Rational for secondary prophylaxis in VWD

Transcription

1 Rational for secondary prophylaxis in VWD Susan Halimeh Medical Thrombosis and Haemophilia treatment Center, Duisburg, Germany Dr. med. Susan Halimeh

2 When is prophylaxis in patients with VWD recommended? 2 von Willebrand disease - Background Therapy Options Definition Prophylaxis and Literature Review Potential Indications to start Prophylaxis

3 Von Willebrand disease Most frequent congenital bleeding disorder approx. 1% of caucasian population Etiology: Reduced or defective production of VWF Dysfunction of VWF release Severity types Type 1 (normally mild phenotype) Type 2 (variable phenotype) Type 3 (severe phenotype) Acquired (rare; variable phenotype) 3

4 Options for clinical phenotyping Medical history of patient Family history Bleeding questionaires specific VWD score* specific questionaires for severity of menstrual bleeding (PBAC) * Rodeghiero et al. J Thromb Haemost 2005: 3;

5 When is prophylaxis in patients with VWD recommended? 5 von Willebrand disease - Background Therapy Options Definition Prophylaxis and Literature Review Potential Indications to start Prophylaxis

6 Von Willebrand disease Dual defect: Primary & secondary haemostasis is affected 1.Dysfunction of platelet adhesion 2.Reduction of factor VIII activity in plasma Therapeutic aim: Correction of both defects 6

7 Von Willebrand disease Therapeutic options Depending on type of VWD in case of Acute bleeding: DDAVP (p.r.n. + Antifibrinolytics) or VWF/FVIII-concentrate Joint bleeding: VWF/FVIII-concentrate prophylaxis Menorrhagia: Antifibrinolytics or VWF/FVIII-concentrate or Estrogenes Surgery: DDAVP (+ Antifibrinolytics) or VWF/FVIII-concentrate (+ Antifibrinolytics) DDAVP Vasopressin-Analogue 7

8 When is prophylaxis in patients with VWD recommended? 8 von Willebrand disease - Background Therapy Options Definition Prophylaxis and Literature Review Potential Indications to start Prophylaxis

9 Literature review Studies on Prophylaxis in VWD [ secondary prophylaxis : n=80] Lethargen S. Thromb Res 2006; 118 Suppl:S9-S11 Berntorp E. Haemophilia 2008; 14 Suppl 5:47-53 Mannucci P.M. et al. Blood Transfus 2009; 7: Halimeh S. et al. Thromb Haemost 2011; 105:

10 Prophylaxis in von Willebrand disease E. BERNTORP Malmö Centre for Thrombosis and Haemostasis, Malmö University Hospital, Lund University, Malmö, Sweden Haemophilia 2008; 14 Suppl 5:47-53 Primary / Secondary Long-term prophylaxis 10

11 Prophylaxis in von Willebrand disease E. BERNTORP Malmö Centre for Thrombosis and Haemostasis, Malmö University Hospital, Lund University, Malmö, Sweden Haemophilia 2008; 14 Suppl 5:47-53 For which bleeding type is long-term prophylaxis indicated? Which single dosis should be given? How often should VWF/FVIII-concentrate be given (Frequency)? When should prophylaxis be started? 11

12 Prophylaxis in von Willebrand disease E. BERNTORP Malmö Centre for Thrombosis and Haemostasis, Malmö University Hospital, Lund University, Malmö, Sweden Haemophilia 2008; 14 Suppl 5:

13 When is prophylaxis in patients with VWD recommended? 13 von Willebrand disease - Background Therapy Options Definition Prophylaxis and Literature Review Potential Indications to start Prophylaxis

14 1) To define indications for primary/secondary prophylaxis 14 Frequent clinically relevant bleeding episodes Joint- / muscular bleeds Anemia [Hr-QoL] Contraindication for DDAVP Consent of patient / parents

15 1) To define indications for primary/secondary prophylaxis 15

16 2) To investigate the impact of long-term VWF/FVIII replacement therapy on patients with VWD (Confirmed diagnosis of VWD types; contraindication for DDAVP): 16 Frequency of bleeding episodes Bleeding score Hemoglobin level Influence on VWF:Rco-/FVIII:C-levels

17 n=3 n=7 n=4 score > 2 n=34 n=2 n=6 n=2 Wilate n= 24 prophylaxis n= 32 Haemate n= 8 17 n=6

18 VWD type of n= 24 on long-term prophylaxis with Wilate n=3 n=7 n=4 n=2 n=6 n=6 n=2 n=2 Type 2U = unknown 18

19 2) To investigate the impact of long-term VWF/FVIII replacement therapy on patients with VWD (Confirmed diagnosis of VWD types; contraindication for DDAVP): 19 Frequency of bleeding episodes Bleeding score Hemoglobin level Influence on VWF:Rco-/FVIII:C-levels

20 Parameter Type 3 Type 1 & 2 Age at start of prophylaxis [years] 4 [0.1-23] 19 [0.1-38] Duration of prophylaxis [months] 26 [18-60] 22 [14-48] Bleeding frequency prior prophylaxis [per month] 4 [1-30] 4 [1-30] 00[0-2] [0-2] 1 [1-14] 2,5 [0-3] 2 [0-3] Bleeding frequency on prophylaxis [per month] Bleeding score prior prophylaxis Bleeding score on prophylaxis 0 [0-0] 20 1 [1-14] [0-0] 00 [0-0] 0 [0-0]

21 2) To investigate the impact of long-term VWF/FVIII replacement therapy on patients with VWD (Confirmed diagnosis of VWD types; contraindication for DDAVP): 21 Frequency of bleeding episodes Bleeding score Hemoglobin level Influence on VWF:Rco-/FVIII:C-levels

22 Modified Bleeding Score 0 to 3 [Rodeghiero et al. J Thromb Haemost 2005: 3; ] 22

23 Modified Bleeding Score 0 to 3 [Rodeghiero et al. J Thromb Haemost 2005: 3; ] Rating Bleeding symptoms 0: no bleeding 1: non severe episodes without need for medical intervention 2: episodes require medical attention, but no factor substitution or transfusion before andrequire 12 months after start of prophylaxis 3: episodes medical attention, treatment includes VWF/FVIII substitution or transfusion 23

24 Parameter Type 3 Type 1 & 2 Age at start of prophylaxis [years] 4 [0.1-23] 19 [0.1-38] Duration of prophylaxis [months] 26 [18-60] 22 [14-48] Bleeding frequency prior prophylaxis [per month] 4 [1-30] 1 [1-14] Bleeding frequency on prophylaxis [per month] 0 [0-2] 0 [0-0] Bleeding score prior prophylaxis 2,5 [0-3] 2 [0-3] 2,5 [0-3] 2 [0-3] 0 [0-0] 0 [0-0] Bleeding score on prophylaxis 0 [0-0] 24 0 [0-0]

25 2) To investigate the impact of long-term VWF/FVIII replacement therapy on patients with VWD (Confirmed diagnosis of VWD types; contraindication for DDAVP): 25 Frequency of bleeding episodes Bleeding score Hemoglobin level Influence on VWF:Rco-/FVIII:C-levels

26 Parameter Type 3 Type 1 & 2 11 [10-13] 12 [10-15] 11[10-13] 12[10-15] HB [g/dl] on prophylaxis 13 [12-15] 14 [ ] 13[12-15] 14[11-14,5] HB [g/dl] prior FVIII:C [%] prior 2 [0-4] 46 [21-60] FVIII:C [%] on prophylaxis 24 [4-65] 64 [29-79] VWF:RCO [%] prior 2 [0-4] 23 [8-51] VWF:RCO [%] on prophylaxis 10 [0-77] 40 [22-60] Trough levels before and during prophylaxis 26

27 2) To investigate the impact of long-term VWF/FVIII replacement therapy on patients with VWD (Confirmed diagnosis of VWD types; contraindication for DDAVP): 27 Frequency of bleeding episodes Bleeding score Hemoglobin level Influence on VWF:Rco-/FVIII:C-levels

28 Parameter Type 3 Type 1 & 2 HB [g/dl] prior 11 [10-13] 12 [10-15] HB [g/dl] on prophylaxis 13 [12-15] 14 [ ] FVIII:C [%] prior 2 [0-4] 46 [21-60] 2[0-4] 46[21-60] 24 [4-65] 64 [29-79] 64[29-79] 24[4-65] FVIII:C [%] on prophylaxis VWF:RCO [%] prior 2 [0-4] 23 [8-51] VWF:RCO [%] on prophylaxis 10 [0-77] 40 [22-60] Trough levels before and during prophylaxis 28

29 Parameter Type 3 Type 1 & 2 HB [g/dl] prior 11 [10-13] 12 [10-15] HB [g/dl] on prophylaxis 13 [12-15] 14 [ ] FVIII:C [%] prior 2 [0-4] 46 [21-60] FVIII:C [%] on prophylaxis 24 [4-65] 64 [29-79] VWF:RCO [%] prior VWF:RCO [%] on prophylaxis 2 [0-4] 23 [8-51] 23[8-51] 2[0-4] 10 [0-77] 40 [22-60] 10[0-77] 40[22-60] Trough levels before and during prophylaxis 29

30 82 patients with confirmed VWD diagnosis 32/82 patients on long-term prophylaxis n= 24 on Wilate n= 8 on Haemate 30

31 Prophylaxis dosis was tailored to the recovery for each patient % % rico vwf:ag F VIII prior 30 min 2h 24h 5y female, VWD type 2A 30 IU/kg Wilate 31 4y male, VWD type 1 30 IU/kg Wilate

32 Wilate n=24 patients Single dose 34 IU/kg [20-47] Frequency/week Patients (n) VWD type 2x 17 Type 1 3x 5 Type 2A 4x 2 Type 3 Weekly dosing 80 IU/kg [50-132] 32

33 Recovery based dose finding: successful pregancy outcome following two abortions % 140 Case: IU/kg Wilate y female, VWD type 1 80 [c.3467c>t; p.t1156m] rico vwfag modified ISTH score = 4 F VIII PBAC score = abortions before 0 prior 60 min 24h Day 2 of of menstruation 33 Patient not included in trial; data from: Dr. Halimeh, Gerinnungszentrum Rhein-Ruhr, Duisburg, Germany & UK-SH Gerinnungsambulanz Prof. Dr. Nowak-Göttl

34 Recovery based dose finding: successful pregancy outcome following two abortions von Willebrand factor antigen [%] Ristocetin cofactor activity [%] vwf:rico [%] 275 vwf:ag [%] year-old female VWD type 1 [c.3467c>t; p.t1156m] median course during pregnancy healthy women [n=20] 34 Patient not included in trial; data from: Dr. Halimeh, Gerinnungszentrum Rhein-Ruhr, Duisburg, Germany & UK-SH Gerinnungsambulanz Prof. Dr. Nowak-Göttl gestational weeks pp FVIIIAg pp FVIIIAG week 35 FVIIIAg week FVIIIAG week FVIIIAG week IU/kg Wilate /week to partus 10 FVIIIAG week 15 pp 0 FVIIIAg week 7 to Rico post partum 30 Rico week 35 Bleeding event 20 Rico week IU/kg Wilate /week 15 Rico week Rico week Rico week 7 to 10 50

35 Summary and take home message -1- potential indications for initiating prophylaxis Clinically relevant bleeding while on-demand treatment Recurrent bleeding from nose and mouth Joint-/muscular bleeding Menorrhagia Persistent anemia [reduced Hr-QoL] Gastrointestinal bleeding contraindication: DDAVP 35

36 Summary and take home message -2- All patients in this patient cohort benefited from long-term prophylaxis. Bleeding frequency, Bleeding Score, Hb, VWF:Rco, FVIII:C, quality of life was improved. No allergic reaction or inhibitor development was observed in n=24 patients using Wilate. Concomitant medication was used in n=1/24 (4,2%). Individual decision between patient/parents and physician! 36

37 Thank you 37 Dr. med. Susan Halimeh gerinnungszentrum rhein-ruhr

38 GZRR 3 doctors Diagnostic und therapy of all coagulation disorders, new patients/week 2 study coordinators 36 members of staff Dr. med. Hannelore Rott gerinnungszentrum rhein-ruhr

39 39 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

40 40 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

41 41 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

42 42 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

43 GZRR 43 Dr. Susan Halimeh

44 Site 44 44