Von Willebrand disease

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1 Von Willebrand disease Dr. Paul Giangrande Oxford Haemophilia & Thrombosis Centre and Nuffield Department of Clinical Medicine University of Oxford

2 Issues to be covered: Clinical manifestations Laboratory diagnosis Genetic basis Treatment: Bleeding episodes Surgery Pregnancy

3 1924: Erich von Willebrand described bleeding disorder in Åland islands. Ascribed to defect in platelets. 1928: Similar cases described by Minot who noted prolongation of bleeding time. 1941: Macfarlane claimed disorder was due to vascular abnormality. 1953: Low level of antihaemophilic factor identified by several workers (Alexander, Larrieu, Quick) 1959: Nilsson reported that haemostatic defect is corrected by transfusion of plasma from haemophiliacs. 1971: Firkin introduced ristocetin as tool for testing platelet function. 1973: VWF in endothelial cells (Jaffe). 1977: Mannucci reported use of DDAVP.

4 Clinical features

5

6

7 von Willebrand factor is essential for platelet adhesion to collagen: platelet endothelial cells collagen

8 von Willebrand factor (VWF): VWF can be thought of as the glue which is needed by platelets to stick to site of injury Made and stored in cells lining blood vessels (endothelial cells) Stored in cylindrical structures called Weibel- Palade bodies Gene on chromosome 12 (not on X-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

9 Weibel-Palade bodies in endothelial cells

10

11 Von Willebrand s 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 disorder Sadler JE Thromb. Haemostasis 84: (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

12 Inheritance of VWD:

13 A baby with severe von Willebrand disease: Non-accidental injury may be suspected in babies with bruising

14 Importance of history taking: Easy bruising Nose bleeds Heavy menstrual periods Bleeding after operations etc: operations dental extractions after giving birth Family history

15 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

16 Frequency of bleeding disorders in women with menorrhagia: Kadir RA et al: Lancet 351: (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.

17

18 Guidelines on the management of menorrhagia in secondary care Royal College of Obstetricians & Gynaecologists, UK (1998) The study emphasises the importance of a careful history specifically with regard to a long history of menorrhagia since menarche, and a history of bleeding after tooth extraction, operations and childbirth. If these factors are present, testing for bleeding disorders should be carried out. This should be arranged in conjunction with the Local haematology department as many of the necessary tests are not routine.

19 2007

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21 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

22 Von Willebrand disease (VWD):..or would either deficiency or disorder be better?

23 Laboratory diagnosis

24 Tests available for diagnosis of VWD: No single test suffices to make a diagnosis of VWD. Panel of tests include: Bleeding time Factor VIII VWF antigen VWF:RCo (ristocetin-induced induced platelet aggregation) VWF:CB (collagen binding assay) VWF multimer analysis

25 VWF levels: Normal level in range of 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

26 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

27

28

29 Use of the PFA-100 in VWD: Uses 800 μl l 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

30 Types of von Willebrand disorder (VWD): ISTH Classification: Thromb. Haemostasis 71: (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]

31 Multimer analysis in VWD: 1 3 2A 2B 2D normal samples

32 Factors which influence VWF level: ABO group Secretor status Age Race Difficult venepuncture Physical exertion Mental stress Oestrogen therapy Menstrual cycle Pregnancy Systemic disease: Malignancy Infection Inflammation Pre-eclampsia eclampsia Postoperative state Hypothyroidism Diabetes mellitus

33 Effect of blood group on VWF level: Gill JC et al. Blood 69: (1987) VWF:Ag (iu/dl) O A B AB Blood group (data derived from analysis of 1117 volunteer blood donors)

34 Changes in VWF during the menstrual cycle: Kadir RA et al. Thromb. Haemost 82: (1999)

35 Hypothyroidism and acquired VWD: Dalton R et al: Lancet i: (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

36 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

37 Molecular basis

38 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

39 Molecular basis of type 2 VWD: D1 D2 D D3 A1 A2 A3 D4 pro-vwf type 2N mutations B C1 C2 aa A1 A2 chrom. 12p 178 kb 52 exons exon 28 type 2B mutations type 2A mutations VWD mutation database:

40 Treatment

41 General measures: Ask for medical card with details of your condition Suggest screening of other family members Avoid aspirin and related anti- inflammatory drugs: Paracetamol is fine When travelling abroad: Find out where nearest treatment centre is Take out medical/travel insurance

42 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: effects: nausea, diarrhoea, abdominal pain, skin rash

43 Lancet i: (1977)

44 Desmopressin (DDAVP): Mannucci PM: Blood (1997) 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

45 Various formulations of DDAVP exist: make sure you use the correct one!

46 Octim is the correct intranasal spray product for the treatment of haemostatic disorders!

47 Response to desmopressin in different types of VWD: Type Response 1 Usually effective 2A Usually ineffective 2B May be contraindicated 2M Predicted to be ineffective 2N Rarely effective 3 Ineffective Mannucci PM: Blood 97: (2001)

48 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

49 Response in VWD: Mannucci PM: Br. J. Haematol. 82: (1992)

50 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 with VWD Makris MT et al. Thromb. Haemostasis 88: (2002).

51 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

52 Haemostasis in normal pregnancy: Thrombosis & Haemostasis 52: (1984) Factor level iu/dl Post Basal Weeks gestation FVIII:C VWF Ag

53 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

54 Pregnancy in women with VWD: NHLBI Guidelines (USA). Haemophilia 14: (2008) www. Check factor levels at 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 partum haemorrhage ( 20%)

55 WFH 2010: abstract 36P05

56 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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