von willebrand disease - haemophilia
TRANSCRIPT
Von Willebrand disease
Dr. Paul GiangrandeOxford Haemophilia and Thrombosis Centre
&Nuffield Department of Clinical Medicine
University of Oxford
Issues to be covered:
• Clinical manifestations• Laboratory diagnosis• Genetic basis• Treatment:
– Bleeding episodes– Surgery– Pregnancy
1924: Erich von Willebrand described bleeding disorder in Åland islands.Ascribed to defect in platelets.
1928: Similar cases described by Minot whonoted prolongation of bleeding time.
1941: Macfarlane claimed disorder was due to vascular abnormality.
1953: Low level of “antihaemophilicfactor” identified by several workers (Alexander, Larrieu, Quick)
1959: Nilsson reported that haemostatic defect is corrected by transfusion ofplasma from haemophiliacs.
1971: Firkin introduced ristocetin as toolfor testing platelet function.
1973: VWF in endothelial cells (Jaffe).1977: Mannucci reported use of DDAVP.
Clinical features
von Willebrand factor is essential for platelet adhesion to collagen:
platelet
endothelial cells
collagen
von Willebrand factor (VWF):VWF can be thought of as the glue which is needed by platelets to stick to site of injuryMade and stored in cells lining blood vessels (endothelial cells)Stored in cylindrical structures called Weibel-Palade bodiesGene on chromosome 12 (not on X-chromosome like factor VIII or IX) VWF is very large protein which circulates in plasma as a series of stacked molecules (multimers)VWF also binds factor VIII in plasma
Weibel-Palade bodies in endothelial cells
Von Willebrand’s disease:• Common but usually mild bleeding disorder
– Up to 1% of population affected as defined by reduced plasma level of VWF, although only
– 125 / million have significant bleeding disorderSadler JE Thromb. Haemostasis 84: 160-174 (2000)
• Autosomal 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 history taking:
• Easy bruising• Nose bleeds• Heavy menstrual periods• Bleeding after operations etc:
– operations– dental extractions– after giving birth
• Family history
Objective criteria include:• Need for blood transfusion• Anaemia• Prolonged bleeding from trivial wounds
lasting > 15 minutes and requiring medical attention
• Haematoma at site of injections (e.g vaccination), bleeding from umbilical stump
• Oral cavity bleeding associated with tooth eruption, bites to lips and tongue
• Menorrhagia without uterine disease
Frequency of bleeding disorders in women with menorrhagia:
Kadir RA et al: Lancet 351: 485-489 (1998)
• 150 women with menorrhagia but no pelvic abnormality screened
• Inherited bleeding disorder in 26 (17%)• Commonest disorders: von Willebrand’s
disease, platelet disorders, factor 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)
“The study emphasises the importance of a carefulhistory specifically with regard to a long history
of menorrhagia since menarche, and a history of bleeding after tooth extraction, operations andchildbirth. If these factors are present, testing
for bleeding disorders should be carried out.This should be arranged in conjunction with theLocal haematology department as many of the necessary tests are not routine.”
2007
A diagnosis of VWD can have significant adverse social
consequences:• Self-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?
Laboratorydiagnosis
Tests available for diagnosis of VWD:
• Bleeding time• Factor VIII• VWF antigen• VWF:RCo (ristocetin-induced platelet
aggregation)• VWF:CB (collagen binding assay)• VWF multimer analysis
No single test suffices to make a diagnosis of VWD. Panel of tests include:
VWF levels:• Normal level in range of 40-240 iu/dl• Various genetic and environmental factors
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 factors
• These may also obscure the diagnosis in some cases
Bleeding time:• Measure time to stop
bleeding after skin incision with 40 mmHg pressure applied to forearm (normal <9 min)
• Limited sensitivity: frequently normal in mild VWD
• BT also prolonged with– low platelet count – platelet disorders– aspirin treatment– low haematocrit
• Poor reproducibility
Use of the PFA-100 in VWD:• Uses 800 μl citrated blood: test within 4
hours of collection• Prolonged closure time using both
collagen/ADP and collagen/epinephrine cartridges in VWD
• Higher sensitivity than bleeding time• Better consistency of results• Useful for initial screening• May also be of value in monitoring treatment
Types of von Willebrand disorder (VWD):
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]
ISTH Classification: Thromb. Haemostasis 71: 520-525 (1994)
Multimer analysis in VWD:
1 3 2A 2B 2D normal samples
Factors which influence VWF level:
• ABO group• Secretor status• Age• Race• Difficult venepuncture• Physical exertion• Mental stress• Oestrogen therapy• Menstrual cycle
• Pregnancy• Systemic disease:
MalignancyInfectionInflammationPre-eclampsiaPostoperative stateHypothyroidismDiabetes mellitus
Effect of blood group on VWF level:Gill JC et al. Blood 69: 1691-1695 (1987)
Changes in VWF during the menstrual cycle:
Kadir RA et al. Thromb. Haemost 82: 1456-61 (1999)
Hypothyroidism and acquired VWD:
Dalton R et al: Lancet i: 1007-1009 (1987)
• Hypothyroidism may be associated with menorrhagia
• Hypothyroidism may also be associated with reduction in von Willebrand factor 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 history• 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 cytosine deletion in exon 18, resulting in frameshift causing a stop codon, identified in original pedigree of type 3 VWD
• Type 1 VWD is certainly not simply due to heterozygosity for type 3 VWD
Molecular basis of type 2 VWD:
VWD mutation database: www.sheffield.ac.uk/vwf
D1 D2 D’ D3 D4A1 A2 A3
B C1 C2
chrom. 12p178 kb52 exonspro-VWF
type 2Nmutations
exon 28A1 A2aa497 909
type 2Bmutations
type 2Amutations
Treatment
Tranexamic acid:• Stops 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: nausea,
diarrhoea, abdominal pain, skin rash
Lancet i: 869-872 (1977)
Desmopressin (DDAVP):
• Chemical analogue of natural hormone called antidiuretic hormone (ADH)
• Boosts levels of factor VIII and VWF• No effect on factor 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 forthe treatment of haemostatic disorders!
Response to desmopressin in different types of VWD:
Type Response 1 Usually effective2A Usually ineffective2B May be contraindicated2M Predicted to be ineffective2N Rarely effective3 Ineffective
Side-effects of DDAVP:
Minor:headacheflushingtachycardiatremorsweatingdizzinessrhinitis (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. Haematol. 82: 87-93 (1992)
Surgery in VWD:• Major procedures that require prolonged correction
of factor VIII level are unlikely to be feasible with DDAVP alone
• FVIII level predictive risk of bleeding• Raise factor VIII level to 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 – Use prophylaxis (e.g. heparin, compression hosiery)
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 (CSL Behring), Alphanate (Grifols); VHP-VWF (LFB), 8Y (BPL)
• Cryoprecipitate may be used but is far from ideal
Haemostasis in normal pregnancy:
050
100150200250300350400450
13 18 23 28 33 38 Post Basal
Weeks gestation
Fact
or le
vel i
u/dl
FVIII:CVWF Ag
Changes during pregnancy in VWD:
• VWF levels start to 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 to 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 factor levels at 34-36 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 to yield
reliable results in type 1 VWD• Increased risk of post-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