Von Willebrand Disease: Management and Complications. Mike Makris Sheffield, UK

Transcription

1 Von Willebrand Disease: Management and Complications Mike Makris Sheffield, UK

2 Disclosures for Mike Makris Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Bayer, Biotest, BPL, CSL Behring, Grifols, Kedrion, LFB, NovoNordisk, Octapharma, Pfizer, SOBI No relevant conflicts of interest to declare CSL Behring No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare NovoNordisk

3 What do I do? Clinician in Haemostasis and Thrombosis Clinical lead for coagulation service laboratory Research European activities: EAHAD, EUHANET, EUHASS Editor Haemophilia journal

4 Available products to correct to treat VWD

5 Tranexamic acid Antifibrinolytic Prevents conversion of plasminogen to plasmin Half life 180 minutes Available for oral use as tablets or liquid and intravenous preparation Good for mucosal surface bleeding

6 Desmopressin (DDAVP)

7 Desmopressin (DDAVP) Available for iv, sc and intranasal use Releases pre-formed FVIII and VWF from endothelial cells Give a trial dose with levels at Pre, 1hr and 4hr Restrict fluid intake to 1.5 litres in following 24 hours Avoid in children <2 years Avoid in patients with cardiac disease Avoid in 2B VWD

8 Desmopressin doses and response in VWD Route of administration Intravenous infusion over min Suggested formulation 4μg/ml diluted in 100ml 0.9% NaCl for infusion Dose 0.3μg/kg Peak levels achieved 15 min after infusion completed Subcutaneous 15μg/ml 0.3μg/kg min after injection Intranasal 150μg per metered spray >50kg: 150μg spray into each nostril <50kg: single 150μg spray 1-4 hr after administration

9 DDAVP response in severe type 1 VWD (Historical FVIII <20iu/dl, VWF:RCo <10iu/dl) Federici AB et al. Blood 2004;103:2032

10 DDAVP response in 2A VWD Federici AB et al. Blood 2004;103:2032

11 DDAVP response in 2M VWD Federici AB et al. Blood 2004;103:2032

12 DDAVP response in 2N VWD Federici AB et al. Blood 2004;103:2032

13 Variation in multimer response post-ddavp Federici AB et al. Blood 2004;103:2032

14 Tachyphylaxis: Diminishing response to successive dosing of a drug Mannucci PM et al. BJH 1992; 82:87-93

15 FVIII/VWF concentrates Plasma derived. Two viral inactivation steps Used for VWD type 3, 2B, or VWD with inadequate DDAVP response Variable FVIII:VWF content Main products in Europe (VWF:FVIII) Haemate P / Voncento 2.4:1.0 Wilate 1.0:1.0

16 Randomised cross over trial of Wilate vs Humate P Kessler C et al. T&H 2011; 106:

17 Randomised cross over trial of Wilate vs Humate P Kessler C et al. T&H 2011; 106:

18 Calculating dose of FVIII/VWF concentrate (Body weight in Kg x desired VWF:Rco rise in u/dl or %) /1.5 Example: 70kg man, Baseline VWF:Rco 5%, aiming for VwF:Rco of 100% for surgery 70x95=6650, 6650/1.5=4433 VWF units

19 Pure VWF concentrate Plasma derived concentrate Made by LFB in France Widely used in France but limited elsewhere Contains no FVIII 12 hours after administration the releasted endogenous FVIII normalises in the circulation For acute bleeding give with FVIII concentrate For surgery give first dose 12 hr before surgery

20 Wilfactin (Pure plasma VWF) in type 3 VWD FVIII:C VWF:RCo VWF:Ag Goudemand J et al. JTH 2005; 3:

21 Pure VWF (Wilfactin) and FVIII/VWF concentrate in severe type 1 VWD Goudemand J et al. JTH 2005; 3:

22 Treatment of VWD Disease Type Treatment Low VWF Type 1 Type 2 Type 3 Desmopressin Desmopressin Desmopressin (if responsive) or FVIII-VWF concentrate or VWF concentrate FVIII-VWF concentrate or VWF concentrate

23 Doses of factor concentrate Mild to moderate bleeding Dose 20-40iu/kg Peak 50-80iu/dl (or %) VWF activity on day 1 Trough >30iu/dl VWF activity after day 1 Treat for 1-3 days Severe bleeding Dose 50iu/kg Peak >100iu/dl (or %) VWF activity on day 1 Trough >50iu/dl VWF activity after day 1 Treat for 7-10 days

24 Doses of factor concentrate for surgery and interventions Intervention Dose Iu/kg Target VWF activity Iu/dl Duration of treatment days Dental extraction 25 Peak >50 on day 1 1 Minor surgery Peak on day 1, trough >30 after day Major surgery Peak >100 on day 1, trough >50 after day Delivery Peak >100 on day 1, >50 after day 1 3-4

25 Management of type 2B VWD Autosomal dominant Increased affinity for platelet glycoprotein 1b Thrombocytopenia (worsens with surgery, pregnancy or other stress/inflammation Increased RIPA at low concentration of ristocetin Desmopressin (DDAVP) contraindicated Treatment is with FVIII/VWF concentrate

26 Management of type 2N VWD Not a uniform group Some patients respond to desmopressin (DDAVP) All patients should have a desmopressin trial with FVIII levels at pre, +1, +4 and if possible +24 hours If desmopressin unresponsive Use FVIII-VWF concentrate Use pure VWF concentrate

27 Type 3 VWD Virtual absence of VWF and FVIII Autosomal recessive Multiple mutations Joint bleeds as well as mucosal bleeding Behave like moderate haemophilia Require concentrate. No response to DDAVP Can develop inhibitors Many patients on prophylaxis

28 Prophylaxis in VWD VWD Prophylaxis network 61 patients 34 type 3, 5 type 1, 10 type 2A, 8 type 2B, 2 type 2M Abshire et al. Haemophilia 2013; 19:76-81

29 Adverse effects of treatments Tranexamic acid Xanthopsia, diarrhoea Desmopressin Fluid retention, seizures Headache and flushing primarily with iv preparation FVIII-VWF concentrate Allergic reaction Thrombosis Alloantibody to VWF (inhibitor)

30 VWD thrombosis Makris et al. T&H 2002; 88:387 Case series of 4 thromboses from 4 centres All treated with VWF concentrate 3 post surgery, 1 post injury Mannucci PM. T&H 2002; 88:378 International survey All treated with VWF concentrate 7 thromboses (3 post-surgery, 3 GI bleeding, 1 target joint) Main conclusion was venous thromboses in multiply concentrate treated patients, often with no monitoring

31 Alloantibodies to VWF Seen in type 3 VWF Very rare Can be associated with allergic reactions Difficult to detect inhibitory activity Can be treated with rfviia High dose continuous FVIII can be used Successful ITI has been reported

32 Frequency of Bleeding Symptoms in Adults with von Willebrand Disease Leebeek FWG. NEJM 2016; 375:2067

33 Bruising Common in VWD but also normal population Not dangerous Often leads to referral for investigation Does not require treatment unless associated with: - Neurovascular complication - Muscle haematoma

34 Epistaxis Very common Usually short in type 1 VWD Can be prolonged in type 2 or 3 VWD Tranexamic acid Cautery: silver nitrate Cautery: laser In type 3 (and 2) prophylactic concentrate

35 Menorrhagia Extremely common Can be formally assessed If iron deficient, no formal assessment needed Treatment options Tranexamic acid Combined oral contraceptive pill Intranasal/sc DDAVP Mirena coil Endometrial ablation Factor concentrate - for type 3 or 2 VWD

36 Management of menorrhagia in VWD James AH et al. Am J Obs Gyn 2009

37 Dental work Do a plan beforehand Tranexamic acid - preferably mouthwash Desmopressin (DDAVP) FVIII-VWF concentrate May not need anything if just infiltration Inferior dental nerve block needs treatment

38 Pregnancy in VWD Type 1 Confirm that levels have normalised at weeks Delivery usually not an issue Type 2 Check FVIII:c and VWF:Ac at 28, 32, 34, 36 weeks If they have not normalised for delivery then use DDAVP or Concentrate Type 3 Levels will not change in pregnancy Use concentrate

39 Delivery of pregnancy in VWD Written plan Document latest FVIII and VWF levels and response to DDVAP/Concentrate Advise on mode of delivery can be vaginal Advise on pre delivery treatment, if any Spinal anaesthesia only if documented normal levels Cord blood measurement of FVIII and VWF Post delivery levels fall over a few days Risk of post partum haemorrhage must be anticipated

40 Angiodysplasia Associated with type 2 and 3 VWD Presents with occult gastrointestinal bleeding Difficult to identify the source Endoscopy and capsule endoscopy useful Treat with VWF concentrate acutely Recurs try octreotide, lenalidomide, high dose atorvastatin, VWF prophylaxis

41 Heyde s Syndrome Aortic stenosis Acquired VWD Occult gastrointestinal bleeding Colonic angiodysplasia

42 Guidelines on management of VWD UK Laffan M, et al. British Journal of Haematology 2014; 167: USA Nichols WL, et al. Haemophilia 2008; 14: Italy Mannucci PM, et al. Blood Transfusion 2009; 7: Netherlands De Wee EM, et al. Seminars in Thromb & Hemost 2011; 37:

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