Rational for secondary prophylaxis in VWD

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

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

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

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; 2619-2626 4

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

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

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

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

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; 7:117-12 Halimeh S. et al. Thromb Haemost 2011; 105: 597-604 9

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

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

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 12

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

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

1) To define indications for primary/secondary prophylaxis 15

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

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

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

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

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]

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

Modified Bleeding Score 0 to 3 [Rodeghiero et al. J Thromb Haemost 2005: 3; 2619-2626] 22

Modified Bleeding Score 0 to 3 [Rodeghiero et al. J Thromb Haemost 2005: 3; 2619-2626] 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

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]

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

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 [11-14.5] 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

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

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 [11-14.5] 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

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 [11-14.5] 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

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

Prophylaxis dosis was tailored to the recovery for each patient % % 100 90 80 70 60 50 40 30 20 10 0 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

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

Recovery based dose finding: successful pregancy outcome following two abortions % 140 Case: 120 20 IU/kg Wilate 100 39 y female, VWD type 1 80 [c.3467c>t; p.t1156m] rico 60 40 20 vwfag modified ISTH score = 4 F VIII PBAC score = 450 2 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

Recovery based dose finding: successful pregancy outcome following two abortions von Willebrand factor antigen [%] Ristocetin cofactor activity [%] vwf:rico [%] 275 vwf:ag [%] 300 250 250 225 200 200 175 150 150 125 100 100 75 50 39-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 25 30 35 gestational weeks pp FVIIIAg pp FVIIIAG week 35 FVIIIAg week 30 20 FVIIIAG week 25 15 FVIIIAG week 20 20 IU/kg Wilate /week to partus 10 FVIIIAG week 15 pp 0 FVIIIAg week 7 to 10 35 Rico post partum 30 Rico week 35 Bleeding event 20 Rico week 30 10-15 IU/kg Wilate /week 15 Rico week 20 10 Rico week 15 25 Rico week 7 to 10 50

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

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

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

GZRR 3 doctors Diagnostic und therapy of all coagulation disorders,120 150 new patients/week 2 study coordinators 36 members of staff 38 38 Dr. med. Hannelore Rott gerinnungszentrum rhein-ruhr

39 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

40 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

41 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

42 Dr. med. Susan Halimeh gerinnungszentrum rheinruhr

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