Federici_relayout.qxp 9/4/09 2:34 pm Page 83
Current Management of von Willebrand Disease
Figure 2: Flow Chart Proposed for the Diagnosis of Different Figure 3: Schematic Representation of the von Willebrand
von Willebrand Disease Types Disease Gene Located in Chromosome 12
a) Plasma VWF:Ag Absent VWD3 f) Platelet VWF 5’ 7 16 28 37 3’
bp 0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Proportionate
Present
Proportionate
VWD1
1-23 163
Multimers S-S
Dimers S-S
(0.7–1.2)
2813
c) Plasma factor H
2
N
D1 D2 D’ D3 A1 A2 A3 D4 C1 C2 CK COOH
b) Plasma VWF:RCo vs VWF:Ag VIII:C vs VWF:Ag
B1
VWF:(RCo/Ag) B2
FVIII GPlb Collagen B3 RGD
Discrepant
(Collagen) botrocetin
(<0.7)
VWD2
Discrepant
Heparin sulphatide
α
llb
β
3
VWD2N
VWD2B
VWD2A 2N 2A 2M 2A 2A
B1-3
Increased
D1 D2 D’ D3 A1 A2 A3 D4 C1 C2 CK
(0.2–0.8)
d) Ristocetin-induced platelet agglutination g) FVIII binding assay
(RIPA) (mg/ml)
NH2 COOH
Absent VWD2A
Decreased
Propeptide Mature VWF
VWD2B e) Plasma high multimers
(<1.2)
Present VWD2M
The main exons are indicated with the number of base pairs from 5’ to 3’ (upper panel). The
VWD3 can be diagnosed in case of immeasurable VWF: Ag (a). A proportionate reduction of
structure of VWF functional domains: the pre-pro-VWF is indicated with amino acids
both VWF: Ag and VWF: RCo with an RCo/Ag ratio >0.7 suggests type one VWD (b). If the
numbered from the amino- (aa 1) to carboxy-terminal portions (aa 2813) of VWF. Note the
VWF: RCo/Ag ratio is <0.7 type two is diagnosed. VWD2B (d) can be identified in cases of
important CK and D3 domains for formation of VWF dimers and multimers. The native
heightened RIPA (<0.8mg/ml), whereas types 2A and 2M cause low RIPA (>1.2mg/ml).
mature subunit of VWF, after the cleaving of the pre-pro VWF, is described with its
Multimeric analysis in plasma (e) is necessary to distinguish between VWD2A (lack of the
functional domains: the VWF binding sites for factor VIII (D’ and D3), GPIb, botrocetin,
largest and intermediate multimers) and VWD2M (all of the multimers present). VWD2N can
heparin, sulphatide, collagen (A1), collagen (A3) and the RGD sequence for binding to αIIbβ3
be suspected in cases of discrepant values for FVIII (c) and VWF: Ag (ratio <0.5), and
(intermediate panel). Distribution of VWF mutations in patients with VWD type 2: the
diagnosis should be confirmed by the specific test (g) of VWF: factor VIII binding capacity
positions of mutations causing VWD2A, VWD2B, VWD2M and VWD2N are indicated with
(VWF: FVIIIB). In VWD1, the ratio between factor VIII and VWF: Ag is always >1 and the
black bars throughout the VWF domains (lower panel).
severity of VWD1 phenotype can usually be evaluated from platelet VWF (f) measurements.
This figure is derived from that originally reported.
4
Table 2: Clinical and Laboratory Parameters Used for
von Willebrand Disease Diagnosis
symptoms. Pre-natal diagnosis is required in the cases of parents
Patients at Risk of VWD
already known to be carriers of VWD3 and with gene defects
Clinical history – lifelong mucocutaneous and post-operative bleeding, to be collected
identified in an affected child. Since young children with VWD3 may
with appropriate questionnaires to calculate the bleeding severity score (BSS)
carry deletions of the VWF gene that predispose to the allo-antibodies
Screening tests – prolonged bleeding time (may be normal); normal platelet count; and
to VWF, every new child with VWD3 should be intensively investigated
prolonged PTT (may be normal)
by searching deletions before starting extensive therapy with Diagnosis and Definition of VWD Type
exogenous VWF concentrates.
VWF antigen (a)
VWF: ristocetin co-factor activity (b)
Treatment and Prevention of Bleeding
Factor VIII (c)
VWF multimeric structure on low-resolution gels (e)
The goal of treatment is to correct the dual defects of haemostasis –
Characterisation of VWD Type
abnormal platelet adhesion due to low or defective VWF and abnormal
Ristocetin-induced platelet agglutination (RIPA) (d)
intrinsic coagulation due to low FVIII.
23
Two main therapeutic
VWF multimeric structure on high-resolution gels (e)
approaches are available: desmopressin (DDAVP), which releases Platelet VWF content (f)
endogenous VWF from endothelial cells; and exogenous VWF
Factor VIII binding assay (g)
contained in VWF/FVIII concentrates. The choice of the two For the use of these tests see the diagnostic flow-chart reported in Figure 3 and also in
reference 4.
approaches related to VWD type is summarised in Table 3.
Desmopressin severity of the bleeding episode. Most patients who are repeatedly
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a treated become less responsive to therapy.
27
The drug is also available
synthetic analogue of vasopressin that is relatively inexpensive and in concentrated forms for subcutaneous and intranasal administration.
carries no risk of transmitting blood-borne infectious agents. DDAVP, This can be convenient for home treatment.
infused intravenously at a dose of 0.3µg/kg and diluted in 50ml of
saline over 30 minutes, usually increases plasma VWF and FVIII three Despite the widespread use of DDAVP in the treatment of VWD,
to five times above baseline levels within 30–60 minutes. The high there are no prospective clinical studies on its efficacy and safety
VWF and FVIII levels generally last for six to eight hours.
24
As the along with determining its benefits and limits. A recent investigator-
responses in a given patient are consistent on different occasions, a driven prospective study will correlate biological response with the
test dose of DDAVP at the time of diagnosis is recommended to clinical efficacy of DDAVP in more than 200 patients with VWD1
establish the individual response patterns.
4
and VWD2.
28
Side effects of DDAVP are usually mild tachycardia,
headache and flushing. These are attributed to the vasomotor effects
The protocols of the infusion test, with clinical and laboratory of the drug and can often be attenuated by slowing the rate of
parameters to be measured, have been previously reported.
25,26
The infusion. Hyponatraemia and volume overload, due to the antidiuretic
criteria for biological responses are shown in Table 4. DDAVP infusions effects of DDAVP, are relatively rare and usually occur only in
can be repeated every 12–24 hours depending on the type and young children.
29
ASIA-PACIFIC ONCOLOGY & HAEMATOLOGY 83
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100