Inherited Bleeding Conditions
Focus on New Treatment Paradigms
Catherine McGuinn, MD
Director Comprehensive Center for Hemophilia and
Coagulation Disorders at NYPH/ Weill Cornell
Disclosures
– Research support:
Baxalta, Biogen, Roche, Spark
– Medical Advisory Board
Baxalta
– I will be discussing off label use of
medications
Outline
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Overview
History
Diagnosis
Classification
Clinical Presentation
Management
New Therapies
VWD
Rare Bleeding Disorders
The Coagulation Cascade
Factor XII
HMWK
Factor XI
Factor XIa
Factor IX
Factor IXa
Factor VIIIa
Factor VIIa
Tissue Factor
Factor Xa
Factor Va
Factor X
II
Fibrinogen
Factor X
IIa
Fibrin
Rethink the approach
Willyard,C. Scientific America (2015)
The Royal Disease
Rogaaev et al. Hemophilia (2009)
www.sciencemag.org ( State Archived of Russian Federation)
www.scientificanemrica.com
Hemophilia is a X-linked disorder
One-third of patients with
hemophilia have new mutations
• 20,000 people
1 in 5,000 males (A)
1 in 20,000 males (B)
• 30% of cases have no
family history
Soucie, JM An J Hematology (1998)
Kukarni et al. Hemophilia (2009)
Women Can Have Hemophilia
• Lyonization of the normal X
chromosome
• Turner syndrome (XO)
• Father with hemophilia / mom
as a carrier
• vWD type 2N (Normandy)
Inversion 22 Inversion is the
most common genetic mutation
• Exact defect known: ~ 95%
• Mild-moderate hemophilia: Missense 85%
Missense
• Severe hemophilia
14%
Invsersion
43%
Frameshift
16%
Small
Deletion
15%
Gouw et al. Blood (2012)
Nonsense
Large 9%
Deletion
3%
• Free Genotyping
to Hemophilia
Community
• Bio-repository
patient samples
for future
research
http://www.mylifeourfuture.org/
Prenatal Diagnosis
• Ultrasound ( 16 weeks)
– Sex Determination
• CVS/ Amniocentesis
– Inversion 22 detection (11/15 wks)
– RFLP: chorionic villi/amnio (11/15 wks)
– 99% accurate if affected male/carrier
• Fetal cord blood for FVIII levels (18 wks)
Future – Free Fetal DNA
Tsui N B Y et al. Blood 2011;117:3684-3691
Hemophilia patients have poor
thrombin generation
Guy Young et al. Blood (2013)
Laboratory classification of severity
Severe
<1%
Moderate
1-5%
Mild
> 5 - 40%
ISTH SSC (2014)
Hemophilia Clinical Presentations
http://www.cdc.gov/ncbddd/hemophilia/data.html
Hemophilia Clinical Presentations
http://www.nlm.nih.gov
> 90% Experience Repeat
Acute Hemarthroses
Joint disease progression in
hemophilia
http://www.hemophilia.in/
Treatment Overview
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Factor replacement
DDAVP
Antifibrinolytics
Fibrin sealant
Stop the bleeding!!
High Priority @ Triage
Treat first 
Diagnostic testing later
Treat based on history even in
the absence of physical signs
Patients often bring their
clotting factor with them
Factor Replacement
• 1u/kg raises FVIII levels by 2%
T 1/2 life: 12 hrs
• 1u/kg raises FIX levels by 1%
T 1/2 life: 20-24 hrs
Dosing may be higher rFIX = 1.3 x pFIX
Advances in safe, effective, home
based therapy for hemophilia
Whole Blood/ FFP (1950’s)
Cryoprecipitate (1960’s)
Lyophilized FVIII /FIX (1970’s)
Viral Inactivation ( 1985-87)
Long Acting (2014)
HIV Infection impact of
hemophilia population
Jones and Ratnoff, 1991 http://www.niaid.nih.gov/topics/hivaids.
Treatment- Episodic
Therapy after bleeding
event
Long Term
Arthropathy
↓QoL
$$
Joint Outcome Study - randomized
control trial of prophylaxis
Joint Outcome Study - randomized
control trial of prophylaxis
Joint Outcome Study - randomized
control trial of prophylaxis
> 1/2 of joint abnormalities detected
by MRI were not apparent on x-ray
Joint Outcome Study - randomized
control trial of prophylaxis
Long Term Outcomes
Johannes Oldenburg Blood 2015;125:2038-2044
©2015 by American Society of Hematology
Prophylaxis : Long Term Goals
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Prevention of chronic arthropathy and sequelae
Prevention of intracranial and other serious bleeds
Prevention of pain and suffering
Improvement in individual/family QoL
Reduction in long-term societal costs through prevention of
disability, improved outcome, and maximization of human
potential
1. Shapiro AD, et al. The Role of Prophylaxis in Managing Hemophilia in Adult and Pediatric Populations. Available at:
http://cme.medscape.com/viewarticle/703176_print. Accessed July 6, 2010; 2. Fischer K, et al. Haemophilia.
2008;14(suppl3):196-201; 3. BerntorpE, et al. Haemophilia.2003;9(suppl1):1-4.
Barriers to Prophylaxis
Peripheral Access
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Non Surgical
No foreign body
Parents Teaching
Young Age
Central Access
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Surgery
Infection
Thrombosis
Ease of Access
What is ideal Target for Prophylaxis ?
Haemophilia
Volume 17, Issue 6, pages 849-853, 5 MAY 2011 DOI: 10.1111/j.1365-2516.2011.02539.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2516.2011.02539.x/full#f2
Inhibitors
• High-titer inhibitor: >5 BU
• Low-titer inhibitor: <5 BU
• Transient inhibitor: persists for 6-8 months
or less and usually low titer
White et al. Thromb Haemost 2001;85:560; Rothschild et al. Thromb Haemost 2000;84:145–146.
Inhibitors develop with median
of 14.5 exposure days
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International
Multicenter
Prospective
Randomized Controlled
Open Label Clinical Trial
Follow for 50 ED or 3 years
Peyvandi et al (2016)
Previously
Untreated
Patients ( PUP)
Plasma
Recombinant
All: 26.7 %
All: 44.5%
High: 18.5%
High: 28.4%
Recombinant Factor
1.87 Fold Higher Incidence Inhibitor
Inhibitor Treatment Options
• High dose Factor therapy
• APCCs
50-75u/kg for mild/mod bleeds, 75-100u/kg for severe
• Activated Factor VII
90 mcg/kg q2hrs vs 270mcg/kg q6hrs
• Immune tolerance: NOT BLEEDING treatment
Treating Bleeding : APCC
Disadvantages
• Not all patients respond
– 67%-75% of patients respond to APCC1,2 (50-80 U/kg)
• No in vitro assay to monitor effect
• Inhibitor anamnesis with some APCC products
• Thrombogenicity with prolonged frequent administration
1. Sjamsoedin et al. N Engl J Med 1981;305:717–721; 2. Abildgaard et al. Blood 1980;56:978–984.
Treating Bleeding : rFVII
Advantage
• 90% of patients respond to 90 µg/kg q2-3h
Disadvantages
• Absence of in vitro assay to monitor effect
– PT may shorten, but PT and FVII level do not predict clinical
response
• Dosing must be given at 2- to 3-hour intervals because of
short half-life
ITI Summary
• ITI is recommended for high-titer inhibitors;
35% of patients fail to respond
however, 20%-
– Often lengthy and difficult process
– International Immune Tolerance Induction Study
Hay and Dimichele, Blood, 2012
Factor IX Inhibitors
• Present in 3%-5% of patients with hemophilia
B
– Most common in patients with deletions or
nonsense or frameshift mutations of the FIX gene
– Anaphylaxis Presentation
– Proteinuria Complication
Katz et al. Haemophilia 1996;2:28–31.
Decision Making
Trough
Schedule
Other
Physical
Activity
Cost
Delivery
Personal PK
Immunogenicity
Infectious Risk
Long Acting Agents for Hemophilia
http://www.biopharminternational.com/biopharm/article/articleDetail.jsp?id=317577&sk=&date=&pageID=3
Hobbs, J. http://www.wikilite.com/wiki/index.php/File:Recycling_of_IgG_by_FcRn.jpg
http://www.transfusion.com.au/
Gene Therapy - Hemophilia
Journal of Thrombosis and Haemostasis
pages S133-S142, 19 JUN 2015 DOI: 10.1111/jth.12926
http://onlinelibrary.wiley.com/doi/10.1111/jth.12926/full#jth12926-fig-0001
Hemophilia B Gene Therapy
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10 patients
Single AAV Vector Infusion
Peripheral Vein
Factor IX 1-6% expression
3 years of follow up
No late toxic effects
Nathwani AC et al. N Engl J Med 2014;371:1994-2004.
Hemophilia B Gene Therapy
Active Gene Therapy Trials:
Factor IX
• Baxalta ( AAV8)
• Spark (AAV)
• St Jude ( AAV)
• Dimension Therapeutics ( AVV)
• UniQure (AVV5)
Factor VIII
• BioMarin (AAV)
Rethink the approach
Antithrombin Modulation
Ragni, NEJM (2015)
Emicizumab – ACE-910
Bispecific Antibody
Makris, Blood (2016)
Von Willebrand Factor
Mediates Interaction of platelets with vessel wall
– Collagen Binding
– Platelet Binding/Adherence
– Carrier for Factor VIII
Sadler, Blood (2008)
Von Willebrand Disease
• von Willebrand Factor is the carrier/stabilizer
of Factor VIII
• Absence/dysfunction of vWF leads to a bleeding
diathesis
– mucosal bleeding
– easy bruising
• In severe vWD, very low FVIII levels result in a
hemophilia phenotype
vonWillebrand Disease: Clinical
Characteristics
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Either sex affected
Common, under diagnosed
Range of clinical severities
Mucosal bleeding
Bruising
Menorrhagia
VWF Classification
Type
Description
1
Partial Quantitative Deficiency
2
Qualitative Defect
3
2A
Decreased Platelet Adhesion (↓ Multimers)
2B
Increased Platelet GP1b Affinity
2M
Decreased Platelet Adhesion (Normal Multimers)
2N
Decreased FVIII Binding
Virtual Complete Deficiency
Adapted Sadler et al. JTH
DDAVP
Contact pathway activation
Plasminogen activation via TPA
Release of vWF and FVIII from endothelial
cells
Increased platelet adhesion
platelet vWF
microparticle release
IIb/IIIa interaction
Treatment
Anti-fibrinolytics:
- E-Aminocaproic Acid (Amicar)
- Tranexamic Acid
WHF, Treatment of Hemophilia, No. 42 (2012)
Von Willebrand Disease Treatment
Ara D. Metjian Blood 2015;126:1975-1976
VWF Containing Concentrates
Product
Contains
Ratio
Alphanate
VWF/ FVIII
1.3 : 1
Plasma
Humate P
VWF/ FVIII
1.8 -2.4 : 1
Plasma
Wilate
VWF/ FVIII
1:1
Plasma
Von-Vendi
VWF
N/A
Recombinant
Neff et al. ASH (201t5)
Treatments
Product
Trade Name
Contains
AntiInfective
First Line
rFVIIa
NovoSeven
FVIIa
N/A
FVII
Deficiency/Inhib
itors
pd-FXIII/
rFXIII
Corifact/Tretten
FXIII
Yes
FXIII Deficiency
pd-FI
RiaSTAP
Fibrinogen
Yes
FI Deficiency
PCC
Profilnine (3)
Bebulin (3)
Kcentra (4)
II, IX,X, VII
Yes
FII Deficiency
VKFD
APCC
FEIBA
IIa, Ixa, Xa,
VIIa
Yes
Inhibitors
SD-FFP
Octaplas
All
Yes
FV, FXI
pd-FX
Coagadex
FX
Yes
Approved 10/15
pd-FXI
Hemoleven
FIX
Yes
Not FDA
Approved
*Blood
Bank
Rare Bleeding Disorders
• 3-5 % of Bleeding Disorders
• Autosomal
• Recessive
• Negative Family History / Consanguity
• Symptomatic Heterozygotes
• Variable Correlation with Level
• Ethnic Predominance:
– Ashkenazi Jewish ( Factor IX)
– Latinos ( Factor II)
• Lack of Evidence Based Management
T (1/2)
Coagulation Factor
FI
FII
FV
FVII
FVIII
FIX
FX
FXI
FXIII
Plasma Half Life ( Hours)
90
65
15
5
10
25
40
45
200
Treatments
Product
Trade Name
Contains
AntiInfective
First Line
rFVIIa
NovoSeven
FVIIa
N/A
FVII Deficiency
pd-FXIII
Corifact/Fibroga
mmin P
FXIII
Yes
FXIII Deficiency
pd-FI
RiaSTAP
Fibrinogen
Yes
FI Deficiency
PCC
Profilnine (3)
Bebulin (3)
Kcentra (4)
II, IX,X, VII
Yes
FII Deficiency
FX Deficiency
VKFD
APCC
FEIBA
Iia, Ixa, Xa,
VIIa
Yes
Inhibitors
No
FV, FXI
FFP
pd-FX
FX-BPL
FX
Yes
Clinical Trial
pd-FXI
Hemoleven
FIX
Yes
Not FDA
Approved
Second
Line
Fibrinogen Deficiency (FI)
• Quantitative
• Afibrongenemia
• Qualitative
• Dysfibrinogenemia / Hypofibrinogenemia
• Half Life: 2-4 days
• Therapeutic Level: ~1 g/L
Fibrinogen Deficiency (FI)
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Mucocutaneous
Soft Tissue
Joint Bleeding
Miscarriage
* Thrombosis Risk
Tx: pd- Fibrinogen Concentrate 50-100mg/kg
Risk: Allergic /Antibodies/ Thrombosis
Consider: Role of PPX ( Pregnancy/ ICH)
Cryoprecipitate
Anti-Fibrinolytic
Prothrombin (Factor II)
• Rare ( < 100 Case Reports) 1 per 1- 3 million
• Autosomal Recessive
– Type 1 : Hypoprothrombinemia < 10% -20%
– Type 2: Dysprothrombinemia
• Synthesis: Liver
• Vitamin K Dependent : Yes
* Acquired Deficiency ( Lupus AC/ Vit K)
Prothrombin (Factor II)
• Hemostatic Level: > 10 %
• Half Life: 3 -4 days
Treatment:
Fresh Frozen Plasma ( sd-FFP)
Prothrombin Concentrate Complex ( PCC)
Bebulin / Profilnine / Kcentra ( 4 Factor PCC)
Factor V
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“Parahemophilia”
1: 1 million estimated
Autosomal Recessive
Synthesis: Liver /Platelets
Activity Level % Limited Correlation w/ Bleed
Skin / Mucosal / Joint / Muscle / ICH
Factor V
• Half Life: ~ 36 hours
• Hemostatic Level: 10-20%
Treatment:
Fresh Frozen Plasma ( sd-FFP)
Platelets
*rVIIa, FEIBA, Liver Transplant
*Preclinical Testing of pd-FV Concentrate
Factor VII Deficiency
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Most Common “rare” bleeding disorder ~ 1/500,000
Autosomal Recessive
Variable Bleeding
Not well correlated with level
• Vitamin K Dependent
• Synthesis: Liver
• Shortest Half Life ( 4 – 6 hours)
* R/O Liver Disease/ Warfarin/ Vit. K Def.
Factor VII Deficiency
• Half Life: 4-6 hours
• Hemostatic Level : > 20 %
• Treatment Options:
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Vitamin K Supplementation
Recombinant Factor VIIa ( NovoSeven)
FFP
Prothrombin Complex Concentrates
*Clinical Trials: Long Acting rFVIIa
Factor X
• Rare (1/1,000,000)
• Autosomal Recessive
• Heterozygotes may manifest symptoms
• Synthesis: Liver
• Vitamin K Dependent : Yes
• Severe Bleeding
• ICH/ Mucocutaneous/ GI/ Joint
Factor X
• Half Life: 40-60 hours
• Hemostatic Level: > 40 %
• Treatment
– pd – FX concentrate (25 u/kg)
– Prothombinase Complex ( PCC) (20-30 u/kg)
– Fresh Frozen Plasma ( sd-FFP)
Factor XI Deficiency
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Bleeding severity not correlated with FXI level
Rarely spontaneous bleeding
Trauma / Injury Related Bleeding
 High Fibrinolysis
Ashkenazi Jewish  Prevalence ( ~ 9%)
• Risk Factor for Thrombosis
Factor XI
• Hemostatic Level: (?)
Treatment Goal: Goal ↑ Factor XI to 30-45%
• Treatment:
– FFP
– Factor XI concentrates ( Risk of Thrombosis)
* rVIIa ( low dose 15 - 30 ug/kg)
Factor XIII Deficency
• Fibrin-Stabilizing Factor
• Autosomal Recessive (Consanguinity)
• Rare: Finnish/ Swiss/ Arab
• Sx:
– Bleeding
• Umbilical Stump Bleeding
• ↑ICH Risk
– Recurrent Abortion
– Impaired Wound Healing
Factor XIII Deficiency
• Diagnosis:
– Normal PT/ PTT
– +/- Mild Prolongation of Thrombin Time
– ↑ clot solubility in urea
– Factor XIII Functional Assay
Factor XIII Deficiency
• Half Life: 9-12 days
• Hemostatic Level: ?? ( 2-5%  30%)
• Treatment:
– pd-Factor XIII Concentrate (Fibrogammin/Corifact)
– rFXIII (Tretten)
Combined Factor V/ VIII
• LMAN1 (lectin mannose binding protein 1)
• MCFD2 (multiple coagulation factor deficiency 2)
Encodes protein for processing/transport FV and FVIII
from the endoplasmic reticulum to the Golgi
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Rare ( < 100 cases)
Autosomal Recessive – Chromosome 18/2
FV and FVIII < 30%
Sx:
– Epistaxis / postsurgical / posttraumatic bleeding
Combined Factor V/ VIII
• Tx: Factor VIII concentrates
Fresh Frozen Plasama ( sd-FFP)
DDAVP
Vitamin K Dependent Deficiency
• Hereditary combined vitamin K-dependent
clotting factors deficiency (VKCFD)
– 2, 7, 9, 10 & Protein C, S
• Mutations:
– gamma-glutamyl carboxylase
– vitamin K2,3-epoxide reductase complex
• Rare (< 30 Kindred)
• Variable Severity
Rare Bleeding Disorders
PT
APTT
Fibrinogen
Thrombin Time
FII Deficiency


Normal
Normal
FV Deficiency
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
Normal
Normal
FVII Deficiency

Normal
Normal
Normal
FX Deficiency
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
Normal
Normal
FXI Deficiency
Normal

Normal
Normal
FXIII
Normal
Normal
Normal
Normal
Combine FV/FVIII


Normal
Normal
Vitamn K Factor Def 

Normal
Normal
Thank You !
Contributions from Beau Mitchell, MD