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Von Willebrand disease

Dr. Paul Giangrande

Oxford Haemophilia & Thrombosis Centre

and

Nuffield Department of Clinical Medicine

University of Oxford

paul.giangrande@ndm.ox.ac.uk


Issues ong>toong> be covered:

• Clinical manifestations

• Laboraong>toong>ry diagnosis

• Genetic basis

• Treatment:

• Bleeding episodes

• Surgery

• Pregnancy


1924: Erich von Willebrand described

bleeding disorder in Åland islands.

Ascribed ong>toong> defect in platelets.

1928: Similar cases described by Minot who

noted prolongation of bleeding time.

1941: Macfarlane claimed disorder was due

ong>toong> vascular abnormality.

1953: Low level of “antihaemophilic

facong>toong>r” identified by several workers

(Alexander, Larrieu, Quick)

1959: Nilsson reported that haemostatic

defect is corrected by transfusion of

plasma from haemophiliacs.

1971: Firkin introduced risong>toong>cetin as ong>toong>ol

for testing platelet function.

1973: VWF in endothelial cells (Jaffe).

1977: Mannucci reported use of DDAVP.


Clinical features


von Willebrand facong>toong>r is essential for

platelet adhesion ong>toong> collagen:

platelet

endothelial cells

collagen


von Willebrand facong>toong>r (VWF):

• VWF can be thought of as the glue which is

needed by platelets ong>toong> stick ong>toong> site of injury

• Made and song>toong>red in cells lining blood vessels

(endothelial cells)

• Song>toong>red in cylindrical structures called Weibel-

Palade bodies

• Gene on chromosome 12 (not on X-X

chromosome like facong>toong>r VIII or IX)

• VWF is very large protein which circulates in

plasma as a series of stacked molecules

(multimers)

• VWF also binds facong>toong>r VIII in plasma


Weibel-Palade bodies in endothelial cells


Von Willebrand’s s disease:

• Common but usually mild bleeding disorder

• Up ong>toong> 1% of population affected as defined by

reduced plasma level of VWF, although only

• 125 / million have significant bleeding disorder

Sadler JE Thromb. Haemostasis 84: 160-174 174 (2000)

• Auong>toong>somal dominant inheritance

• Typical features include:

• Easy bruising

• Prolonged bleeding from cuts and scratches

• Nose bleeds (epistaxis)

• Heavy menstrual bleeding (menorrhagia)

• Joint bleeding not a typical feature


Inheritance of VWD:


A baby with severe von

Willebrand disease:

Non-accidental injury may be suspected in babies with bruising


Importance of hisong>toong>ry taking:

• Easy bruising

• Nose bleeds

• Heavy menstrual periods

• Bleeding after operations etc:

• operations

• dental extractions

• after giving birth

• Family hisong>toong>ry


Objective criteria include:

• Need for blood transfusion

• Anaemia

• Prolonged bleeding from trivial wounds

lasting > 15 minutes and requiring

medical attention

• Haemaong>toong>ma at site of injections (e.g

vaccination), bleeding from umbilical

stump

• Oral cavity bleeding associated with

ong>toong>oth eruption, bites ong>toong> lips and ong>toong>ngue

• Menorrhagia without uterine disease


Frequency of bleeding disorders in

women with menorrhagia:

Kadir RA et al: Lancet 351: 485-489 489 (1998)

• 150 women with menorrhagia but no pelvic

abnormality screened

• Inherited bleeding disorder in 26 (17%)

• Commonest disorders: von Willebrand’s

disease, platelet disorders, facong>toong>r XI deficiency.

• “Inherited bleeding disorders are found in a

substantial proportion of women with

menorrhagia and a normal pelvis.”


Guidelines on the management of

menorrhagia in secondary care

Royal College of Obstetricians & Gynaecologists, UK (1998)

“The study emphasises the importance of a careful

hisong>toong>ry specifically with regard ong>toong> a long hisong>toong>ry

of menorrhagia since menarche, and a hisong>toong>ry of

bleeding after ong>toong>oth extraction, operations and

childbirth. If these facong>toong>rs are present, testing

for bleeding disorders should be carried out.

This should be arranged in conjunction with the

Local haemaong>toong>logy department as many of the

necessary tests are not routine.”


2007


A diagnosis of VWD can have

significant adverse social

consequences:

• Self-esteem

esteem

• School

• Employment

• Participation in sports

• Life insurance

• Credit rating (e.g mortgage)

• Travel insurance

• Marriage prospects


Von Willebrand disease (VWD):

…..or would either

“deficiency” or “disorder”

be better?


Laboraong>toong>ry

diagnosis


Tests available for diagnosis of

VWD:

No single test suffices ong>toong> make a

diagnosis of VWD. Panel of tests include:

• Bleeding time

• Facong>toong>r VIII

• VWF antigen

• VWF:RCo (risong>toong>cetin-induced induced platelet

aggregation)

• VWF:CB (collagen binding assay)

• VWF multimer analysis


VWF levels:

• Normal level in range of 40-240 iu/dl

• Various genetic and environmental facong>toong>rs

influence the plasma level: e.g. blood

group, age, race, hormones.

• The presence of VWD, or at least the

severity, are frequently determined by a

combination of these facong>toong>rs

• These may also obscure the diagnosis in

some cases


Bleeding time:

• Measure time ong>toong> song>toong>p

bleeding after skin incision

with 40 mmHg pressure

applied ong>toong> forearm (normal


Types of von Willebrand disorder (VWD):

ISTH Classification: Thromb. Haemostasis 71: 520-525 (1994)

Type 1: Partial quantitative deficiency [reduced

level of qualitatively normal VWF]

Type 2: Qualitative deficiency [absolute level of

VWF may be normal or low, but VWF

present is qualitatively defective]

Type 3: Total quantitative deficiency

[no VWF produced]


Multimer analysis in VWD:

1 3 2A 2B 2D normal samples


Facong>toong>rs which influence VWF

level:

• ABO group

• Secreong>toong>r status

• Age

• Race

• Difficult venepuncture

• Physical exertion

• Mental stress

• Oestrogen therapy

• Menstrual cycle

• Pregnancy

• Systemic disease:

• Malignancy

• Infection

• Inflammation

• Pre-eclampsia

eclampsia

• Posong>toong>perative state

• Hypothyroidism

• Diabetes mellitus


Effect of blood group on VWF

level:

Gill JC et al. Blood 69: 1691-1695 1695 (1987)

VWF:Ag (iu/dl)

140

120

100

80

60

40

20

0

O A B AB

Blood group

(data derived from analysis of 1117 volunteer blood donors)


Changes in VWF during the menstrual

cycle:

Kadir RA et al. Thromb. Haemost 82: 1456-61 61 (1999)


Hypothyroidism and acquired

VWD:

Dalong>toong>n R et al: Lancet i: 1007-1009 1009 (1987)

• Hypothyroidism may be associated

with menorrhagia

• Hypothyroidism may also be

associated with reduction in von

Willebrand facong>toong>r level

• Secondary VWD is associated with an

acquired bleeding tendency

• VWF level rises with thyroxine therapy


Summary of key

recommendations for diagnosis:

• No single test suffices

• Normal APTT does not exclude mild form

• Take note of bleeding hisong>toong>ry

• Repeat tests if borderline

• Beware of conditions which modify VWF levels

• PFA-100 test and functional tests of VWF

activity (VWF:RCo & VWF:CB) particularly

important


Molecular basis


Molecular basis of VWD:

• No mutation identified in majority of case of

type 1

• Postulated that most cases of type 1 VWD

result from defect in a linked gene which

controls gene transcription

• Several defects described in type 3 VWD e.g.

large deletions

• Single cyong>toong>sine deletion in exon 18, resulting

in frameshift causing a song>toong>p codon, identified

in original pedigree of type 3 VWD

• Type 1 VWD is certainly not simply due ong>toong>

heterozygosity for type 3 VWD


Molecular basis of type 2 VWD:

D1 D2 D’ D3 A1 A2 A3 D4

pro-VWF

type 2N

mutations

B C1 C2

aa497 909

A1

A2

chrom. 12p

178 kb

52 exons

exon 28

type 2B

mutations

type 2A

mutations

VWD mutation database: www.sheffield.ac.uk/vwf


Tranexamic acid:

• Song>toong>ps clots from being broken down

(“fibrinolysis”)

• Widely used for treatment of menorrhagia,

recurrent nosebleeds, oral bleeding etc.

• Do not use in cases of blood in the urine

(“haematuria”)

• Risk of venous thrombosis not increased

• Minor and infrequent side-effects: effects: nausea,

diarrhoea, abdominal pain, skin rash


Lancet i: 869-872 (1977)


Desmopressin (DDAVP):

Mannucci PM: Blood 2515-2521 2521 (1997)

• Chemical analogue of natural hormone called

antidiuretic hormone (ADH)

• Boosts levels of facong>toong>r VIII and VWF

• No effect on facong>toong>r IX level

• Cheap and free of risk of viral transmission

• Choice of administration:

• subcutaneous injection

• intravenous infusion

• nasal spray

• Peak effect seen after one hour

• May be used during pregnancy


Various formulations of DDAVP exist:

make sure you use the correct one!


“Octim” is the correct intranasal spray product for

the treatment of haemostatic disorders!


Response ong>toong> desmopressin in

different types of VWD:

Type Response

1 Usually effective

2A

Usually ineffective

2B

May be contraindicated

2M

Predicted ong>toong> be ineffective

2N

Rarely effective

3 Ineffective

Mannucci PM: Blood 97: 1915-1919 (2001)


Side-effects of DDAVP:

• Minor:

‣ headache

‣ flushing

‣ tachycardia

‣ tremor

‣ sweating

‣ dizziness

‣ rhinitis (runny nose)

‣ abdominal cramps

• Major:

‣ hyponatraemia (low

sodium level)

‣ marked hypotension

(very low blood

pressure)

‣ myocardial infarction

(heart attack)

‣ other arterial thrombosis


Response in VWD:

Mannucci PM: Br. J. Haemaong>toong>l. 82: 87-93 (1992)


Surgery in VWD:

• Major procedures that require prolonged correction

of facong>toong>r VIII level are unlikely ong>toong> be feasible with

DDAVP alone

• FVIII level predictive risk of bleeding

• Raise facong>toong>r VIII level ong>toong> around 100 iu/dl peri-

operatively, and maintain at or above 50 iu/dl until

wound healing is complete

• Correction of bleeding time is not always observed

and is not vital

• Cases of DVT have been reported in some

patients with VWD

Makris MT et al. Thromb. Haemostasis 88: 387-388 388 (2002).


Blood products:

• Used in type 2 & 3, and in type 1 if DDAVP

unsuitable.

• No recombinant VWF product yet

• High-purity plasma or recombinant FVIII

products of no value

• Commonly used plasma-derived

concentrates include: Wilate (Octapharma);

Haemate-P P (CSL Behring), Alphanate

(Grifols); VHP-VWF VWF (LFB), 8Y (BPL)

• Cryoprecipitate may be used but is far from

ideal


Haemostasis in normal pregnancy:

Thrombosis & Haemostasis 52: 176-182 (1984)

Facong>toong>r level iu/dl

450

400

350

300

250

200

150

100

50

0

13 18 23 28 33 38 Post Basal

Weeks gestation

FVIII:C

VWF Ag


Changes during pregnancy in

VWD:

• VWF levels start ong>toong> rise by sixth week of

gestation in VWD types 1 and 2

• Level often well within normal range at

term in type 1 VWD

• VWF level does not rise in the rare type 3

VWD subtype

• Levels drop down ong>toong> original baseline

within a few days after delivery


Pregnancy in women with VWD:

NHLBI Guidelines (USA). Haemophilia 14: 171-232 (2008)

www. www.nhlbi.nih.gov/guidelines/vwd

• Check facong>toong>r levels at 34-36 36 weeks

• Vaginal delivery generally regarded as safe if

VWF activity is ≥50 iu/dl

• Similar threshold for Caesarean section and

epidural anaesthetic

• DDAVP may be used

• Avoid aspirin-like analgesics

• Cord blood screening of baby is unlikely ong>toong> yield

reliable results in type 1 VWD

• Increased risk of post-partum partum haemorrhage

(≈20%)


WFH 2010:

abstract 36P05


Conclusions:

• VWD is the commonest inherited bleeding

disorder

• No single test exists for diagnosis

• Repeat testing may be need in borderline

cases

• DDAVP is a very useful agent

• No recombinant VWF concentrate

available yet

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