries no risk of transmitting blood- borne infectious agents. When infused intravenously over 30 min at a
dose of 0.2–0.3 μg/kg, desmopressin is expected to increase
plasma FVIII and VWF two- to fourfold above basal levels. In
general, high FVIII/VWF concentrations last in plasma for at
least 8–10 h and infusions can be repeated every 12–24 h
depending on the type and severity of the bleeding episode.
At the time of diagnosis, a DDAVP infusion test should be
performed to evaluate individual response patterns. If the
baseline plasma levels of FVIII/VWF are between 10 and
20 IU/dL or higher, patients are more likely to achieve hemostasis following desmopressin administration. Nevertheless,
variables such as the type and severity of the bleeding episode
and the level of FVIII/VWF required to maintain hemostasis
should be taken into account. The recent joint guidelines on
VWD proposed the definition for desmopressin response: an
increase of at least >2 times the baseline VWF activity level
and a sustained increase of both VWF and FVIII:C levels
>50 IU/dL for at least 4h. Even though most patients with
mild hemophilia A treated repeatedly with desmopressin
become less responsive to therapy, this problem is less frequent and prominent in patients with type 1 VWD. The drug
is also available in concentrated forms for subcutaneous
andintranasal administration (at doses of 0.3
150–300 μg, respectively), which can be convenient for home
treatment.
Desmopressin side effects are usually mild tachycardia,
headache, and facial flushing. Hyponatremia and volume
overload due to the antidiuretic effect of desmopressin are
relatively rare if fluid intake is not excessive during treatment. Even though no thrombotic episodes have been
reported in VWD patients treated with desmopressin, this
compound should be used with caution in elderly patients
with cardiovascular disease because a few cases of myocardial infarction and stroke have occurred in treated patients
with hemophilia and uremia. The main target group of
μg/kg and of
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244 Molecular Hematology
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desmopressin administration is type 1 VWD because it is
particularly effective in these patients. A prospective clinical
study reported that in 77 patients with type 1 a complete
response was observed in 83%, partial response in 13%, and
no response only in 4% of the patients. The type of VWF
variant seems to strongly modulate the desmopressin
responses. In a study of 190 patients with type 1 VWD, it was
found that all patients with type 1who do not have a VWF
variant, as well as 64.3% of those who do, completely respond
to desmopressin. Of note, in patients with type 1 VWD and
enhanced VWF clearance (i.e. type 1C), the use of desmopressin in severe bleeds is limited because, despite an initial
response, VWF levels fall rapidly to baseline. As type 1C
accounts for almost 20–30% of type 1 VWD, desmopressin
trials are essential for appropriate treatment planning, especially for major surgeries where sustained normal FVIII/
VWF levels are necessary. In other VWD types, responsiveness is less certain (Table17.2). In fact, in a prospective trial,
only 18% of the type 2 VWD patients were responsive. In this
study, only one out of 15 type 2A patients was responsive to
DDAVP. Similar results were obtained in type 2M, where
DDAVP was effective only in 3 patients out of 21. In type 2N
FVIII:C levels increase following desmopressin, but released
FVIII circulates for a relatively short time in patients’ plasma
because the stabilizing effect of VWF on FVIII is impaired.
Therefore, plasma concentrates containing FVIII and VWF
form are usually preferable. In type 2B patients, desmopressin releases VWF from the ECs, though there is only a transient increased of VWF plasma level. This is because the
ULVWF, of this gain- of- function variant, spontaneously
agglutinates platelets worsening or causing patients thrombocytopenia. Therefore, it is unclear if the use of desmopressin can provide clinical benefit in the case of type 2B patients.
However, mild type 2B patients who present a full set of multimers, as those carrying the mutations p.Pro1266Leu,
p.Arg1308Leu and p.Arg1379Cys, have been treated with
desmopressin without any complications. In a more recent
study of 45 type 2A, 16 type 2M, and 9 type 2N VWD
Table17.2 Indications fordesmopressin indifferent types ofvon
Willebrand disease
Type Response
1 Usually effective
1C May be contraindicated in surgery
2A Usually ineffective
2B May be contraindicated
2M Usually ineffective
2N Rarely effective
3 Ineffective
patients, 31.3% of them responded to desmopressin. Patients
with type 3 VWD are unresponsive to desmopressin because
they lack releasable stores of VWF.
Transfusional therapies
Transfusion therapy with FVIII/VWF concentrates is the
treatment of choice to prevent or stop bleeding when desmopressin therapy is not effective, or its use is contraindicated.
Fresh frozen plasma (FFP) was historically used for the infusion of FVIII and VWF, but its use is severely limited by the
large volumes required. Cryoprecipitate has been the mainstay of treatment in VWD patients for many years because it
contained 5–10 times more FVIII and VWF than FFP and
was administered every 12–24 h to normalize plasma FVIII.
Nevertheless, given that this product carries a small risk of
transmitting blood- borne infectious agents, it is not largely
used anymore. Therefore, virus- inactivated FVIII/VWF concentrates, originally developed for the treatment of hemophilia A, were perceived as safer and were preferred in the
management of VWD patients. Nowadays, several plasmaderived products are licensed for treating VWD, and even
though they contain both VWF and FVIII, the ratio varies by
product. All products licensed for VWD treatment have been
evaluated for safety and efficacy in prospective clinical trials.
It appears that currently available plasma- derived products
have similar efficacy, with the large majority of VWD patients
having a satisfactory response. The FVIII half- life after infusion of these products is significantly longer than that of
VWF activity, since endogenous FVIII is added to the exogenous FVIII due to stabilizing effect of VWF.
Furthermore, a rVWF product has been approved in the
United States and Europe for VWD patients. The rVWF is
obtained by a genetically engineered cell line (Chinese
Hamster Ovary); hence, there is, virtually, no risk of bloodborne virus transmission. Similar to VWF derived from
ECs, rVWF contains ULVWF, while plasma- derived products are typically deficient in HMWM. The presence of
ULVWF which is due to the fact that ADAMTS13 is not present during the manufacturing process, along with its high
purity, confer to this product a higher specific activity (VWF
activity/VWF:Ag >1). Indeed, this product has a stronger
hemostatic potential in comparison to plasma-
derived concentrates, which could be used in crucial bleeding situations
such as VWD associated with gastrointestinal angiodysplasia, where traditional FVIII/VWF products seem to be less
effective. A phase I and III trial using a fixed dosage ratio of
rVWF concentrate along with FVIII product established a
good efficacy and safety profile in VWD patients. Moreover,
a phase III study evaluating this product in elective surgery
demonstrated excellent or good hemostatic efficacy in all
surgical operations. The rVWF does not contain FVIII;
hence, it may need to be supplemented with rFVIII in
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The molecular basis ofvon Willebrand disease 245
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Table17.3 Dosages ofVWF:RCo/FVIII:C recommended inpatients
withvon Willebrand disease treated withFVIII/VWF concentrates
Target plasma
Type of
bleeding
Major surgery 40–60 Every 12
Minor surgery 30–50 Once a day ≥50 IU/dL until
Dental
extractions
Spontaneous
or traumatic
bleeding
VWF, von Willebrand factor; VWF:RCo, VWF ristocetin cofactor
activity; FVIII:C, Factor VIII clotting activity.
Dose
(IU/kg)
Number of
infusions
h initially
then once a day
20–30 A single dose prior
to procedure
20–60 Once a day >30
VWF:RCo and
FVIII:C level
≥50 IU/dL maintain
≥50 IU/dL for >12 h
level until healing
is complete
(3–10 d)
healing is
complete (may
require 1–3 d)
IU/dL until
bleeding stops
emergency situations, depending on the endogenous FVIII
levels of the patient.
The dosages recommended for the control or prevention of
bleeding are summarized in Table 17.3. Since FVIII has a
longer half- life in VWD patients than in patients with hemophilia A (20–24 versus 12–14 h), the infusion of one daily dose
is sufficient to reach and maintain adequate plasma levels for
the treatment of spontaneous bleeding episodes and to prevent excessive bleeding. The doses of this concentrate recommended for their demonstrated efficacy in large, prospective
clinical trials are 40–60 IU/kg of VWF:RCo (50–75 IU/kg in
children because of the lower invivo recovery), which usually
results in VWF:RCo plasma levels of 80–120 IU/dL or higher.
Of note, in this paragraph VWF:RCo refers to the VWF activity because most commercial FVIII/VWF concentrates are
labeled as VWF:RCo IU/dL. Even though the plasma half-
life
of VWF:RCo is much shorter than that of FVIII:C (8–10 versus 20–24 h), usually these doses do not need to be repeated
more often than every 24 h, although sometimes treatment
intervals must be tailored to the clinical situation.
It is usually not necessary to carry out laboratory tests to
monitor replacement therapy in patients with spontaneous
bleeding episodes. For managing the major surgical interventions, the joint guidelines suggest targeting both FVIII
and VWF activity levels of >50 IU/dL for at least 3days after
surgery. In this regard, we recommend measuring FVIII:C
and VWF:RCo every 12 h on the operation day and then
every 24 h. Major surgical procedures are successfully carried out and spontaneous bleeding episodes controlled following the infusion of FVIII/VWF concentrates or rVWF.
In the relatively rare instances when bleeding is not controlled, platelet concentrates (given immediately after FVIII/
VWF- containing preparations, at doses of 4–5 × 1011 platelets) are effective, particularly in patients with type 3 VWD.
Platelets from type 3 patients lack VWF completely and there
is no uptake of VWF from plasma after infusion of concentrates. The hemostatic effectiveness of the transfusion of normal platelets is likely to be due to the fact that these cells
transport and localize ULVWF at sites of vascular injury.
From a practical standpoint, it must be emphasized that in
one of the largest prospective studies carried out in VWD
patients, platelet concentrates became necessary to prevent
or stop bleeding in one case only.
To avoid the risk of life- threatening anaphylactic reactions,
type 3 VWD patients who develop alloantibodies against
VWF must not be treated with products containing VWF.
Instead, treatment can be done with continuous intravenous
infusion of rFVIII or using bypassing agents such as
recombinant- activated FVII. Only recently, emicizumab has
become an additional option in this context (see later).
Venous thromboembolic episodes may seldom occur during
repeated FVIII/VWF concentrate infusions. As mentioned
above, therapy should be daily monitored also to avoid reaching very high FVIII plasma levels known to be a risk factor for
venous thromboembolism. For patients at higher risk of
thrombosis, prolonged increases in VWF and FVIII levels to
greater than 150 IU/dL are usually not recommended.
Long- term prophylaxis with VWF concentrate is recommended for VWD patients with a history of severe and frequent bleeds, such as epistaxis, gastrointestinal bleeding, or
hemarthrosis.
In conclusion, the different options currently available for
the management of VWD are summarized in Table 17.4.
Treatment of spontaneous bleeding episodes and their prevention at the time of invasive procedures is relatively simple
and can certainly be tackled by the average clinical hematologist with access to a minimum of laboratory testing (FVIII:C
and VWF activity). However, the patients need to be wellcharacterized phenotypically because the choice of treatment
must be tailored to the different types of the disease. Such
characterization is not simple, so that in most clinical centers, it is probably not worthy to set up relatively complicated
tests such as multimer analysis assay when samples can be
sent for analysis to more expert laboratories that have
become proficient during the study of large series of patients.
New therapies forvon
Willebranddisease
Several potential treatment approaches, such as genetic,
protein, and antibody- based, are being developed or tested
off- label for VWD. In patients with VWD type 2N and 3,
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246 Molecular Hematology
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Table17.4 Summary ofmanagement ofdifferent types andsubtypes ofvon Willebrand disease
Treatment of
Type
Type 1 Desmopressin
Type 2A Desmopressin
Type 2B Factor VIII/VWF
Type 2
M Desmopressin
Type 2N Desmopressin
Type 3 Factor VIII/VWF
Type 3
complicated by
alloantibodies
VWF, von Willebrand factor.
a
DDAVP should also be trialed for VWD types 2A, 2M, and 2N
patients, even though it will likely be insufficiently effective for
most of these cases and therefore FVIII/VWF concentrates will
berequired.
choice
Factor VIII/VWF
concentrates
Recombinant VWF
Factor VIII/VWF
concentrates
Recombinant VWF
concentrates
Recombinant VWF
Factor VIII/VWF
concentrates
Recombinant VWF
Factor VIII/VWF
concentrates
Recombinant VWF
concentrates
Recombinant VWF
Recombinant
factor VIII
Alternative or
adjunctive therapy
Antifibrinolytic amino
acids
a
As above
As above
a
As above
a
As above
Antifibrinolytic amino
acids, platelet
concentrates
Recombinant
activatedfactor
VII, Emicizumab
FVIII levels are significantly reduced; therefore, FVIII level
needs to be corrected. Several cases of off- label use of emicizumab in VWD patients, especially type 3with inhibitors,
have been reported so far. Emicizumab is a humanized
bispecific monoclonal antibody that mimics some of the
FVIII functions and is developed for the treatment of hemophilia A. Emicizumab with a half- life of about 4 weeks is
administered subcutaneously in a weekly or biweekly manner. Another potential treatment for VWD type 3 and 2N is
Efanesoctocog/BIVV001, which is a FVIII- variant with a
half- life of 38–43 h. A newly developed therapy for VWD
(and mild/moderate hemophilia) is BT200, a pegylated
aptamer that binds to the VWF A1 domain and reduces the
clearance of the VWF/FVIII complex, resulting in an increase
plasma level of both proteins. This aptamer increases VWF
levels in normal volunteers by three- to fourfold, and in a
small trial on five patients with 2B VWD, it increased platelet
counts threefold and VWF and FVIII to twofold.
von Willebrand disease resources onthe
internet
European Association for Haemophilia and Allied Disorders
(EAHAD). Coagulation Factor Variant Databases. Available
at: https://databases.lovd.nl/shared/genes/VWF (Accessed
June 2023).
The Human Gene Mutation Database (HGMD). www.
hgmd.cf.ac.uk/ac/gene.php?gene=VWF (Accessed June 2023).
OMIMTM On line Mendelian Inheritance in Men. https://
omim.org/entry/193400 (Accessed June 2023).
Further reading
General
Leebeek, F.W. and Eikenboom, J.C. (2016). von Willebrand’s disease.
N.Engl. J. Med. 375 (21): 2067–2080.
Nichols, W.L., Hultin, M.B., James, A.H. etal. (2008). von Willebrand
disease (VWD): evidencelines, the National, Heart, Lung and Blood Institute (NHLBI) Expert
Panel report (USA). Haemophilia 14: 171–232.
Sadler, J.E., Mannucci, P.M., Berntorp, E. etal. (2000). Impact, diagnosis
and treatment of von Willebrand disease. Thromb. Haemost. 84:
160–174.
von Willebrand factor
Ginsburg, D., Handin, R.I., Bonthron, D.T. et al. (1985). Human von
Willebrand factor (vWF): isolation of complementary DNA (cDNA)
clones and chromosomal localization. Science 228: 1401–1406.
Lenting, P.J., Christophe, O.D., and Denis, C.V. (2015). von Willebrand
factor biosynthesis, secretion, and clearance: connecting the far ends.
Blood 125: 2019–2028.
Mancuso, D.J., Tuley, E.A., Westfield, L.A. et al. (1989). Structure of
the gene for human von Willebrand factor. J. Biol. Chem. 264:
19514–19527.
Springer, T.A. (2014). von Willebrand factor, Jedi knight of the
bloodstream. Blood 124 (9): 1412–1425.
Zhou, Y.F., Eng, E.T., Zhu, J. et al. (2012). Sequence and structure
relationships within von Willebrand factor. Blood 120: 449–458.
von Willebrand disease andits
classification
De Jong, A. and Eikenboom, J. (2016). Developments in the diagnostic
procedures for von Willebrand disease. J. Thromb. Haemost. 14:
449–460.
Fogarty, H., Doherty, D., and O’Donnell, J.S. (2020). New developments
in von Willebrand disease. Br. J. Haematol. 191 (3): 329–339.
James, P.D., Connell, N.T., Ameer, B. et al. (2021). ASH ISTH NHF
WFH 2021 guidelines on the diagnosis of von Willebrand disease.
Blood Adv. 5 (1): 280–300.
based diagnosis and management guide-
本书版权归John Wiley & Sons Inc.所有
The molecular basis ofvon Willebrand disease 247
https://t.me/med1917
Sadler, J.E. (1994). A revised classification of von Willebrand disease.
Thromb. Haemost. 71: 520–525.
Sadler, J.E., Budde, U., Eikenboom, J.C.J. et al. (2006). Update on the
pathophysiology and classification of von Willebrand disease: a
report of the subcommittee on von Willebrand factor. J. Thromb.
Haemost. 4: 1–12.
Genetic defects invon Willebrand disease
Baronciani, L., Peake, I., Schneppenheim, R. etal. (2021). Genotypes of
European and Iranian patients with type 3 von Willebrand disease
enrolled in 3WINTERS-
Batlle, J., Pérez-
clinical profile of von Willebrand disease in Spain (PCM–EVW–ES):
proposal for a new diagnostic paradigm. Thromb. Haemost. 2: 1–11.
Bodo, I., Katsumi, A., Tuley, E.A. etal. (2001). Type 1 von Willebrand
disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood 98: 2973–2979.
Bowen, D.J. and Collins, P.W. (2006). Insights into von Willebrand fac-
tor proteolysis: clinical implications. Br. J. Haematol. 133: 457–467.
Bowman, M., Tuttle, A., Notley, C. etal. (2013). The genetics of Canadian
type 3 von Willebrand disease: further evidence for coinheritance of mutant alleles. J. Thromb. Haemost. 11 (3): 512–520.
Casari, C., Paul, D.S., Susen, S. etal. (2018). Protein kinase C signaling
dysfunction in von Willebrand disease (p.V1316M) type 2B platelets.
Blood Adv. 2: 1417–1428.
Christopherson, P.A., Haberichter, S.L., Flood, V.H. et al. (2022).
Molecular pathogenesis and heterogeneity in type 3 VWD families in
U.S. Zimmerman program. J. Thromb. Haemost. 20 (7): 1576–1588.
Corrales, I., Catarino, S., Ayats, J. et al. (2012). High- throughput
molecular diagnosis of von Willebrand disease by next generation
sequencing methods. Haematologica 97: 1003–1007.
Cumming, A., Grundy, P., Keeney, S. etal. (2006). An investigation of
the von Willebrand factor genotype in UK patients diagnosed to
have type 1 von Willebrand disease. Thromb. Haemost. 96: 630–641.
de Jong, A. and Eikenboom, J. (2017). von Willebrand disease mutation
spectrum and associated mutation mechanisms. Thromb. Res. 159:
65–75.
Eikenboom, J.C. (2001). Congenital von Willebrand disease type 3:
clinical manifestations, pathophysiology and molecular biology. Best
Pract. Res. Clin. Haematol. 14 (2): 365–379.
Eikenboom, J.C.J., Matsushita, T., Reitsma, P.H. etal. (1996). Dominant
type I von Willebrand disease caused by mutated cysteine residues in
the D3 domain of von Willebrand factor. Blood 88: 2433–2441.
Enayat, M.S., Guilliatt, A.M., Surdhar, G.K. et al. (2001). Aberrant
dimerization of von Willebrand factor as the result of mutations in
the carboxybers of 3 different families with type 2A (phenotype IID) von
Willebrand disease. Blood 98: 674–680.
Federici, A.B., Mannucci, P.M., Castaman, G. etal. (2009). Clinical and
molecular predictors of thrombocytopenia and risk of bleeding in
patients with von Willebrand disease type 2B: a cohort study of 67
patients. Blood 113: 526–534.
Fidalgo, T., Salvado, R., Corrales, I. etal. (2016). Genotype–phenotype
correlation in a cohort of Portuguese patients comprising the entire
spectrum of VWD types: impact of NGS. Thromb. Haemost.
116:17–31.
Rodríguez, A., Corrales, I. etal. (2015). Molecular and
terminal region: identification of 3mutations in mem-
IPS. Blood Adv. 5 (15): 2987–3001.
dominant
Goodeve, A., Eikenboom, J.C.J., Castaman, G. et al. (2007).
Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study,
molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM109: 112–121.
Haberichter, S.L., Balistreri, M., Christopherson, P. etal. (2006). Assay
of the von Willebrand factor (VWF) propeptide to identify patients
with type 1 von Willebrand disease with decreased VWF survival.
Blood 108: 3344–3351.
Hassenpflug, W.A., Budde, U., Obser, T. etal. (2006). Impact of muta-
tions in the von Willebrand factor A2 domain on ADAMTS13dependent proteolysis. Blood 107: 2339–2345.
James, P.D., Notley, C., Hegadom, C. etal. (2007). The mutational spec-
trum of type 1 von Willebrand disease: results from a Canadian
cohort study. Blood 109: 145–154.
Keeling, D., Beavis, J., Marr, R. et al. (2012). A family with type 2M
VWD with normal VWF:RCo but reduced VWF:CB and a M1761K
mutation in the A3 domain. Haemophilia 18: e33.
Lyons, S.E., Bruck, M.E., Bowie, E.J.W., and Ginsburg, D. (1992).
Impaired intracellular transport produced by a subset of type IIA von
Willebrand disease mutations. J. Biol. Chem. 267: 4424–4430.
Mannucci, P.M., Lombardi, R., Castaman, G. et al. (1988). von
Willebrand disease “Vicenza” with largermal) von Willebrand factor multimers. Blood 71: 65–70.
Mazurier, C. and Meyer, D. (1996). Factor VIII binding assay of
vonWillebrand factor and the diagnosis of type 2N von Willebrand
disease– results of an international survey. On behalf of the subcommittee on von Willebrand factor of the scientific and standardization
committee of the ISTH. Thromb. Haemost. 76: 270–274.
Nurden, P., Gobbi, G., Nurden, A. et al. (2010). Abnormal VWF
modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B.
Blood 115: 2649–2656.
Othman, M. and Gresele, P. (2020). Guidance on the diagnosis and
management of platelet- type von Willebrand disease: a communication from the platelet physiology subcommittee of the ISTH.
J.Thromb. Haemost. 18 (8): 1855–1858.
Pagliari, M.T., Rosendaal, F.R., Ahmadinejad, M. et al. (2022). Von
Willebrand factor propeptide and pathophysiological mechanisms in
European and Iranian patients with type 3 von Willebrand disease
enrolled in the 3WINTERS1106–1114.
Penas, N., Perez- Rodriguez, A., Torea, J.H. etal. (2005). Von Willebrand
disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am. J.
Hematol. 80: 188–196.
Richards, S., Aziz, N., Bale, S. etal. (2015). ACMG standards and guide-
lines standards and guidelines for the interpretation of sequence
variants: a joint consensus recommendation of the American College
of Medical Genetics and Genomics and the Association for Molecular
Pathology. Genet. Med. 17: 405–424.
Ruggeri, Z.M., Pareti, F.I., Mannucci, P.M. et al. (1980). Heightened
interaction between platelets and factor VIII/von Willebrand factor
in a new subtype of von Willebrand disease. N. Engl. J. Med. 302 (19):
1047–1051.
Schneppenheim, R., Michiels, J.J., Obser, T. et al. (2010). A cluster of
mutations in the D3 domain of von Willebrand factor correlates with
IPS study. J. Thromb. Haemost. 20 (5):
than- normal (supranor-
1VWD). Blood
本书版权归John Wiley & Sons Inc.所有
248 Molecular Hematology
https://t.me/med1917
a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood
115: 4894–4901.
Seidizadeh, O., Baronciani, L., Pagliari, M.T. etal. (2022). Phenotypic
and genetic characterizations of the Milan cohort of von Willebrand
disease type 2. Blood Adv. 6 (13): 4031–4040.
Seidizadeh, O., Peyvandi, F., and Mannucci, P.M. (2021). von Willebrand
disease type 2N: an update. J. Thromb. Haemost. 19 (4): 909–916.
Veyradier, A., Boisseau, P., Fressinaud, E. et al. (2016). A laboratory
phenotype/genotype correlation of 1167 French patients from 670
families with von Willebrand disease: a new epidemiologic picture.
Medicine (Baltimore) 95: e3038.
Yadegari, H. and Oldenburg, J. (2020). The current understanding of
molecular pathogenesis of quantitative von Willebrand disease, types
1 and 3. Hamostaseologie 40 (1): 105–118.
Zimmerman, T.S., Dent, J.A., Ruggeri, Z.M., and Nannini, L.H. (1986).
Subunit composition of plasma von Willebrand factor. Cleavage is
present in normal individuals, increased in IIA and IIB von
Willebrand disease, but minimal in variants with aberrant structure
of individual oligomers (types IIC, IID, and IIE). J. Clin. Invest.
77(3): 947–951.
Zolkova, J., Sokol, J., Simurda, T. etal. (2020). Genetic background of
von Willebrand disease: history, current state, and future perspectives. Semin. Thromb. Hemost. 46 (4): 484–500.
Treatment ofvon Willebrand disease
Atiq, F., Heijdra, J., Snijders, F. etal. (2022). Desmopressin response
depends on the presence and type of genetic variants in patients
with type 1 and type 2 von Willebrand disease. Blood Adv. 6 (18):
5317–5326.
Ay C, Pabinger I, Kovacevic KD, Gelbenegger G, Schörgenhofer C,
Quehenberger P, et al. The VWF binding aptamer rondoraptivon
pegol increases platelet counts and VWF/FVIII in type 2B von
Willebrand disease. Blood Adv. 2022.27; 6(18): 5467–5476.
Berntorp, E., Archey, W., Auerswald, G. etal. (2008). A systematic over-
view of the first pasteurized VWF/FVIII medicinal product, Haemate
P/Humate Suppl. 80 (Suppl.70): 3–35.
Berntorp, E., Windyga, J., and European Wilate Study Group (2009).
Treatment and prevention of acute bleedings in von Willebrand
disease- efficac y and safety of Wilate, a new generation von Willebrand
factor/factor VIII concentrate. Haemophilia 15: 122–130.
Bond, L. and Bevan, D. (1988). Myocardial infarction in a patient with
hemophilia treated with DDAVP (letter). N. Engl. J. Med. 318: 121.
Borel-
Treatment of severe von Willebrand disease with a high- purity von
Willebrand factor concentrate (Wilfactin): a prospective study of
50patients. J. Thromb. Haemost. 5: 1115–1124.
Brooker, M. (2012). Registry of Clotting Factor Concentrates, 9e.
Montréal: World Federation of Hemophilia. www.wfh.org.
Castaman, G., Coppola, A., Zanon, E. etal. (2013). Efficacy and safety
during formulation switch of a pasteurized VWF/FVIII concentrate:
results from an Italian prospective observational study in patients
with von Willebrand disease. Haemophilia 19: 82–88.
Castaman, G., Lethagen, S., Federici, A.B. et al. (2008). Response to
desmopressin is influenced by the genotype and phenotype in type 1
P: history and clinical performance. Eur. J. Haematol.
Derlon, A., Federici, A.B., Roussel- Robert, V. et al. (2007).
von Willebrand disease (VWD): results from the European Study
MCMDM-
Castillo, R., Monteagudo, J., Escolar, G. etal. (1991). Hemostatic effect
of normal platelet transfusion in severe von Willebrand disease
patients. Blood 77: 1901–1905.
Connell, N.T., Flood, V.H., Brignardello-
ISTH NHF WFH 2021 guidelines on the management of von
Willebrand disease. Blood Adv. 5 (1): 301–325.
Coppola, A., Franchini, M., Makris, M. et al. (2012). Thrombotic
adverse events to coagulation factor concentrates for treatment of
patients with haemophilia and von Willebrand disease: a systematic
review of prospective studies. Haemophilia 18: e173–e187.
Favaloro, E.J., Franchini, M., and Lippi, G. (2012). Biological therapies
for von Willebrand disease. Expert. Opin. Biol. Ther. 12 (5): 551–564.
Federici, A.B. (2008). The use of desmopressin in von Willebrand dis-
ease: the experience of the first 30
14 (Suppl 1): 5–14.
Federici, A.B., Baudo, F., Caracciolo, C. etal. (2002). Clinical efficacy of
highly purified, doubly virusfactor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 8: 761–767.
Franchini, M. and Mannucci, P.M. (2014). Gastrointestinal angiodys-
plasia and bleeding in von Willebrand disease. Thromb. Haemost.
112: 427–431.
Franchini, M. and Mannucci, P.M. (2016). von Willebrand factor
(Vonvendi
of von Willebrand disease. Expert. Rev. Hematol. 9: 825–830.
Goudemand, J., Scharrer, I., Berntorp, E. etal. (2005). Pharmacokinetic
studies on Wilfactin, a von Willebrand factor concentrate with a low
factor VIII content treated with three virus- inactivation/removal
methods. J. Thromb. Haemost. 3: 2219–2227.
Holmberg, L., Nilsson, I.M., Borge, L. etal. (1983). Platelet aggregation
induced by 1IIB von Willebrand’s disease. N. Engl. J. Med. 309: 816–821.
James, P.D., Lillicrap, D., and Mannucci, P.M. (2013). Alloantibodies in
von Willebrand disease. Blood 122: 636–640.
Lenting, P.J., Kizlik- Manson, C., and Casari, C. (2022). Towards novel
treatment options in von Willebrand disease. Haemophilia 28 (Suppl
4): 5–10.
Mannucci, P.M. (2002). Venous thromboembolism in von Willebrand
disease. Thromb. Haemost. 88: 378–379.
Mannucci, P.M. (2004). Treatment of von Willebrand disease. N. Engl. J.
Med. 351: 683–694.
Mannucci, P.M., Bettega, D., and Cattaneo, M. (1992). Patterns of
development of tachyphylaxis in patients with haemophilia and von
Willebrand disease after repeated doses of desmopressin (DDAVP).
Br. J. Haematol. 82: 87–93.
Mannucci, P.M., Chediak, J., Hanna, W. et al. (2002). Treatment
of von Willebrand’s disease with a high- purity factor VIII/von
Willebrand factor concentrate: a prospective, multicenter study.
Blood 99: 450–456.
Mannucci, P.M., Franchini, M., Castaman, G. etal. (2009). Evidence-
based recommendations on the treatment of von Willebrand disease
in Italy. Blood Transfus. 7 (2): 117–126.
Mannucci, P.M., Ruggeri, Z.M., Pareti, F.I., and Capitanio, A. (1977).
1- Deamino- 8- - arginine vasopressin: a new pharmacological
1VWD. Blood 111: 3531–3539.
Petersen, R. etal. (2021). ASH
years (1977–2007). Haemophilia
inactivated factor VIII/von Willebrand
®
): the first recombinant product licensed for the treatment
desamino- 8- - arginine vasopressin (DDAVP) in type
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approach to the management of haemophilia and von Willebrand
disease. Lancet 1: 869–872.
Mazurier, C., Gaucher, C., Jorieux, S., and Goudeman, M.C.G.
(1994). Biological effect of demopressin in eight patients with type
2N (“Normandy”) von Willebrand disease. Br. J. Haematol. 88:
849–854.
Perkins, H.A. (1967). Correction of the hemostatic defects in von
Willebrand disease. Blood 30: 375–380.
Peyvandi, F., Kouides, P., Turecek, P.L. et al. (2019). Evolution of
replacement therapy for von Willebrand disease: from plasma
fraction to recombinant von Willebrand factor. Blood Rev. 38:
100572.
Rivard, G.E., Aledort, L., and Alphanate Surgical Investigators (2008).
Efficacy of factor VIII/von Willebrand factor concentrate Alphanate
in preventing excessive bleeding during surgery in subjects with von
Willebrand disease. Haemophilia 14: 271–275.
Shahani, T., Lavend’homme, R., Luttun, A. etal. (2010). Activation of
human endothelial cells from specific vascular beds induces the
release of a FVIII storage pool. Blood 115 (23): 4902–4909.
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Chapter18
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Platelet disorders
Kenneth J. Clemetson
University of Berne, Theodor Kocher Institute, Berne, Switzerland
Normal platelet function, 251
Diagnosis of platelet defects in bleeding disorders, 251
Platelet adhesion disorders, 252
Collagen receptor defects, 255
Platelet aggregation defects, 256
Agonist receptor defects, 257
Defects in intracellular signaling pathways, 258
Normal platelet function
Following damage to the endothelium that protects the
vascular system, which may simply be caused by loss of “old”
endothelial cells due to the high shear stress in the arterial
system, platelets adhere to the subendothelium via glycoprotein (GP) Ib on the platelet and von Willebrand factor (VWF)
attached to extracellular matrix proteins, particularly collagen (Figure18.1). This interaction alone is sufficient to start
platelet activation, but following initial platelet adhesion
other receptors such as the collagen receptor GPVI are
recruited. GPVI comes into contact with collagen and signals via its Fcγ subunit to enhance platelet activation and
recruit integrins, which increase the binding of adherent
platelets and provide attachment for further aggregating
platelets. Activation of αIIbβ3 allows platelet–platelet aggregation via ligands such as fibrinogen. Activated platelets
release ADP, ATP, serotonin, and Ca2+ from dense granules
and a wide range of proteins from α- granules that contribute
to platelet activation and aggregation, including fibrinogen,
high-
mul- timer VWF, and thrombospondin, as well as
growth factors and chemokines that affect endothelial cells
and leukocytes involved in wound repair. The major collagen
adhesive receptor α2β1 is also activated, increasing platelet
adhesion to the exposed collagen of the subendothelium.
Both these integrins use disulfide bond reshuffling mechanisms via thiol isomerase to change disulfide bond patterns
in the β subunits to control the resting or active state.
Activated platelets also show surface changes, with
exposure of negatively charged phospholipids that act,
together with surface receptors such as GPIb, to assemble
and activate coagulation factors, leading to the conversion of
Platelet secretion defects (storage pool disease), 258
Procoagulant regulation defects, 259
Giant platelet syndromes and cytoskeletal defects, 260
Transcription factor defects, 261
Platelet protein polymorphisms and tendency to thrombosis, 261
Further reading, 262
prothrombin to thrombin. The major effect of thrombin is to
convert fibrinogen to fibrin, stabilizing and solidifying the
thrombus. However, thrombin also feeds back to platelets via
receptors including GPIb and the seven- transmembrane
PAR1 and PAR4, activating them further. When platelets are
strongly activated by a combination of agonists such as
thrombin/collagen, that part of the activated platelet population with strong Ca2+ fluxes shows enhanced procoagulant
properties through ballooning via water intake to present an
increased surface and by covalent binding of coagulation factors. When platelets are treated with Ca2+- ionophores all
platelets fall in this hyperactive category. It is not yet clear
why with thrombin/collagen activation, only part of the
platelet population is hyperactivated.
Diagnosis ofplatelet defects
inbleeding disorders
Most patients with clinically relevant platelet defects seek
medical assistance because of bleeding problems, ranging
from easy or excessive bruising, epistaxis, gingival bleeding,
menorrhagia to excessive bleeding following tooth extraction or other surgery. Such patients are normally screened
for coagulation defects; if none are detected, examination for
platelet problems is the next logical step. Normally, a complete blood count is done to exclude thrombocytopenia and
a peripheral blood smear is examined to check platelet morphology. A number of wholeavailable to check platelet function including PFA- 100 and
Impact technologies. These should indicate the presence of a
platelet defect and its likely origin. Platelet aggregation tests
with a battery of agonists, including ADP, collagen, TRAP
blood techniques are now
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© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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251
252 Molecular Hematology
AggregationActivationAdhesionTethering
α
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= VWF
= Collagen
= Fibrinogen
Figure18.1 Platelet thrombus formation. Following vessel wall injury, the matrix of the subendothelium is exposed. Under high- shear
conditions, platelets adhere and become tethered via GPIb- V- IX on platelets binding to von Willebrand factor (VWF) in the matrix. This interaction
starts platelet activation, but also brings platelets into contact with the subendothelium, allowing other receptors, such as GPVI, to interact with
collagen and enhance activation. Under static or low- shear conditions, the GPVI- collagen interaction is mainly responsible for the initial activation.
Platelet activation brings additional receptor- ligand interactions into play, such as α2β1- collagen, since this receptor does not bind in the resting
state. Platelet activation also leads to shape change, release of granule contents, activation of other receptors, such as αIIbβ3, and exposure of
negatively charged phospholipids, critical for procoagulant activity. Binding of VWF and fibrinogen to GPIb- V- IX and αIIbβ3 on adjacent platelets
leads to platelet aggregation and the formation of a thrombus.
(thrombin receptor activation peptide), arachidonic acid,
epinephrine, and ristocetin, should also help to narrow down
which responses are defective. Flow cytometry or Western
blotting with specific monoclonal antibodies may be used to
check for the absence of receptors or to determine the
amounts present. Flow cytometry may also be used to examine the expression of P- selectin or the activation of αIIbβ3 or
the exposure of negatively charged phospholipids in response
to the classic agonists. All these techniques can provide valuable information in leading to a molecular diagnosis. If a
defect can be ascribed to a given platelet molecule, coding
regions can be amplified from genomic DNA and sequenced.
In rare cases, it may also be necessary to sequence noncoding regions to establish a genetic reason for a particular
platelet protein deficiency. Regardless of whether a disorder
is homozygous or compound heterozygous in recessive disease, or present in only one allele in dominant disease, it is
extremely useful to establish the familial inheritance by
analyzing DNA from other family members. Modern “nextgeneration” sequencing methods are increasing being used
routinely for molecular diagnosis of bleeding disorders of
platelet origin. These are much more effective when applied
to patients with a clear phenotype where likely genes can be
targeted. However, problems arise where the phenotype is
simply mild bleeding and it is difficult to ascribe the problem
to poorly defined mutations/SNPs in genes for unclearly
related proteins. In those cases where this has been effective,
there have generally been sufficient family members with
and without the phenotype to show a clear relationship. In
some cases, it has been possible to establish mouse models of
these disorders confirming and extending the diagnosis.
= GPIb-V-IX
= GPVI
=
IIbβ3
= Activated α2β1
= Activated αIIbβ3
Platelet adhesion disorders
Bernard–Soulier syndrome
Bernard–Soulier syndrome (BSS) is a rare bleeding disorder
caused by defective expression or function of the GPIb–V–
IX receptor complex (Figure18.2). With a few still unclear
exceptions, it is inherited in an autosomal recessive way and
homozygous cases are often associated with consanguinity.
BSS is characterized by thrombocytopenia, giant platelets
(up to 20 μm diameter), decreased platelet adhesion, reduced
platelet survival, and abnormal prothrombin consumption.
BSS platelets do not aggregate in response to ristocetin or
botrocetin and show weaker and slower responses to thrombin due to the lack/deficiency of GPIb as thrombin receptor
that accelerates responses. As well as interacting with VWF
and thrombin, GPIb is a receptor for a wide range of ligands
with various physiological roles, including Pbospondin 1, factors XI and XII, αMβ2 and high- molecularweight kininogen; its absence in BSS may therefore contribute
to other aspects of this disorder. Four separate genes, GPIBA
(chromosome 17), GPIBB (chromosome 22), GP5, and GP9
(chromosome 3), code for the subunits of the GPIb complex,
which are expressed relatively late in megakaryocyte maturation. All 4 subunits belong to the leucine- rich repeat (LRR)
family of proteins, with 8, 2, 16, and 2 repeats present, respectively. GPIbα and GPIbβ are linked covalently via disulfide
bonds, probably in a 1 : 2 ratio, while GPIX and GPV associate non- covalently with GPIb, probably in 1 : 1 and 2 : 1 ratios,
respectively (Figure 18.3). While GPIbβ and GPIX are
certainly critical for the function of the complex, with
selectin, throm-
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