Diagnosis and Management of von Willebrand Disease in China

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, Peoples Republic of China.
Seminars in Thrombosis and Hemostasis (Impact Factor: 3.88). 07/2011; 37(5):607-14. DOI: 10.1055/s-0031-1281050
Source: PubMed
ABSTRACT
In China, the care of patients with a bleeding disorder is not organized into designated centers with a national protocol. However, currently developed organizations of hematologists and hemophilia patients are beginning to ensure better diagnosis, treatment, and care of affected patients. The diagnosis of von Willebrand disease (VWD) in China is still at an early stage. Misdiagnosis of the disease is difficult to avoid, and there is a need to improve our current diagnostic strategy. Our data show that assessment of von Willebrand factor (VWF) antigen levels is pivotal in ranking VWD clinical severity for replacement therapy. Treatment choices for VWD in China are currently limited to replacement therapy and antifibrinolytic drugs. Most VWD patients in China do not need replacement therapy. New phenotypic assays and genetic testing of VWF for research purposes have developed with results published in the Chinese medical literature in the last few years, and many are practical and feasible for diagnostic application. However, more efforts are needed for their widespread use for precise VWD diagnosis in China.

Full-text

Available from: Changgeng Ruan, Jun 19, 2014
CME June 2007 Vol.25 No.6
Erik von Willebrand rst described inherited von Willebrand
disease (vWD) in 1926, when he documented an autosomal-
dominant pattern of inheritance of excessive bleeding (as opposed
to X-linked transmission that characterises the common 2 types
of haemophilia) in a family from the Åland Islands in the Gulf of
Bothnia. vWD is caused by a decreased level or function of von
Willebrand factor (vWF) and may be inherited or acquired. While
we have come a long way in characterising the disorder, much
remains to be claried regarding both diagnostic assessment and
pathophysiology and, to a lesser extent, clinical management of
this common bleeding disorder.
Sucr n nci  
Wlrn actr
vWF is a glycoprotein that is synthesised in both endothelial cells
and megakaryocytes (in the bone marrow). is large gene, of
approximately 178 kilobases, is situated on chromosome 12 (with
a pseudogene located on chromosome 22). e protein undergoes
extensive post-translational modication and homodimerisation,
followed by formation of disulde-linked large multimers in the
circulation. is form of the protein is highly active and is rapidly
degraded into smaller multimers by ADAMTS13. It may be either
secreted constitutively, or stored in Weibel-Palade bodies in the
endothelial cells or α-granules of platelets for later secretion.
vWF has two major functions:
To enable platelet–subendothelial and platelet–platelet adhesion
via its collagen and (platelet) GPIb binding domains. is is
particularly important under conditions of high shear stress,
such as that found in the arterial circulation. Platelet interaction
is also facilitated by adhesion to the platelet receptor GPIIb-IIIa
IIb
β
3
integrin) on activated platelets.
To bind and protect factor VIII from premature proteolysis with
a shortened half-life in the circulation. e association with vWF
also helps locate factor VIII at the site of vascular injury.
e level of vWF in the circulation is variable and may be aected
by inherited factors such as ABO blood group (people with blood
group O having levels reduced by 25%), race (studies in the USA
show that black women have higher levels than white women)
and environmental factors such as age (young infants have higher
levels), oestrogen and thyroid hormone levels (deciencies may
cause lower levels) and stress.
Clfici   Wlrn e
e most recent classication was proposed in 1994: vWD is divided
into 3 major groups – 2 quantitative deciencies and 1 qualitative
deciency (with 4 major subgroups). Further subdivisions have
been proposed, but are not relevant for this review. e classication
is presented in Table I.
Type 1 is thought to represent 80% of all cases and may be present
in 0.8% of the general population – the majority of these cases are
mild, but it should be noted that type 1 may be severe, with levels so
low that they approach those found in severe type 3. In many recent
trials it has also been found that type 2 has been misdiagnosed as
type 1, further contributing to the general diculty of accurately
classifying this disorder in clinical practice.
Diagns   Wlrn e
To diagnose vWD the following general features should be
present:
a signicant bleeding history that generally dates back to
childhood
• a low level of vWF or its activity
a family history (autosomal dominant or rarely recessive) – this
criterion need not be lled in case of a new mutation.
Diagns n nagm  
Wlrn e
Diagnosis of von Willebrand disease requires an understanding of the
classication of the condition.
ANDREW MCDONALD, MB ChB, FCP(SA)
Clinical Haematologist, Groote Schuur Hospital, Cape Town
Andrew McDonalds interests include the diagnosis and treatment of bleeding disorders, and thrombophilia.
264
Table I. Classication of von Willebrand disease
Quantitative deciency of vWF
Type 1: Partial (mild to severe)
Type 3: Complete
Qualitative deciency of vWF
Type 2A: Decreased platelet-dependent function with
absent high molecular weight multimers
Type 2B: Increased anity with platelet GP1bα, with
thrombocytopenia
Type 2M: Decreased platelet-dependent function with
normal high molecular weight multimers
Type 2N: Decreased anity for factor VIII, with low
circulating factor VIII levels
pg264-266.indd 264 6/15/07 2:49:31 PM
Page 1
vo n W i l l e b r a n d d i s e a s e
June 2007 Vol.25 No.6 CME
Clinical assessment
Up to 25% of the general population
may respond positively to a question
regarding excessive bleeding or bruising;
for this reason attempts have been made
to standardise the history, as well as to
provide an objective, quantitative score
and correlate this with a signicant positive
predictive value. e predominant bleeding
sites in vWD are mucous membranes and
skin. An approach to signicant bleeding
symptoms is outlined below:
1
Nose bleeding. Two or more episodes
(without a history of trauma) not
stopped by short compression of < 10
min, or one or more episode requiring
blood transfusion.
Cutaneous haemorrhage and bruising
with minimal or no apparent trauma
as a presenting symptom or requiring
medical treatment.
Prolonged bleeding from trivial
wounds, lasting 15 min or recurring
spontaneously during the 7 days aer
wounding.
Oral cavity bleeding that requires
medical attention, such as gingival
bleeding, or bleeding with tooth eruption
or bites to lips and tongue.
Spontaneous gastrointestinal bleeding
requiring medical attention or resulting
in acute or chronic anaemia, unexplained
by ulceration or portal hypertension.
Tooth extraction or other oral surgery
such as tonsillectomy and adenoidectomy
followed by heavy, prolonged, or
recurrent bleeding requiring medical
attention.
Menorrhagia resulting in acute or
chronic anaemia, or requiring medical
treatment, not associated with structural
lesions of the uterus.
Bleeding from other
skin or mucous
membrane surfaces (e.g. eye, ear,
respiratory tract, genitourinary tract
other than uterus) requiring medical
treatment.
Criteria for bleeding symptoms
A signicant mucocutaneous bleeding
history requires:
at least two symptoms in the absence of
a blood transfusion history, or
one symptom requiring treatment with
blood transfusion, or
one symptom recurring on at least 3
distinct occasions.
Criteria for family history
A positive family history compatible with
vWD type 1 requires that
• at least 1 rst-degree relative, or
at least 2 second-degree relatives
have a personal history of signicant
mucocutaneous bleeding and labo-
ratory tests compatible with vWD
type 1. A more rigorous and validated
questionnaire with a bleeding score
may be found at: http://www.med.unc.
edu/isth/SSC/collaboration/Bleeding_
Type1_VWD.pdf
2
It can be seen from the above that the
history remains an integral and essential
part of the diagnostic strategy that should
not be glossed over, particularly in the
light of diculties in interpreting von
Willebrand assays, which are outlined
below. A strong history should prompt
ongoing investigation despite initial
normal results; conversely, false-positive
laboratory results may result in a wrong
diagnosis of vWD in a patient with a weak
history of bleeding.
A drug history is also vitally important,
especially relating to antiplatelet agents
and non-selective NSAIDs a history
of worsening bleeding aer ingestion of
these drugs provides a useful clue to the
presence of vWD, but is not at all specic.
e use of oestrogen-containing oral
contraceptives should also be noted; low-
dose preparations may not aect diagnosis,
but high doses may elevate vWF and give a
false-negative result.
Laboratory diagnosis
A few baseline investigations should
always be performed in the workup of an
unexplained bleeding disorder these are
tabulated and the likely ndings in vWD
noted:
FBC (and more particularly platelet
count) – normal (except type 2B – low)
aPTT normal, or borderline to
moderately elevated
• prothrombin time (INR) – normal
• brinogen – normal.
e bleeding time is a commonly
performed screening test for vWD
– however, it suers from a number of
problems in that it is neither sensitive
nor specic; aspirin should be avoided
for 10 days and NSAIDs for 3 days prior
to the test. It also requires an experienced
technologist and standardised equipment.
A normal bleeding time does not exclude
the diagnosis of vWD.
An alternative new assay is the use of the
PFA-100 analyser, which mimics high shear
stress conditions in vitro, and produces a
reading called the platelet closure time.
is is prolonged in vWD and appears to
be more sensitive (although not specic);
however, its utility is still debated and it is
not widely available in South Africa.
e standard von Willebrand assays are
(requiring a citrated blood sample):
von Willebrand antigen level (vWF:Ag)
measure of function ristocetin co-
factor activity (vWF:Rco) (note that
other functional assays such as the
collagen-binding assay have now also
been described)
factor VIII level (usually determined by
functional assay)
multimer assay (for use in dicult
cases)
factor VIII binding assay for type 2N
(Normandy).
Using a combination of these tests it is
possible to diagnose and classify vWD
if the VWF:Ag and vWF:RCo show
concordance, then the diagnosis is
either type 1 or 3 (depending on levels);
if there is a less than 0.7 ratio between
vWF:Ag and vWF:RCo (i.e. VWF:RCo is
disproportionably low), then the diagnosis
is likely to be type 2.
Not infrequently the assays give either
normal, borderline or conicting results.
In the situation of a strong bleeding history,
it is useful to repeat the tests a number of
times: in women of childbearing age, the
sample should be taken in the rst week
of the menstrual cycle. An assessment of
thyroid function as well as ABO blood
group should be performed (although it
is debatable whether to correct normal
ranges for blood group O).
If the sample has to be transported from a
remote clinic or practice, it should either
be transported at room temperature
as whole blood, or centrifuged and the
plasma supernatant frozen for transport
refrigeration or freezing of whole blood
renders the sample useless for evaluation.
Genetic diagnosis is still problematic,
particularly for the common type 1.
Mutations for the various type 2 and 3
variants have been well described and
localised with good structure-function
relationships. In the MCMDM-1VWD
study, 150 families with type 1 vWD were
analysed for mutations, and only 70% of
patients had demonstrable mutations in
the vWF gene.
3
In 19 families, there was no
demonstrable linkage to the vWF gene at
all, suggesting that alternative factors (such
265
The level of vWF in the circulation
is variable and may be affected by
inherited factors such as ABO blood
group.
pg264-266.indd 265 6/15/07 2:49:32 PM
Page 2
vo n W i l l e b r a n d d i s e a s e
CME June 2007 Vol.25 No.6
266
as blood group O) may be contributing to
the von Willebrand bleeding phenotype.
e majority of mutations in this study,
and also in the UK and Canadian series, are
mis-sense mutations and many are novel
and private. Together with the incomplete
penetrance and variable expressivity,
genetic diagnosis for type 1 vWD is still
not feasible at this time.
Try
Eective therapy is available for people
living with vWD; this may be required
for frequent ongoing complications such
as epistaxis or menorrhagia, or more
signicant but rare stressors such as
surgical intervention. e rst aspect
that should be stressed is avoidance
of all aspirin-containing medication,
including low-dose prophylactic doses;
aspirin irreversibly inhibits platelet
cyclo-oxygenase and the platelet is non-
functional for its entire lifespan. NSAIDs
are relatively contraindicated, but may be
given in short courses (note that the newer
COX-2 selective agents have a far less anti-
platelet eect and are safer).
A Medic-Alert disc should be obtained,
and the patient data entered into the
condential national database, the South
African Haemophilia Register (Professor
C Karabus, Red Cross Childrens Hospital,
ckarabus@ich.uct.ac.za, or Sr A-L Cruick-
shank, Groote Schuur Hospital).
Anti-fibrinolytics
Tranexamic acid (and to a lesser extent
epsilon-aminocaproic acid) inhibits
plasminogen activation to plasmin, and
thus prevents clot breakdown. ey are
highly eective agents, particularly in
menorrhagia, epistaxis and oral cavity
bleeds, which are common in vWD,
and may be used as single agents or in
combination with other modalities. When
used for menorrhagia, they should be taken
for the rst 3 - 4 days of the menstrual
cycle. e usual dose for tranexamic acid is
1 g 6 - 8 hourly as an oral formulation; an
intravenous preparation is also available.
It is also highly eective when used as a
mouthwash the tablet may be crushed
and placed in water, or the eervescent
formulation, if available, may be used for
this purpose.
Desmopressin
Desmopressin (DDAVP) is a synthetic
analogue of arginine vasopressin, and was
originally developed for use in diabetes
insipidus. It releases vWF, factor VIII and
plasminogen activator from storage sites,
as well as causing mild platelet activation
and adhesion to sites of injury. Both
nasal and intravenous preparations are
available; the IV dose is 0.3 μg/kg given
as an infusion over 20 minutes; facial
ushing and headache are commonly
reported symptoms. e nasal preparation
is a much higher dose than the standard
intranasal DDAVP used in the therapy
of diabetes insipidus (viz. 300 µg versus
10 µg bd). e high-dose nasal preparation
is currently not easily obtainable in South
Africa.
DDAVP is useful for patients with type
1 disease where there is still a signicant
circulating level of functional protein;
it may occasionally be of benet in type
2A, and is theoretically contraindicated
in type 2B (where it may worsen the
thrombocytopenia). All patients for
whom DDAVP is considered should have
a diagnostic trial of this agent with blood
levels determined aer infusion to ensure
that adequate elevation of vWF is achieved.
Patients in whom the elevation is not
satisfactory may still derive some benet
owing to the platelet activation obtained.
It is considered good practice to add an
antibrinolytic (owing to the concomitant
release of plasminogen activator) when
using DDAVP.
Caution is advised with multiple repeat
doses owing to the water retention and
subsequent hyponatraemia; and in older
individuals where the risk of thrombotic
events is increased.
Factor VIII concentrate
Most plasma-derived factor VIII
concentrates have equimolar or higher
concentrations of vWF; this does not apply
to recombinant factor VIII concentrates.
e preparations vary in the amount
of vWF as well as the amount of active
high molecular weight multimers. All
preparations are now carefully screened for
infections, contain viral inactivation steps
in the manufacture, and are considered
safe. ese should be used in types 2 and 3,
as well as severe type 1 with an inadequate
response to DDAVP. Dosages should be
discussed with clinicians familiar with the
use of these products.
Cnci
vWD is a common but signicantly
under-diagnosed bleeding entity in the
general population. Diagnosis may be
problematic, but the standard tests are
widely available and should be utilised
more frequently in patients who have
a strong personal and family history
of a mucocutaneous bleeding disorder.
Eective therapy is widely available, and is
in all likelihood being used to good eect
in patients who have the disorder, but have
not been diagnosed as such. Much more
work is required to elucidate the genetic
underpinnings of the common type 1
disorder and its pathophysiology, and
this may hopefully translate into better
diagnostic strategies in the future.
References
1. Sadler JE, Rodeghiero F. Provisional criteria
for the diagnosis of VWD Type 1. Journal of
rombosis and Haemostasis 2005; 3(4): 775-
777.
2. Tosetto A, Castaman G, Rodeghiero F.
Assessing bleeding in von Willebrand disease
with bleeding score. Blood Rev 2007; 21(2):
89-97.
3. Goodeve A, Eikenboom J, Castaman G,
et
al. 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 (MCMDM-1VWD).
Blood 2007; 109(1): 112-121.
A very good and easily readable reference by Carol
Kasper for those who require more detail is found
at: http://www.med.unc.edu/isth/publications/
vwd_monogaph/VWD_monograph_2005.pdf
I  t
Mild type 1 vWD is common and sig-
nicantly underdiagnosed.
A detailed history of mucocutaneous
bleeding (epistaxis, mouth, menorrha-
gia, bruising) since childhood is an es-
sential tool in the diagnosis of vWD.
In women in whom the tests are not
diagnostic the best time to sample blood
is during the rst week of the menstrual
period.
Aspirin should be avoided in patients
with vWD, and NSAIDs prescribed
with caution.
Tranexamic acid is very eective in con
-
trolling most minor bleeds as well as
menorrhagia (for which the combined
oral contraceptive pill is also eective).
DDAVP should be considered in type
1 disease, but access to the intranasal
preparation is limited.
Patients should be registered with Medic-
Alert and the data sent to the South Af-
rican Haemophilia Register.
pg264-266.indd 266 6/15/07 2:49:32 PM
Page 3
  • [Show abstract] [Hide abstract] ABSTRACT: von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). The current report overviews the diagnosis and management of VWD as reflected by differential processes applied within centers around the world. The prevalence of VWD, as well as the frequency of different VWD types, is also reported. VWD prevalence data varies according to methodology used, with epidemiological/population screening estimates approximating 1% of the population (or 10,000 cases per million population), several orders of magnitude higher than estimates from bleeding disorders registry data or regional/center analysis (which instead range from <1 to ~450 cases per million population). Frequency of different VWD types also varies according to source and analysis, with type 1 VWD identified as the clear dominant type in most developed countries (ranging from 40% to 90% of all VWD cases), whereas type 3 VWD predominates in developing countries such as India and Iran. The frequency of qualitative (i.e., type 2) VWD also varies considerably among different reports, ranging from 3% to >50% of all VWD cases, as does the frequency of specific qualitative VWD types (i.e., 2A, 2B, 2M, and 2N). Although type 2A VWD is considered the most common form of type 2 VWD, in some reports workers consider type 2M VWD to be as, or more, common. Although not considered to be a "true" VWD, given its platelet origin, platelet-type VWD is only rarely identified. Finally, management of VWD also differs according to geographic region. Most developed countries use standard therapy, employing desmopressin (DDAVP) wherever possible, factor concentrate in other situations, and antifibrinolytic therapy as required. In contrast, the relative high cost and unavailability of factor concentrates in developing countries, and sometimes the unavailability of DDAVP, requires different management strategies to be applied.
    No preview · Article · Jul 2011 · Seminars in Thrombosis and Hemostasis
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction: von Willebrand factor (VWF)-related disorders are generally distinguished as either acquired (von Willebrand Syndrome; VWS) or congenital (von Willebrand Disease; VWD). VWD is the most common inherited bleeding disorder and is due to deficiencies and/or defects in VWF. VWS arises from a large variety of causes. Areas covered: The current report briefly overviews the diagnosis of VWD and VWS, but primarily covers the management of these disorders, as reflected by differential processes applied within different centers worldwide, also focusing on emerging trends in biological therapies. Most developed countries currently use standard therapy to manage bleeding, employing desmopressin wherever possible, factor concentrate in other situations and additional (e.g., antifibrinolytic) therapy when required. With regards to factor concentrates, there are differences in content between those available in relation to levels and composition of VWF and factor VIII, and only selective concentrates are available in different localities. Expert opinion: All these aspects reflect important but sometimes overlooked issues when using replacement therapy, or attempting to follow expert guidelines. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may change the VWD management landscape in the near future.
    No preview · Article · Mar 2012 · Expert opinion on biological therapy
  • [Show abstract] [Hide abstract] ABSTRACT: Bleeding disorder panels often include the prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen level, and thrombin time (TT). We explored the detection of abnormalities from bleeding disorders by these tests among subjects referred for bleeding disorder assessments, using data from a bleeding disorder study to determine sensitivities and specificities. Among subjects referred to hematologists for bleeding disorder assessment, coagulation defects were uncommon and the APTT and TT detected many nonsignificant abnormalities. While all test and panel specificities were acceptable (88 to 100%), coagulation screening tests were less sensitive to clinically significant abnormalities (1.0 to 2.1%) than von Willebrand disease (VWD) screens (6.7%), and light transmission platelet aggregometry (LTA) (26%). Accordingly, panels comprising PT/INR, APTT, fibrinogen, and TT had lower sensitivity to bleeding disorders (3.7%) than panels expanded to include VWD screens (8.5%), or VWD screens and LTA (30%). These findings have important implications for bleeding disorder diagnosis.
    No preview · Article · Sep 2012 · Seminars in Thrombosis and Hemostasis
Show more