Course at the SISET Training Center

Florence, 26-30th September 2016

Management of Inherited von Willebrand Disease:

Toward a more evidence-based approach

Augusto B. FEDERICI

Hematology and Transfusion Medicine

Luigi Sacco University Hospital, University of Milan

augusto.federici@unimi.it

Employment NONE

Research support NONE

Scientific advisory board BAXALTA CSL-BEHRING, GRIFOLS,

KEDRION-LFB, OCTAPHARMA, WERFEN-IL

Consultancy NONE

Speakers bureau BAXALTA, CSL-BEHRING, GRIFOLS,

KEDRION-LFB, OCTAPHARMA, WERFEN-IL

Major stockholder NONE

Patents NONE

Honoraria BAXALTA CSL-BEHRING, GRIFOLS,

KEDRION-LFB, OCTAPHARMA, WERFEN-IL

Travel support NONE

Other NONE

Disclosures:

A.B. Federici

Milestones on VWD Management

(1926-2006)

1926

1951

1964

1971

1973

1977

1982

1985

1992

1994

2002

2006

First description by Erik von Willebrand

Cross transfusion by HA plasma in VWD

Pool’s cryoprecipitate in VWD

Immunologic difference of HA and VWD

Synthesis of VWF by cultured EC

First report on the use of DDAVP in VWD

Epidemiology of VWD in general population

Discovery of VWF gene by four laboratories

First PK trials with FVIII/VWF concentrates

Classification of VWD

National guidelines for VWD management

Molecular & clinical markers of VWD type 1

Milestones on VWD Management

(2006-2016)

2006

2008

2011

2013

2014

2015

2015

2016

2016

Updated Classification of VWD by ISTH

US Recommendation on VWD Management

ISTH Bleeding Assessment Tool (BAT)

PK and Safety of Recombinant VWF

BS and VWF in Clinical Outcomes in VWD

Prospective data about Prophylaxis in VWD

Novel tests Platelet-Dependent activities

More automatic lab diagnosis of VWD

Recombinant VWF available in US (FDA)

First Publication about VWD patients

By Erik A. von Willebrand (1926)

Erik Adolf von Willebrand (1870-1949)

The Pedigree of the First VWD Family

Located in Foglo

Classification of VWD Types

Based on Several Assays

NIH US Guidelines

• The most common inherited bleeding disorder

• More women VWD despite autosomic inheritance

• Type 1 VWD is the most frequent type

• Type 3 VWD is the most severe form

• Gastrointestinal bleeds occur only in severe VWD

• DDAVP is the treatment of choice in most VWD

• VWF/FVIII concentrates are always efficacious

Common Concepts reported in VWD:

Are all of them really true?

• Improve tests for VWF activity

• Identify risk factors of bleeding in VWD

• Better diagnose & treat GI bleeding

• Monitor VWF concentrates in surgery

• Identify & treat anti-VWF antibodies

• Indications & protocols of prophylaxis

Current Challenges and Unmet Needs

In VWD Management

List of Clinical and Laboratory Tools

Used for VWD Diagnosis

Basic Tests

Patient & Family History

Bleeding Score

Bleeding Time

PFA 100

PTT

FVIII:C

Specific tests

VWF:Ag

VWF:RCo

VWF:CB

VWF:RCo/Ag

VWF:CB/Ag

VIII:C/VWF:Ag

Additional tests

RIPA test

VWF:FVIIIB

Multimeric analysis

Molecular genetics

More Than One Test Always Needed

Criteria for Correct Diagnosis

(Bleeding History, Low VWF Activity, Inheritance)

Tosetto et al JTH 2006

Platelet

GPIb

A1

C C C C

A2

SubEndothelium Collagen I and III

Collagen VI

Heparin

Sulphatide

VWF:RCo

VWF:CBA3

ADAMTS 13

W

W

WI:1

III:3W

I

II

III

Platelet Dependent-VWF Activity(Nomenclature and Methodology)

Bodó et al on behalf of ISTH-SSC-SC on VWF JTH 2014

Flow chart for VWD Diagnosis

Used in Italian Registry

• VWD is the most common inherited bleeding

disorder and is due to quantitative (VWD3 &

VWD1) and/or qualitative (VWD2A, VWD2B,

VWD2M, VWD2N) defects of VWF: in severe

VWD3, VWD1 & VWD2N FVIII is also reduced

• Despite the complex and heterogeneous nature

of the VWF defects, nowadays all VWD types

can be managed efficiently in most patients.

VWD: what do we need to know

Background 2016 (1)

• However, correct VWD diagnosis & classification

cannot be always available in several Centers

to provide the best therapeutic approach.

• Differently from HA easily classified (severe,

moderate, mild) by baseline FVIII levels, VWD

severity is not well defined within types so far.

VWD: what do we need to know

Background 2016 (2)

• Identify patients at risk of bleeding

• Better diagnose & treat GI bleeding

• Monitor VWF concentrates in surgery

• Indications & protocols of prophylaxis

• Identify & treat anti-VWF antibodies

VWD: what do we need to know

Current challenges in VWD

• Type and/or severity of VWD patients:

baseline VWF & FVIII levels

• Clinical settings: acute bleeding

surgery

prophylaxis

• VWF Concentrates: VWF:FVIII ratios

Management of VWD patients

Three main factors

• Clinical and lab data obtained in VWD from the

registries and/or retrospective studies are not

always reliable due to non correct lab test for

VWD diagnosis & classification at local sites

• Therefore only prospective studies on VWD with

lab parameters tested by expert centers should

be considered in clinical trials

Move to evidence-based VWD management

The 10-year experience (2004-13)

• RENAWI-2 is a prospective observational cohort

study carried out in VWD patients with centrally

confirmed diagnosis and followed-up at 6

Hemophilia Centers, members of the Italian

Association of Hemophilia Centers (AICE)

• This study is the continuation of the previous

retrospective Italian Registry on VWD (RENAWI-1)

Design of RENAWI-2

To evaluate the incidence, types and severity of

spontaneous bleeding episodes requiring DDAVP

and/or VWF/FVIII concentrates in large cohort of

VWD patients: i.e. how to characterize bleeding

phenotype in different VWD types and to predict

clinical outcome in these patients.

Aims of RENAWI-2

1,529

1,234VWD confirmed

diagnosis

796included

in follow-up

295unmet

inclusion criteria

437not included

In follow-up

Cross sectional study

[RENAWI-1]

16 centers

Prospective study

[RENAWI-2]

6 centers

VWD1(n = 457)

VWD2A(n = 65)

VWD2B(n = 56)

VWD2M(n = 169)

VWD3(n = 49)

VWD1(n = 23)

VWD2A(n = 10)

VWD2B(n = 5)

VWD2M(n = 12)

VWD3(n = 25)

75bleeding

at follow-up

Flow Chart of the Italian Studies on VWD:

From RENAWI-1 to RENAWI-2

Heterogeneity of VWD Patients

Based on Cohort Studies

 

VWF:RCo <10 U/dL

+ FVIII:C < 20 U/dL

VWF:RCo 10-30 U/dL

+ FVIII:C 20-40 U/dL

VWF:RCo 30-50 U/dL

+ FVIII:C 40-70 U/dL

VWD Severe Forms:

VWD1, VWD2A, VWD3

VWD Moderate Forms

VWD1, VWD2B, VWD2M, VWD2N

Bleeders: VWD1 Mild Forms

Non bleeders:

Low Levels of VWF

Diagnosed VWD: the tip of the iceberg?

Federici AB et al, Blood 2014; 123: 4037-44.

Heterogeneous VWD Cohort:

Italian Registries (RENAWI)

Bleeders versus Non Bleeders

• For different risk categories, actual incidence

of mucosal and non mucosal bleedings was

calculated in the VWD followed for 1 year

• A Cox’s proportional hazard model was used to

assess the risk of bleeds in different categories:

BS = < 5; 5-10; > 10;

BT = < 10’; 10’-20’; > 20’(min);

VWF:RCo = < 10; 10-30; 31-54 (U/dL);

FVIII:C = < 20; 20-40; > 40 (U/dL).

Methods to assess severity of VWD

Prospective registry (RENAWI-2)

Bleeding Phenotype in VWD

Evidence-Based Methods

Federici AB et al, Blood 2014; 123: 4037-4044

Restricted Cubic Spline Curve Cox’s Proportional Hazard Model

Summary of results (1)

Prospective study (RENAWI-2)

Federici et al. Blood, 2014

In the prospective study based on 797/1234 (66%)

of the retrospective registry (RENAWI-1).

BS > 10

BT > 20’

VWF:RCo < 10 U/dL

FVIII:C < 20 U/dL

Parameters

6.80 (3.80-12.30)

5.67 (3.22-10.05)

3.27 (1.77-6.06)

4.20 (2.43-7.26)

Hazard ratio (95% CI)

are associated with high risk of bleeding

• By multivariate model including all variables,

BS > 10 [HR = 5.5 (2.8-10.8)] was the most

significant determinant of bleeds

• The incidence of bleeding at one year (%/year)

correlates with BS and increases significantly

from VWD1 (5.2), VWD2M (7.3), VWD2B (9.6)

to VWD2A (17.2) and VWD3 (80.4)

Summary of results (2)

Prospective study (RENAWI-2)

Federici et al. Blood, 2014

Bleeding survival (1)

VWD types versus BS and VWF:RCo

Federici AB et al, Blood 2014; 123: 4037-4044

Federici AB et al, Blood 2014; 123: 4037-4044

Bleeding survival (2)

BS in VWD1 (VWF:RCo) and VWD3 (FVIII)

Bleeding Phenotype in VWD typesType of Bleeding Symptoms

The bleeding score helps to predict clinical outcomes

in adult patients with VWD.

High bleeding scores correlate with intensive on

demand therapy and may identify cases requiring

regular prophylaxis

Conclusion of RENAWI-2

• DDAVP (endogenous VWF)

• VWF Concentrates (+ or – FVIII)

• Additional support (TA, Hormones)

Management of VWD

Therapeutic approaches

Summary on Desmopressin

(DDAVP: 1977-2016)

• DDAVP is a long-acting V2 receptor-selective analog of AVP.

• DDAVP has complex effects on the coagulation process with both pro-

hemostatic (dominant) and anti-fibrinolytic effects (t-PA).

• Doses of DDAVP required for effects on coagulation are leading to peak

plasma concentrations ~ 50-200 times above maximally anti-diuretic

plasma concentrations.

• High intra-individual reproducibility of desmopressin-induced increase

in FVIII plasma concentration.

• Tachyphylaxis of DDAVP-induced increase in FVIII and VWF plasma

concentrations by daily dosing is moderate, limited, and do not lead to

a clinically significant impairment of the hemostatic effects.

Biological

Response

in VWD1

No Biological

Response

in VWD2A

(Ruggeri et al Blood 1982)

DDAVP TreatmentBiological Response to Predict Effective Therapy

Blood 2008; 111: 3531-39

Blood 2004; 103: 2032-38

DDAVP TreatmentBiological Response to Predict Effective Therapy

Biological response to DDAVP

in VWD1 (n = 26)

Tachyphylaxis in Repeated Doses

FVIII VWF:RCo

Repeated DDAVP Administrations:

Lower Effect of the Drug

• DDAVP is considered the treatment of choice of VWD

but questions about its efficacy and safety remain

when DDAVP is repeated in bleeds and surgery.

• Most hematologists prefer to use VWF concentrates

during deliveries and major surgery also in VWD

patients proven to be responsive to DDAVP.

• No prospective data available to correlate biological

response with efficacy (See: Pro-Des-Will Study 2016).

Evidence-based DDAVP efficacy-safety

Current Data in 2016

• Treatment Drug regimens: DDAVP was given

intravenously or subcutaneously (0.3 ug/Kg) or by

nasal spray (4 ug/Kg) according to preparations

available in the different countries;

• Anti-fibrinolytic agents (Epsilon-amino-caproic acid,

EACA or Tranexamic Acid, TA) could be used

together with DDAVP with standard doses;

• In case of major surgery, DDAVP was given together

with TA using a 3dayOn-4dayOff-3dayOn schedule

according to a pre-scheduled scheme.

DDAVP in inherited VWD

Methods: (III)

0 12 24

1 2 3 4 5 6 7 8 9 10

2 3 4 5

DDAVP ev o sc1 6 7 8

Tranexamic Acid

2 6

Surgery

Regimen of DDAVP administration with TA

in major surgery (3+4-3+)

2006-2016

BIOSTATE

WILATE

VONVENDI

(US)

List of VWF concentrates used in

Clinical practice (1982-2016)

Federici AB and Thompson A. Haemophilia, 2006

List of VWF concentrates used in

Clinical practice (1982-2006)

VWF/FVIII ConcentratesIn VWD3 patients

< 3

10

35

8

28

61

20

45

82

24

78

90

75

90

95

120

165

85

< 3

< 3

7

VWF:RCo =

VWF:Ag =

FVIII:C =

VWF/FVIII Concentrates in VWD3

WILATE PK studies

0

25

50

75

100

125

150

175

200

0 12 24 36 48 60 72

Hours post-injection

IU/d

l

vWF:RCo

vWF:Ag

FVIII:C

FVIII / vWF (60 IU/kg vWF:RCo)

0

25

50

75

100

125

150

175

200

0 12 24 36 48 60 72

Hours post-injection

IU/d

l

vWF: RCo

vWF:Ag

FVIII:C

WILFACTIN (60 IU/kg vWF:RCo)

VWF/FVIII WILFACTIN

VWF Concentrates with or without FVIII:

Pharmacokinetic (PK) studies in VWD3 (n = 6)

Days

Before D 2

n = 12

D 3

n = 11

D 4

n = 6

D 5

n = 6

D 6

n = 6

0

20

40

60

80

100

120

140

160

180

200

IU/d

l

endogenous FVIII

trough value for VWF:RCo

Days

Before

n = 26

D 2

n = 23

D 3

n = 18

D 4

n = 12

D 5

n = 11

D 6

n = 7

VWF and FVIII plasma levels (median) & repeated infusions of WILFACTIN

normal (hemostatic) FVIII levels

are obtained after repeated VWF injections

French studyEuropean study

Post-operative VWF/FVIII plasma levels

rhVWF pdVWF

Expressed in CHO cells Synthesized in endothelial cells and

megakaryocytes

Pro-peptide removal mediated in vitro

through exposure of the pro-VWF to a

second recombinant protein (the pro-

peptide-processing enzyme furin)

Post-translational modification of pro-peptide removal occurs intra-cellularly during passage of the protein to the Golgi and post-Golgi compartments

No exposure to ADAMTS13

intact VWF subunits

ultralarge VWF multimers present

Consists of VWF subunits that have been exposed to plasma ADAMTS13

subunits cleaved at TYR1605-MET1606

Ultralarge VWF multimers absent

Glycosylation: ABO blood group

glycans absent

Glycosylation: ABO blood group

glycans present

Plasma-derived VWF concentrate contain

other proteins incl. ADAMTS13

Differences between rhVWF (VONVENDI) &

plasma-derived VWF

* Low resolution agarose (1% Seakem) / Samples adjusted to VWF:Ag content

** SDS-PAGE / Immunoblot with polyclonal anti-VWF Ab / Samples undiluted

176 kDa

dimer

high

low

15

min

30

min

1

hr

3

hrs

6

hrs

9

hrs

12

hrs

24

hrs

28

hrs

32

hrs

48

hrs

72

hrs

96

hrs

VWF multimer analysis*

ADAMTS13 subunit cleavage products**

VWD

Type 2A

rhVWF multimers and ADAMTS13 cleavage

Questions?

augusto.federici@unimi.it

VWD Management: what do we need to know

Current perspective 2016