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Thrombosis in patients with inherited bleeding disorders

Mike Makris Sheffield, UK Areas to be discussed

1. Baseline risk 2. Concentrate related risk 3. Use of What is the baseline thrombotic risk in patients with inherited bleeding disorders? Baseline thrombotic risk in untreated patients with inherited bleeding disorders

• Little / No good data • Why is it so difficult to get good data – Based on case reports or case series assuming all cases published – Poor separation between baseline risk and concentrate related risk – Little attention to severity of bleeding disorder – Poor reporting of additional risk factors and age Reported cases (267) of in literature

Defect Prevalence Arterial thrombosis Venous thrombosis 1/1,000,000 13 12 FII 1/1,500,000 0 0 FV 1/1,500,000 1 8 FVII 1/600,000 6 24 FVIII 1/10,000 67 18 FIX 1/50,000 18 36 VWF 1/1,000 11 19 FX 1/2,000,000 0 0 FXI 1/1,000,000 30 5 FXIII 1/2,000,000 0 2

Girolami et al. JTT 2010; 29:299-302 Girolami et al. JTT 2014; 37:293-297 Girolami et al. JTT 2006; 21:175-178 EUHASS (European Safety Surveillance)

• Adverse event surveillance scheme • All adverse events including thrombosis • All products (70) • All inherited bleeding disorders • All severities • Sentinel centres in Europe (83 in 26 countries) • Prospective

• Started 1st Oct 2008 EUHASS 2008 – 30 September 2017

Events reported

Allergic reactions 165 Transfusion transmitted infections 0 Centres participating 80 New inhibitors 430 Countries participating 27 Recurrent inhibitors 49 Patients 38,804 Thromboses 205 Malignancies 536 Deaths 908

TOTAL 2293 EUHASS Thrombosis Reporting

• Prospective reporting – Less than 30 days since last concentrate • Actual time is reported – More than 30 days since last concentrate • Event types – Myocardial infarction – Angina (first episode only) – Thrombotic – TIA (first episode only) – – – Thrombophlebitis – Port thrombosis – Other - specify Thrombosis in patients who have had no concentrate in last 30 days

Oct 2008 – Dec 2015 Total number of events 63 35 6 Acquired haemophilia A 1 VWD type 1 6 VWD type 2 8 Afibrinogenemia 1 2 Factor VII 2 Factor XI 2 Thrombosis in patients who have had no concentrate in last 30 days

Oct 2008 – Dec 2015 Myocardial infarction 21 Thrombotic stroke 13 Angina (first ever episodes) 12 Transient ischaemic attack 7 Deep vein thrombosis 5 Arterial thrombosis 3 Portal vein thrombosis 1 Thrombosis (unspecified) 1 What is the thrombotic risk associated with concentrate treatment? Regulatory studies

• Highly detailed data but small number of patients. • For haemophilia A, B and VWD 71 studies reviewed by Coppola et al (Haemophilia 2012; 18:e173-187)

Disorder Patients Arterial Venous Thrombo Thrombotic Thrombotic (studies) thrombosis thrombosis -phlebitis AE/pt (%) AE/infusion % Haem A 4420 (45) 0 0 2 0.045 0.0002 Haem B 749 (15) 0 0 11 1.47 0.006 VWD 361 (11) 0 2 5 1.94 0.048 All 5528 (71) 0 2 18 0.36 0.00113

Thrombophlebitis: 15/18 at infusion site (12 on CI), 1 in leg and 2 no details given FIX concentrate and thrombosis

• Pre-1990 Definite association with PCC use especially after • No thrombogenicity excess in association with the pure plasma derived IX or recombinant standard or long acting products • Evidence for the thrombogenicity safety of the long acting products so far minimal 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 Concentrate for FVII deficiency

• Often not needed • 10% FVII usually haemostatic • Clinical history important

• Thrombosis was a problem in years 1-3 of EUHASS • Many less thromboses recently in EUHASS

• If you are going to use a concentrate • Use rFVIIa or pure FVII • Avoid PCC and APCC BPL FXI concentrate

• Not licensed • 1985-2001: UK plasma, post-2001: USA plasma • Bolton-Maggs (Lancet 1994; 344:748-9) – PE in 61 year old, 21 days post FXI for CABG – MI in 74 year old, 1 hour post FXI for epistaxis – MI in 66 year old, “a few hours” post FXI for – Stroke in 85 year old, 4 days post FXI for leg • Since 1993 antithrombin and heparin have been added to the product • 2013 update: No further thrombotic events reported to BPL LFB FXI concentrate

• Not licensed • French plasma source • Bolton-Maggs (Haemophilia 2014; 20:e349-351) – Since 2002, 12 thrombotic episodes, 5 of which were fatal – PE: 7, Stroke: 3, TIA:1, DIC: 1 – 8 had baseline FXI of <10IU/dl – 11 had other risk factors for thrombosis – All had <30u/kg FXI concentrate – LFB estimates 140 patients treated per year with LFB FXI concentrate • No FXIa in any of the batches of concentrate • No antithrombin or heparin in final product FXI concentrate and thrombosis

• Thrombogenic potential is very real • Often no treatment is required • Clinical history important • started pre-op or at time of anaesthesia is usually be sufficient • If you are going to use FXI concentrate, guide therapy with FXI levels

• Proposal: Manufacturers should maintain a register of all the patients receiving their product and whether they had a thrombosis or not in the 30 days post exposure FEIBA related thrombosis

Ehrlich et al , 2002 Aledort et al, 2004 Event Number Incidence (per 105 Number Incidence (per 105 infusions) infusions) DIC 7 1.77 3 1.55 MI 5 1.27 5 2.58 PE 2 0.51 2 1.03 CVA 0 0 2 1.03 Other 2 0.51 4 2.06 Total 16 4.05 16 8.24

Ehrlich: 10-year Baxter pharmacovigilance database (Haemophilia 2002; 8:83-90) Aledort: 3 years MedWatch database (JTH 2004; 2:1700-1708)

4.8% thrombotic risk in acquired hemophilia (Baudo F et al, 2012; 120:39-46) rFVIIa and Thrombosis

Neufeld EJ et al. Blood Reviews 2015; 29:S34-41 Antithrombotics in patients with inherited bleeding disorders

1. Post op thromboprophylaxis 2. Post PCI for acute coronary syndrome 3. In patients with AF Should you use thromboprophylaxis after major surgery in haemophilia A?

• Hermans et al. JTH 2010; 8:1138-1140 • 29 major orthopaedic • No heparin thromboprophylaxis • Ultrasound scans at 4-14 days • No clinical DVT • 3 subclinical distal DVTs – 2 resolved untreated – 1 in mild haemophilia A treated for 2 weeks • Conclusion: 10% subclinical DVT Post PCI in patients with bleeding disorders

• Always go for PCI if that would have been offered to a patient without bleeding disorder • Treat to 100% pre-PCI • Use radial artery approach • Use metal rather than drug eluting stent • Dual antiplatelet for 4-6 weeks and single for 1 year • Use lansoprazole or another PPI • Aim for a trough of 3-5% factor level Anticoagulation in AF in patients with inherited bleeding disorders

• Increasingly common • Bleeding disorder patients probably have some protection that is difficult to quantify • Use catheter ablation if possible • Use CHADS2-VASC score • Offer anticoagulation for score of 2 or higher • We use 2.5mg twice daily • All of our patients so far have had FVIII/IX of >5%

• Single patient with 2% FIX who needed cardioversion given apixaban 5mg bd, with maintenance of FIX above 30% for 6 weeks with daily FIX Schutgens R et al, Blood 2016; 128:2471-2474 Acknowledgement

• All the centre directors, data managers and nurses at the participating centres

• Funding: – 60% European Commission DG SANCO – 40% Baxter, Bayer, Biotest, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, SOBI/Biogen, BPL, LFB

This presentation arises from the EUHANET project which has received funding from the European Union, in the framework of the Public Health Programme.