management of hemophilia with emphasis on bypassing agents

1. - Dr. Pooja Hurkat

2. Overview
• Facts
• Hemophilia defined
• Epidemiology
• Pathophysiology
• Etiology
• Diagnosis
• Relationship of bleeding severity
and clotting level
• Etiological classification
• Clinical manifestation and
complication
• Chronic complication
• Major advances in treatment and
their associated outcomes
• Treatment consideration and options
• Treatment of hemophilia A
• Treatment of Hemophilia B
• Factors contributing to inhibitor
development
• Inhibitor diagnosis
• Current treatment strategies of patients
who develop inhibitors
• How are inhibitors treated
• Mechanism of action of Bypassing agents
• BPA prophylaxis regimen
• Choosing a BPA
• When to discontinue BPA
• Comparison of available BPA agents
• Pros and cons of BPA
• Inhibitors under clinical trial
• Case study
• BPA in News
• Current outcomes and remaining
challenges in therapeutic strategies
• Novel therapies
• Gene therapy
• Guidelines in management of hemophilia

3. https://www.hemophilia.org/About-Us/Fast-Facts
Royal disease
Hemophilia B, 1
in 25,000 to
30,000 males
Worldwide
incidence
> 400000
Affects both
men and women
75% of patients
receive
inadequate
treatment
Currently no
cure for
hemophilia
von Willebrand
disease most
common bleeding
disorder.
Hemophilia A
occurs in 1 in
5,000 male births

4. Hemophilia is an X-linked congenital bleeding disorder caused by
a deficiency of coagulation factor VIII (FVIII) (in hemophilia A)
or factor IX (FIX) (in hemophilia B). The deficiency is the result
of mutations of the respective clotting factor genes.
Hemophilia defined

5. Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost 2012; 38:727.
Shetty S. Haemophilia - diagnosis and management challenges. Mol Cytogenet 2014; 7:I44.
WHF estimates
43% hemophilia
population lives in
India, Bangladesh,
Indonesia, and
China
Hemophilia B
1 in 30,000 live
male
Hemophilia A
1 in 5000 live
male
Hemophilia occurs in all ethnic groups and throughout the
world.

6. Pathophysiology of blood coagulation
https://nurseslabs.com/hemophilia/

7. Etiology
BleedingDisorders.DeniseM.Goodman,MD,MS;AlisonE.Burke,MA;EdwardH.Livingston,MD.JAMA:2012;308(14):1492

8. Screening tests
Complete blood Count
Activated partial Prothrombin time (APTT)
Prothrombin test (PT)
Fibrinogen test
Clotting factor test

9. Relationship Of Bleeding Severity to
Clotting Factor Level
Severity Percent of
patients
affected
Percent normal factor
level
Bleeding
Episodes
Severe (50-70%) < 1 IU/dL
(< 0.01IU /mL)
< 1% of normal
Bleeding after
trivial injury or
spontaneous
Moderate (10%) 1-5 IU/dl (0.01-0.05 IU/ml)
or
1-5% of normal
Bleeding after
minor injury;
occasional
spontaneous
bleeds
Mild 30-40% 5-40 IU/dl (0.05-0.40
IU/ml) or
5-<40% of normal
Following major
trauma, surgical
or dental
procedure
Guidelines For The Management Of Hemophilia ‹. World Health federation 2012

10. Etiological Classification
Hemophilia A Hemophilia B Hemophilia C Acquired
factor
deficiencies
Inhibitors
Inherited
deficiency of
factor VIII; an
X-linked
recessive
disorder.
Inherited
deficiency of
factor IX also
called Christmas
disease; an X-
linked recessive
disorder.
Inherited
deficiency of
factor XI (factor
11); also called
Rosenthal
syndrome; an
autosomal
recessive disorder.
Acquired
coagulation
factor
deficiencies
caused by an
autoantibody
(often to
factor VIII)
are sometimes
referred to as
acquired
hemophilia..
In hemophilia,
inhibitor refers
to an
autoantibody
that typically
forms in
response to
infused factor.
Inhibitors are
most common
in individuals
with very low
baseline factor
levels.

11. Clinical Manifestation and Complication
Easy Bruising Nosebleeds Bleeding from the gums
Hematuria Prolonged bleeding with cuts Bleeding into joints or muscles
• Heavy or abnormal menstrual periods
• Bleeding into critical organs

12. Chronic Complications
I. Musculoskeletal complications:
Chronic hemophilic arthropathy; Chronic synovitis; Deforming arthropathy;
Contractures; Pseudo-tumour formation (soft tissue and bone); Fracture
II. Inhibitors against FVIII/FIX
III. Transfusion-related infections of concern in people with hemophilia:
Human immunodeficiency virus (HIV); Hepatitis B virus (HBV); Hepatitis
C virus (HCV); Hepatitis A virus (HAV); Parvovirus B19;
Others

13. Major advances in therapy for hemophilia
and their associated outcomes.
Pre- Replacement
Therapy
• Supportive care only
• Hospital or clinic based
care
• Recurrent Acute and
chronic Pain
• Debilitating joint disease
• High Mortality
• Definitive bleed
prevention
• Home based care
until curative
treatment
• Inhibitor risk
eliminated
• No further
morbidity from
joint disease
• No bleeding
related mortality
Replacement Therapy
Non-Replacement Therapy
Gene Therapy
• Effective Blood
treatment and prevention
• Home based care
(high to low intensity)
• Inhibitor risk emerges
• Reduced morbidity from
joint disease
• Low mortality
• Effective bread
treatment and
prevention
• Home based care
(Low intensity,
Liberation from IV
infusion)
• Inhibitor risk
ameliorated
• Reduced morbidity
from joint disease
• Low mortality
On
demand
Prophylaxis
Steven W. Pipe. New therapies for hemophilia. American Society of Hematology. 2016. 650-656

14. Considerations
Goal: Rapid and
effective replacement of
missing coagulation
factor
Approach: Comprehensive
hemophilia treatment center
staffed with multidisciplinary
expert team
Strategies: Episodic or on demand
factor replacement.
Prophylaxis
Options
Replacement of missing
clotting protein: factor
VIII and IX
DDAVP (IV,intranasal) in
mild FVIII deficiency
Adjunctive therapies:
Antifibrinolytic agents:
Amicar/lysteda
Supportive measures:
“RICE”-rest, ice, compression
and elevation
Immobilization
Hemophilia facts. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed March 2018.
Types of Bleeding Disorders. National Hemophilia Foundation Web site. https://www.hemophilia.org/Bleeding‐Disorders/Types‐of‐Bleeding‐Disorders. Accessed March 2018.

15. Treatment of Hemophilia A
Treatment option Dosage
FVIII concentrates • Vials of factor concentrates are available in
dosages ranging from approximately 250 to 2000
units each.
• Each FVIII unit per kilogram of body weight
infused intravenously will raise the plasma FVIII
level approximately 2%.
• The half-life is approximately 8–12 hours.
Cryoprecipitate/fresh frozen
plasma
• Only use cryoprecipitate if factor concentrates are
not available.
• Cryoprecipitate is best prepared from repeatedly
tested and virus-negative donors.
• FVIII content per bag of cryoprecipitate is 60-
100 units (average - 80 units) in a volume of 30-
40 ml.
• One ml of fresh frozen plasma contains 1 unit of
factor activity
Desmopressin (DDAVP) • DDAVP is useful in the treatment of persons with
mild hemophilia who have a 5% or
• greater FVIII level and who have been shown to
be responsive in pre-tests.
Guidelines for the Management of Hemophilia

16. Treatment of Hemophilia B
Treatment option Dosage
FIX concentrates • Vials of FIX concentrates are available in doses
ranging from approximately 300 to 1200 units
each.
• Each FIX unit per kilogram of body weight
infused intravenously will raise the plasma
• FIX level approximately 1%. The half-life is
about 18-24 hours. Verify
Fresh frozen plasma (FFP) • FIX levels above 25% are difficult to achieve. An
acceptable starting dose is 15-20 ml/kg.
• Solvent/detergent-treated FFP is available in
some countries.
Antifibrinolytic agents • Due to increased risk for thromboses,
antifibrinolytic agents, either as primary or
adjunctive therapy, are not recommended for
treatment of patients with FIXdeficiency already
receiving large doses of prothrombin complex
concentrates.
Guidelines for the Management of Hemophilia

17. Factors contributing to inhibitor development in
hemophilic patients.
Multiple genetic and environmental factors interact during the first exposures to
factor concentrate replacement treatment. Most data have been obtained from
studies in hemophilia A patients, who develop inhibitors with higher frequency than
those with hemophilia B.

18. How are inhibitors diagnosed?
• Inhibitors are often suspected during a routine blood test called the
activated partial thromboplastin time (APTT).
• In order to confirm the diagnosis, a Bethesda assay, or a
modification thereof, the Nijmegen method, is performed. This test
can determine the strength (titer) of the inhibitor.
• Inhibitor levels vary from one individual to another and can also
vary within the same person over time.
• The amount of inhibitors in a person's blood is measured in
Bethesda Units (BU) and referred to as “high titer” (more than 5
BU) or “low titer” (less than 5 BU).
Inhibitors are also classified as “low responding” or “high responding”
according to how strongly the person's immune system reacts to factor
concentrates based on memory from a previous encounter - this is called the
anamnestic response.

19. Current treatment strategies for patients with
hemophilia who develop inhibitor

20. How are inhibitors treated?
https://www.cdc.gov/ncbddd/hemophilia/documents/Inhibitor-Treatment.pdf
Strategies
Immune tolerance induction With the goal of getting rid of the inhibitor, factor
is given (infused into the bloodstream through a
vein) regularly over a period of time until the
body’s immune system is trained to accept the
factor without trying to destroy it. It is effective
in many, but not all patients.
Treating and preventing bleeding
events
High-dosage clotting factor
concentrates
If factor still works, but maybe not as well, the
dose or frequency of infusing the factor can be
increased to overcome the inhibitor..
Use of bypassing agents These medications help the blood form normal
clots in people with inhibitors, without increasing
the amount of inhibitor in the blood. Bypassing
agents do not replace the missing clotting factor.
Instead, they correct the clotting process by
going around (or bypassing) the factor that does
not work because of the inhibitor. Bypassing
agents can also be given on a routine schedule to
prevent bleeding.

21. Mechanism of action of bypassing
agents (BPA)
Hoffman M, Monroe DM. Platelet binding and activity of recombinant factor VIIa. Thromb Res 2010; 125 (Suppl. 1): S16–18.

22. Choosing a BPA
• Multiple factors, including the phase of Immune tolerance induction therapy,
bleeding frequency, patient convenience (ie, dosing frequency and infusion
volumes), and clinical efficacy for the patient.
• rVIIa is often chosen as the first-line BPA for patients with hemophilia A and
B with inhibitors before the start of ITI because of the potential risk for
anamnesis and allergic reaction with aPCC resulting from small amounts of
Fviii and the presence of fIX, respectively.
• There is a theoretical higher thrombotic risk with high doses of either agent,
although very few cases of thrombosis have been reported.
Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011; 365(18):1684-
1692.
Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia
patients with inhibitors. J Thromb Haemost. 2007;5(9):1904-1913.

23. AmyD.ShapiroandUllaHedner.Advancesinbypassingagenttherapyforhemophiliapatientswithinhibitorstoclosecaregapsandimprove
outcomes..TherAdvDrugSaf.2011.2(5):213-225
Comparison of available bypass therapies in patients with
hemophilia and inhibitors
Parameter rFVIIa pd-aPCC
Source Recombinant produced protein Pooled Human Plasma
Composition Highly purified recombinant protein Mixture of coagulation proteins (FII,FIX, FX
inactivated, FVIII activated, trace amounts of FVII)
and other plasma components
MOA rFVIIa binds to platelet activated by small
amount of thrombin generated by initial TF-
FVIIa-FXa complex, further activation of FX
converts additional prothrombin to thrombin
forming tight fibrin hemostatic plug.
Prothrombin complex zymogens in pd-aPCC;
Small amounts of thrombin activate prothrombinase
complex consisting of prothrombin (FII) and
activated FX which generates excess thrombin that
triggers feedback mechanism involving FIX,
activated by FXIa and FVIIa and zymogen FX,
activated by FIXa and FVIIa, for coagulation
independent FVIII or FVIIIa
Storage Stable at room temperature; reconstituted
solution may be stored at room temperature or
refrigerated upto 3 h
Must be kept refrigerated.
Time to mix Rapid reconstitution to clear colourless solution Storage vial and diluent must be at room temperature
before reconstituent; once diluent added, must be
swirled gently until completely dissolved
Vol. of
administration
Dependent on dose upto 5.2 mL Dependent on dose Kg body weight up-to a few
hundred mL
Time to administer 2-5 min as a slow IV bolus, depending on dose
administered within 3 h after reconstitution
Max infusion rate not to exceed 2U/Kg/min; infusion
time dependent on number of units to be
administered.
Tmax Resolves joint bleeds in ≤ 5 h May involve multiple administration at 12 h interval
T1/2 2.3 h (range – 1.7-2.7 h) 4-7 h measured by thrombin generation (TG); peak
TG estimated after 15-30 min infusion
Dosing interval 90µg/Kg every 2 h until homeostasis achieved,
then post hemostasis every 3-6 h for severe
bleeds and surgery. One dose of 90-120 µg/Kg
or 270µg/Kg is recommended for mild to
A function of type and severity of bleeds; 50-100
U/kg every 6-12 h but limited to a total daily patient
exposure of no more than 200U/Kg.

25. When to discontinue BPA prophylaxis
• Anti-fVIII inhibitor titer, as measured by the Bethesda assay and
fVIII levels, are monitored regularly in the clinic to trend the
inhibitor titer and assess for fVIII recovery.
• It is routinely seen some level of factor recovery as the titer drops
below 100 BU/mL and begin checking peak fVIII levels (fVIII
activity 15 minutes after an infusion) during routine inhibitor
monitoring visits.
• The majority of patients have measurable recovery before their
titers drop below 10 to 20 BU/mL, and we frequently observe not
only measurable fVIII levels but also high fVIII levels (.100%)
before achieving a negative inhibitor titer.
• Any measurable peak recovery higher than 10% is evaluated
further. The kinetics of fVIII inhibition are assessed both in the
laboratory and in the clinic with further pharmacokinetics to
evaluate whether a patient would be a good candidate to stop
BPAs,
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.Hematology. 2016; 657-662

26. Case illustration
 An 18-month-old with severe hemophilia A, who initially presented with
an inhibitor titer of 40 BU/mL after circumcision, was started on ITI at 200
U/kg/d, and rfVIIa was added shortly afterward secondary to bleeding at
his port site with access.
 His titer peaked at ~1000 BU/mL in the first month, and 6 months later was
down to 75 BU/mL.
 His father reported that he no longer seemed to have bleeding after port
access. After his dose of 200 IU/kg fVIII, a peak fVIII level in clinic
returned at 4%, and subsequent testing showed a persistent fVIII level of
4% 6 hours later. Subsequently, his BPA prophylaxis was stopped.
 He has had no joint bleeds off BPA prophylaxis now for more than 1 year,
with titers ranging from 34 to 166BU/mL.
 He has had multiple traumatic injuries/lacerations to his face, which have
required on-demand use of BPAs, but no joint bleeds.
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.Hematology. 2016; 657-662

27. Inhibitors currently in clinical trial
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic
approaches.Hematology. 2016; 657-662

28. This report, described the use of sequential BPA therapy to prevent surgical
bleeding in a patient with moderately severe hemophilia A (FVIII 5 0.03
IU/mL) and a high-titer inhibitor.

29. Methods
 58-year-old male with severe hemophilia A and a high-titer
inhibitor underwent total knee arthroplasty for advanced
arthropathy.
 The patient presented severe left knee pain, and diagnosed with
septic arthritis and bacteremia.
 Antibiotic therapy initiated with cefazolin.
 Orthopedic surgery recommended urgent left knee arthrotomy,
synovectomy, and excisional debridement of soft tissue to bone.
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery:
a new approach to hemostasis.2017.1(17); 1309-1311

30. Sequential BPA treatment regimen
CraigD.SeamanandMargaretV.Ragni.Sequentialbypassingagentsduringmajororthopedicsurgery:
anewapproachtohemostasis.2017.1(17);1309-1311

31. Observations
 Perioperative sequential BPA therapy was effective in maintaining
hemostasis without adverse events
 Intraoperatively minimal blood loss .
 A Jackson Pratt drain was placed at the time of surgery and drainage
monitored postoperatively, which was removed at 8th day POD.
 Serosanguinous drainage was present without any evidence of overt
bleeding.
 Normal postoperative pain and swelling
 No evidence of overt hemarthrosis
 Hemoglobin remained stable
 No evidence of deep venous thrombosis, pulmonary embolism, or other
thrombotic event.
 No other adverse events were experienced
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis.2017.1(17); 1309-1311

32. Conclusion
 The effectiveness of sequential BPA therapy is probably related to the
differing effect of each drug on the coagulation cascade.
 Whether alternating BPA agents is hemostatically more effective than
single-agent BPA treatment will require a clinical trial; however, the
present study suggested the use of sequential BPA therapy should be
considered.
 Given the prevalence of advanced arthropathy, pain, and disability in
inhibitor patients, this treatment option may provide an approach to
achieving hemostasis not previously possible in surgical settings and
thereby improve the quality of life of such patients.
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis.2017.1(17); 1309-1311

33. Bypass agents in News

34. Comprehensive care

35. Current outcomes and remaining challenges in
therapeutic strategies
Outcomes Challenges
Widespread availability of safe and
efficacious factor VIII & IX
Remaining barrier to adoption/ adherence
of prophylaxis: Venous access, time, cost,
health system access
Primary prophylaxis in children
Prevent joint bleeding , overall bleeding
and joint disease
Impact of Inhibitors
Secondary prophylaxis in
adolescent/adults
Prevent joint bleeding , overall bleeding
and slows progression of joint disease ,
permits increased activity, improved
HRQoL
Adapting to phenotypic/pharmacokinetic
variability
Tertiary prophylaxis in adults
Reduces joint bleeding, maintain mobility,
reduces pain, improved HRQoL
Long term follow up data with current
therapeutic approaches limited to 25-30
yrs
Annualized bleed rates are not zero
Joint disease still occurs in young adults
What happens in life time?

36. Novel Therapies
Valder R. Arruda, Bhavya S. Doshi, Benjamin J. Samelson-Jones. Novel approaches to hemophilia therapy: successes and challenges. Blood First Edition Paper,
prepublished online October 10, 2017

37. Guidelines Management of Hemophilia
WHF

38. https://hemaware.org/community-pulse/new-era-hemophilia-care-research
“Further effective and safe treatment options
for people with haemophilia are needed to
enable them to better manage their condition
and live their lives with less burden from
treatment”