TAILORING PROPHYLAXIS AND TREATMENT OF

HEMOPHILIA
SANDEEP DEVABHAKTHUNI, PHARM.D.

TAILORING PROPHYLAXIS AND TREATMENT OF HEMOPHILIA

ACTIVITY DESCRIPTION

ACCREDITATION

Patients with hemophilia and their health care providers

often search for a treatment solution that is just right. The
most effective prophylaxis protocols are tailored to the
individual based on many factors (such as age, bleeding
patterns, joint health and levels of physical activity). The
science of treating hemophilia continues to improve;
getting the art of individualizing treatment continues to be
a challenge. As the bridge between patients and
physicians, pharmacists are in the position to play an
integral part of a multi-pronged solution to this challenge
of individualizing treatment. Because pharmacotherapy
and knowledge of a patients pharmacokinetics play a
prominent role in individualizing treating of hemophilia, it
is also a perfect opportunity for the pharmacist to be
involved. This program will satisfy the education need by
creating a program for pharmacists that will enhance their
understanding of hemophilia, pharmacotherapy,
counseling points, and information needed to work with
the patient to maximize the benefits of medications, limit
side effects and identify drug-drug or drug-disease
interactions.

PHARMACY
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NURSING
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BN are accepted by most State Boards of Nursing.
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education organization for applicants seeking renewal
through continuing education credit. For additional
information, please visit
http://www.nursecredentialing.org/RenewalRequirements.aspx

TARGET AUDIENCE
The target audience for this activity is pharmacists,
pharmacy technicians and nurses in hospital,
community, and retail pharmacy settings.

Universal Activity No.: 0798-0000-14-191-H01-P&T

Credits: 2 contact hours (0.2 CEU)

LEARNING OBJECTIVES

Release Date: December 15, 2014

Expiration Date: December 15, 2016

After completing this activity, the pharmacist and nurse

will be able to:
Outline the many factors such as age, bleeding
patterns, joint health and levels of physical
activity) that must be considered when tailoring
prophylaxis protocols for individual treatment
Review the current and emerging
pharmacological approaches to the management
of hemophilia (pharmacologic profiles, efficacy,
side effects, & adverse events)
Describe the role pharmacists can play in
counseling hemophiliac patients on lifestyle
changes, drug treatment strategies and
medication adherence to improve quality of life
After completing this activity, the pharmacy technician
will be able to:

List symptoms of hemophilia

List treatments available for hemophilia

ACTIVITY TYPE
Knowledge-Based Home Study Monograph

FINANCIAL SUPPORT BY
Baxter

ABOUT THE AUTHOR

Dr. Sandeep Devabhakthuni is an Assistant Professor in
the Department of Pharmacy Practice and Science at
the University of Maryland School of Pharmacy. He
graduated with a Bachelor of Engineering in Biomedical
Engineering degree from University of Pittsburgh
School of Engineering and a Doctor of Pharmacy
degree from the University of Pittsburgh School of
Pharmacy. He then completed his pharmacy practice
residency at the University of Maryland Medical Center.
He also completed his specialty residency in Cardiology
and Critical Care at the University of Pittsburgh Medical
Center. Currently, Dr. Devabhakthuni is a board certified
pharmacotherapy specialist at the University of
Maryland Medical Center, and he has a clinical practice
on the Cardiology and Medical Intensive Care services.

Sandeep Devabhakthuni, PharmD, BCPS

Assistant Professor, University of Maryland
School of Pharmacy

FACULTY DISCLOSURE
It is the policy of PharmCon, Inc. to require the
disclosure of the existence of any significant financial
interest or any other relationship a faculty member or
a sponsor has with the manufacturer of any
commercial product(s) and/or service(s) discussed in
an educational activity. Sandeep Devabhakthuni
reports no actual or potential conflict of interest in
relation to this activity.
Peer review of the material in this CE activity was
conducted to assess and resolve potential conflict of
interest. Reviewers unanimously found that the
activity is fair balanced and lacks commercial bias.
Please Note: PharmCon, Inc. does not view the existence of
relationships as an implication of bias or that the value of
the material is decreased. The content of the activity was
planned to be balanced and objective. Occasionally,
authors may express opinions that represent their own
viewpoint. Participants have an implied responsibility to use
the newly acquired information to enhance patient
outcomes and their own professional development. The
information presented in this activity is not meant to serve
as a guideline for patient or pharmacy management.
Conclusions drawn by participants should be derived from
objective analysis of scientific data presented from this
monograph and other unrelated sources.

Introduction
Hemophilia A and B are rare congenital bleeding disorders caused by a deficiency or
absence of coagulation factor VIII (FVIII) or factor IX (FIX), respectively.1 Hemophilia is a genetic
disorder that affects over 400,000 people worldwide with a majority of them as males. 2
Hemophilia A is the most common form of hemophilia, counting for 80-85% of cases. Because
there is no cure for these X-linked disorders, appropriate management is necessary to avoid
devastating consequences including crippling arthropathy. The severity of the disorder is
typically characterized by the residual endogenous FVIII/FIX concentrations. Patients with a
factor level of < 0.01 IU/mL are classified as severe hemophiliacs and represent about half of
diagnosed cases. Patients with factor levels between 0.01-0.05 IU/mL and > 0.05 IU/mL have
moderate and mild hemophilia, respectively. While the bleeding phenotype may be
heterogeneous even in severe hemophilia, this classification by FVIII/FIX concentrations
correlates with the severity of clinical symptoms, with spontaneous joint and muscle bleeds
being largely confined to patients with severe hemophilia.3
Hemophilia A and B are difficult to differentiate from clinical presentation.
Replacement of hemostatic concentrations of the deficient factor is the mainstay of treatment
for bleeding episodes according to type and severity of bleeds. Without proper management,
patients can experience recurrent joint bleeds, leading to mobility problems, which was the
classic progression of this disease prior to 1970s when coagulation factors were not yet
available.4 Prior to development of coagulation factors, mortality was extremely high, and the
life expectancy of people with hemophilia was lower when compared to the general
population.5 Then, the discovery of cryoprecipitate and lyophilized formulations of factor

concentrates served as a catalyst for the more effective hemophilia replacement therapy. Also,
these innovative strategies allowed for increased patient convenience including the possibility
of home therapy and treating joint bleeds as soon as possible. This also led to significant
reduction in potential complications and improved the quality of life for patients with
hemophilia.
In the late 1970s and early 1980s, there was a huge concern when widespread bloodborne virus transmission occurred due to use of pooled plasma in manufacturing of factor
concentrates. This event triggered a closer inspection to ensure safety of treatment for a
population that is at a higher risk of fatal complications. This led to the development of viral
inactivation techniques for the production of plasma-derived factor concentrates. Then,
recombinant gene technology and protein purification were implemented, which led to the
creation of highly purified recombinant FVIII and FIX products, which have become the first-line
agents for correction of factor deficiencies associated with hemophilia.6 These advances in
management significantly improved treatment for hemophilia patients and contributed to the
increased use of primary prophylaxis, where regular infusion of factor concentrates are
administered to prevent bleeding and resulting joint damage. With the development of
strategies to improve viral safety, the most serious and challenging complication of treatment is
the risk of inhibitory alloantibodies.7
With recent technological advances, patients with hemophilia may now receive optimal
treatment and can achieve excellent quality of life if effective approaches are used to provide
multidisciplinary comprehensive care. The objectives of this review are to address current

advances and emerging pharmacological approaches for treatment of hemophilia and to

describe ongoing issues and importance of multidisciplinary comprehensive care.
Clinical Assessment of Hemophilia
Symptoms of hemophilia can range from mild to severe depending on the amount of
clotting factors present in blood. In general, patients with hemophilia bleed for a longer period
of time compared to healthy people because of coagulation factor deficiency. Common
symptoms can include large bruises, spontaneous bleeding from gums or nose, pain or
tightness in joints, and blood in stool or urine. Severe symptoms usually involve bleeding into
the joints, brain, or internal organs or substantial bleeding after injury or surgery that could
potentially be fatal. Furthermore, bleeding in the joints can develop into swelling that can lead
to breakdown of cartilage, resulting in chronic pain and immobility that can be permanent. 8
An accurate diagnosis is essential to ensure that a patient receives the appropriate
treatment since different bleeding disorders may have very similar symptoms. A correct
diagnosis can only be made with the support of comprehensive coagulation laboratory testing.
This testing helps clinicians to understand the clinical features of hemophilia. Using screening
tests can identify potential causes of bleeding. For patients with hemophilia, the coagulation
tests are characterized by a normal prothrombin time (PT), bleeding time (BT), and platelet
count, but the activated partial thromboplastin time (aPTT) is prolonged. The reason aPTT is
prolonged is because this test measures the intrinsic pathway for the coagulation cascade,
whereas PT measures the extrinsic pathway. The intrinsic pathway requires adequate sources
of both factors VIII and IX to function properly. Since either hemophilia type A or B is

characterized by a deficiency in one of these factors, this leads to problems with the intrinsic
pathway, which ultimately can result in bleeding consequences.8
In addition to evaluating coagulation tests, assessment of factor assays is needed to
confirm diagnosis since a deficiency in a coagulation factor can guide clinicians in determining
the type of hemophilia. The severity of the disease is correlated with the degree of the
deficiency, and the classification of hemophilia severity by the factor concentration is shown in
Table 1.8 The most common hindrance in hemophilia treatment is the production of inhibitors,
or antibodies against injected coagulation factor replacement, which can occur up to 20% of
patients.9 In hemophilia patients with suspected inhibitors, testing can be performed using a
Bethesda titer to determine presence of antibodies to specific clotting factors.
Preventive and Supportive Measures for Hemophilia
When managing a patient diagnosed with hemophilia, the goals of therapy include
promotion of adequate hemostasis with minimal side effects with deficient clotting factor,
prevention of viral transmission, promotion of hemostasis in the presence of inhibitors, and
optimizing patient adherence by considering cost and ease of use. Because early recognition is
crucial to prevent mobility complications, patients need to be educated on signs/symptoms of
bleeding, injury avoidance, prompt self treatment, and need for immunizations against
Hepatitis A and B prior to receiving replacement coagulation factors. Acute bleeds should be
treated as quickly as possible, preferably within two hours.8 Most patients should be counseled
on home treatment since this strategy can improve quality of life due to less pain and disability,
fewer hospitalizations, and decreased time away from work or school.10 In addition, patients

should be prepared for any surgical interventions by maintaining factor levels of at least 0.5-0.7
units/mL (50-70%). Dental extraction in hemophiliacs is also associated with a high risk of
bleeding and requires a multidisciplinary approach and stringent protocol. 11
Besides considering preventative strategies, patients may require supportive therapy
depending on the severity of hemophilia. If patients have significant swelling in their joints, this
may lead to either acute pain from bleeding or chronic pain from joint damage due to cartilage
destruction. Adequate assessment of the cause of pain is necessary to guide proper
management. Hemophilia patients can experience pain due to venous access, joint or muscle
bleeding, operation, or chronic hemophilic arthropathy. For appropriate management of pain,
clinicians can consider corticosteroids, acetaminophen, and narcotics.12 For chronic hemophilic
arthropathy, cyclooxygenase-2 (COX-2) inhibitors have a greater role in management. If pain is
disabling, orthopedic surgery may be indicated.13-16
Treatment Options for Hemophilia
The types of treatment methods available today are plasma-derived products,
recombinant coagulation factors, and gene therapy. Dosing for coagulation factors is based on
volume of distribution (both intravascular and extravascular compartments), half-life, and
factor level required for hemostasis. The available plasma-derived products or recombinant
clotting factors are listed in Table 2. Patients who develop an immune response to therapy or
have acquired hemophilia are extremely difficult to manage.17 The treatment options for this
complication include prothrombin complex concentrates, activated recombinant factor VII
therapies, and immunosuppressive medications.

Plasma-Derived Coagulation Factors

Plasma-derived coagulation factors in whole blood and in plasma fractions are used as
replacements for any absent factors in hemophiliacs.18 Available plasma products include fresh
frozen plasma, freeze-dried concentrates, and cryoprecipitate (slowly thawed plasma
precipitate).19 Transfusions with healthy blood were the earliest successful treatment of
hemophilia. Blood transfusions provide the patient with missing clotting factors and replenish
lost blood volume during bleeds. However, these products need to be used repeatedly in order
to replenish live tissue cells.
Treatment with these products requires suitable methods to cleanse blood and plasma
from pathogens. For plasma-derived products, the most common methods for purification
include moderate dry heating, strong dry heating, and wet heating of blood products. The use
of these methods decreased the incidence of Human Immunodeficiency Virus (HIV) and
Hepatitis C transmission, which are deadly blood-borne pathogens.17 In the 1980s, 60-80% of
patients with severe hemophilia contracted HIV from blood-derived products. Most of the
viruses commonly transmitted through blood transfusions have a long, asymptomatic carrier
state, which is problematic since healthy donors may actually be carriers of a pathogen. 18
Standard screenings have been placed to remove blood samples with these viruses, but
there still is a potential risk for transmission. Viruses can evolve into different strains or
different pathogens, which may not be detected by routine techniques. So there is a potential
threat of emerging viruses because a pathogen can make contact with a new species or
population and establish itself in that vulnerable population, like patients with hemophilia.

Thus, there have been improvements made in detection methods such as nucleic-acid
screening and incorporation of products that reduce viral activity, making blood products safe
from HIV and Hepatitis B and C.18 There is an increased focus on the use of reagents that are
completely independent of human plasma.18 Another concern with plasma-derived factors is
the possibility of an adverse immune reaction, leading to decreased efficacy with repeat
administration.17
Blood products are generally cost effective; yet, proper purification techniques are not
easily accessible in some third-world countries, which increases the risk of viral transmission
and causes complications in hemophilia patients. Approximately 80% of hemophiliacs continue
to use plasma-derived factors due to limited resources.20
Recombinant Coagulation Factors
Recombinant coagulation factors treatments deliver clotting factors that hemophilia
patients are missing and have become the first-line agents for management of acute bleeds.17,21
The first generation recombinant factors were derived from DNA by using albumin in the
synthetic steps. However, albumin was not included in the final product, which decreases the
risk of hypersensitivity reactions. Newer recombinant factors have been produced that use no
human proteins in the synthetic or final stages of production. Because of this process, these
factors are though to be safer in terms of viral transmission compared to plasma-derived
factors; however, the risk is not completely eliminated.17 The recovery time for patients using
recombinant factors has been shown to be slower than those for plasma-derived factors.22

A single dose of recombinant factors can eliminate 80% of uncontrolled bleeds and
subsequent use increases the success rate to 90-95%.17 Recombinant factors are considered as
effective as plasma-derived coagulation factors. In a study of 95 children with moderate to
severe hemophilia A, recombinant FVIII for average of 1.5 years was given in response to
excessive bleeds and prior to surgical/dental procedures. The average number of transfusions
needed was 34.9 infusions per individual, with effective response and minimal side effects
reported.23 Another study suggested a different method of administration, which was
continuous injection of clotting factor to prevent highs and lows in coagulating factor level.
This promotes homeostasis and stops large bleeds before they occur. This method also reduces
the overall amount of factor required for treatment.24
Several factors are considered when determining appropriate dosing for recombinant
coagulation factors, including site of bleeding, volume of distribution, half-life, and joint health.
Dosing for factor replacement is dependent on site of bleed, which helps to determine percent
correction to target factor concentration that is needed as well as duration. Guidelines for
factor replacement based on site of bleed and need for prophylaxis for surgery are provided in
Table 3. Specific dosing instructions for recombinant FVIII and FIX products are provided in
Table 4. Because recombinant FVIII concentrates are larger molecules, the volume of
distribution is 0.5 so this requires half the amount needed for appropriate recombinant FIX
concentrate replacement. Recombinant FIX concentrates also have a longer half-life and
require less frequent dosing compared to recombinant FVIII products. These recombinant
concentrates should be infused slowly by intravenous injection at a rate not to exceed 3
mL/min in adults and 100 units/min in young children.

10

Administration of recombinant factor concentrates requires close monitoring.

Important efficacy parameters include plasma factor levels 15 minutes after infusion completed
to verify accuracy of calculated dose and control of bleeding. If the target factor concentration
is not achieved with appropriate dosing, then testing for inhibitor development is warranted.
For monitoring of safety, patients should be educated on the possibility of hypotension,
injection site reaction/pain, dyspnea, hypersensitivity, and thrombosis (more common with
recombinant FIX products). In addition, recombinant FIX concentrates have an increased risk
for hypersensitivity reaction and disseminated intravascular coagulopathy in patients who have
liver disease, are undergoing surgery, or are neonates.25,26
The main concern with recombinant factors is the development of inhibitors
(approximately 28-33%).25,26 For hemophiliac patients, a normally functional coagulation factor
is deficient. So the bodys immune system will see a recombinant product derived from foreign
DNA as a pathogen. Thus, an immune response is mounted to destroy and remove the infused
coagulating factor.27 If not recognized, hemophilia patients with inhibiting antibodies could
have an increased bleeding risk that is potentially fatal.28 The reported incidence of inhibitor
development has been variable due to different study designs. A study by Knobe and
colleagues tested 116 people with hemophilia for presence of inhibitors after factor
replacement treatment that last 14-16 days. Of these people, 19% of hemophilia A patients
developed inhibitors compared to 37% of hemophilia B patients. The study suggested that
inhibitor development could be genetically related because all patients who had inhibitors were
found to have impaired protein synthesis due to a mutation.29

11

Despite recombinant factors being more expensive than plasma-based factors by 2050%, these factors are used by 60-70% of severe hemophiliacs in the United States and all
patients in Canada and Ireland use recombinant factors over plasma-derived products.
Increased cost is likely due to amount of coagulation factor that can be extracted from a blood
sample is only 5-10% of the quantity of factor present in the sample.17 Although dosing
patterns will vary, a typical individual with hemophilia receiving primary prophylaxis will need
approximately 2000 IU of clotting factor 3 times per week with the average cost per dose
ranging from $1,000 to $2,000. This translates into an approximate monthly cost of $12,000 to
$24,000 or $1444,000 to $288,000 per year in medication expenses alone.30 The discrepancy in
price is the reason why it is challenging to provide recombinant factors in developing
countries.31 Methods to decrease amount needed for replacement such as factor clearance
receptor antagonist, continuous infusion of product, and increased half-life of recombinant
factor may lead to substantial healthcare cost savings.17,24 Possible solutions to prevent
inhibitor development include re-engineering the recombinant factor so that it is less likely to
induce an immune response.32
Adjunctive Therapies for Hemophilia
While coagulation factor replacement therapy is the mainstay treatment for hemophilia
patients, there are adjunctive therapies that can be used depending on the type and severity of
hemophilia. Desmopressin is a vasopressin synthetic analog that causes release of von
Willebrand factor and factor VIII, which makes it suitable for treatment of hemophilia A only. 33
Desmopressin is frequently used for treatment of mild or moderate bleeding episodes in
patients with hemophilia A with a good response rate of 80-90%. It can be given either

12

intravenously by administering 0.3 mcg/kg in 50 mL of 0.9% sodium chloride over 15-30

minutes or intranasally with 150 300 mcg per dose (1 spray = 150 mcg). Desmopressin can be
given daily for 2-3 days, but a 30% lower response is expected with second dose due to
tachyphylaxis.34,35 Major adverse effects of treatment include flushing (most common),
thrombosis (rare), headaches, tachycardia, and hypotension. Because of its antidiuretic effect,
desmopressin also promotes fluid retention, which can cause profound hyponatremia so it
should be used cautiously in patients with heart failure experiencing fluid overload or existing
hyponatremia.34,35
Antifibrinolytic therapy can be used as adjunctive therapy for procedures expected to
cause mucosal bleeding. This type of therapy prevents fibrin breakdown by inhibiting
fibrinolytic enzymes found in saliva. Aminocaproic acid can be given as oral or intravenous dose
of 100 mg/kg (maximum of 6 grams) every 6 hours. Aminocaproic acid is used less often due to
short half-life, low potency and potential for toxicity. Tranexamic acid is 10 times more potent
compared to aminocaproic acid so it can be administered as 25 mg/kg (maximum 1.5 grams)
orally every 8 hours or 10 mg/kg (maximum 1 gram) intravenously every 8 hours.36,37 Either
agent is usually given for 7 days following dental extractions to prevent post-operative
bleeding. They are contraindicated in hematuria since they may cause serious obstructive
uropathy and should be avoided in combination with prothrombin complex concentrates due to
additive risk of thromboembolism. These agents can cause thrombosis, headache, renal failure
(requiring dose adjustments), and hypotension. Aminocaproic acid also can cause
rhabdomyolosis, and tranexamic acid has been associated with visual disturbances and
increased incidence of anaphylaxis.36,37

13

Another adjunctive therapy for patients with Hemophilia B is the use of prothrombin
complex concentrates (PCCs). These products contain non-activated factors II, VII, IX, and X.
Activated PCCs contain greater quantities of the activated factors. However, PCCs are not used
as first-line for management of patients with Hemophilia B because of lower purity and risk of
thrombosis. The risk of thrombosis is higher in patients with hepatic disease, neonates, and
patients experiencing crush injury or major surgery. Other adverse effects include dizziness,
nausea, hives, flushing, headaches, and hypersensitivity reactions. Other adjunctive therapies
include fresh frozen plasma and cryoprecipitate, but neither of these agents is recommended
routinely due to concerns about safety and quality.
Prophylaxis versus On-Demand Replacement Therapy
Current factor treatment regimens include on-demand treatment, which is infusing
clotting factor when a bleed occurs, or prophylaxis, where factors are infused to prevent bleeds
by maintaining levels of FVIII or FIX at appropriate levels. The use of prophylaxis is intended to
prevent bleeding episodes through the administration of regular infusions. The frequency of
prophylactic infusion depends on several factors and is determined by the patient and primary
care provider. The prophylaxis options are provided in Table 5. Several studies have
demonstrated that prophylaxis therapy gives children the best chance to reach adulthood
without damage to their joints.38-40 If patients have recurrent joint bleeds, this can lead to
severe and debilitating injuries that often require physical therapy. Also prophylactic
administration can convert severe hemophilia into milder form with much lower incidence of
chronic arthropathy.

14

To prevent bleeding and joint destruction by preserving normal musculoskeletal

function, the typical goal of infusion is to maintain at minimum of 0.01 units/mL (1%). Studies
have shown that this can still prevent joint bleeds even if the goal cannot be achieved. 38-40 For
FVIII and FIX, the most common regimens studied are 25 50 units/kg three times weekly and
40-100 units/kg twice weekly, respectively. These regimens have been proven to be costeffective long-term because they eliminate the high cost associated with subsequent
management of damaged joints and improves quality of life.30,41 Primary prophylaxis is typically
started before 2 years of age with almost no previous history of bleeding episodes and normal
joint evaluations. However, this type of prophylaxis is not widely accepted because of high
cost, inconvenience to families leading to noncompliance, and risk of infection or thrombosis
with central venous access. Secondary prophylaxis after significant joint bleeding is more
common and is associated with significant reduction in number of recurrent episodes; however,
radiological evidence of joint disease rarely improves and often progresses despite
prophylaxis.41 The National Hemophilia Foundations Medical and Scientific Advisory Council
recommend that prophylaxis be considered optimal therapy for individuals for severe
hemophilia A or B. Prophylactic therapy should be instituted early (prior to onset of frequent
bleeding) with the aim of keeping FVIII/FIX level above 1% between doses.42
Treatment Options for Hemophilia Patients with Inhibitors
One of the most serious complications of hemophilia is the development of inhibitors or
neutralizing antibodies to the infused clotting factor. In some individuals with hemophilia A,
the factor product used to prevent or treat bleeds is viewed as a foreign body. This results in an
immune reaction by the body to make that infused clotting factor inactive and harmless to the

15

system, which leaves the individual unprotected from bleeds. Inhibitors develop in about 30%
of patients with severe Hemophilia A and up to 5% of those with hemophilia B. 30 Individuals
with inhibitors are certainly at higher risk for serious bleeding episodes and significant joint
damage.
There are numerous risk factors for the development of inhibitors that have been
identified. These risk factors include age, race, type of hemophilia, presence of other immune
disorder, and frequency and dose of factor. High-intensity treatment with factor replacement
is a major risk factor for inhibitor development. Also, choosing continuous infusion of clotting
factor over bolus dosing can increase the risk. Other risk factors include surgical procedure
during first 50 exposure days, severe hemophilia A, family history, certain FVIII and FIX genetic
mutations, and other genetic factors (African American, Asian, and Hispanic ethnicity). 43
Inhibitor development is more common during the first year of treatment, but it can occur at
anytime. Inhibitor development should be suspected with decreased clinical response to factor
replacement, and lab testing should be considered in this situation.
When hemophilia patients develop inhibitors, treatment goals are to treat acute
bleeding episodes and eradicate inhibitor development if possible.44-46 The decision to treat
hemophilia patients with inhibitors is dependent on whether they are having an active bleed. If
the patients are bleeding, then treatment strategies are dependent on the degree of inhibitor
development. If a low titer < 5 BU is measured, then high-dose factor replacement is the best
option, which would require 2-3 times the usual replacement doses more frequently. However,
if a high titer > 5 BU is measured, then other alternative strategies are warranted, which include

16

the use of the use of PCCs, recombinant FVIIa concentrate, or porcine FVIII concentrate (for
patients with hemophilia A only).45,46
For hemophilia patients with high titers of inhibitors, activated PCCs will be more
effective since PCC includes only trace amounts of FVIII and larger amounts of FIX, which is
more helpful in patients with hemophilia B. Activated PCCs also contain FVIII Inhibitor
Bypassing Activity, which activates the synthesis of thrombin by stimulating prothrombinase,
which bypasses the synthesis of FIX and FVIII. Using aPCCs is an option for either type of
hemophilia with inhibitors present. The disadvantages of this treatment strategy is that the
products have lower purity, high risk of thrombosis, no suitable monitoring strategy, and
possibility of an anamnestic response, which means that the body may develop an immune
response upon repeated exposure. For these reasons, recombinant FVIIa (NovoSeven) is a
preferred strategy to manage bleeds in hemophilia patients with high titers of inhibitors.
Recombinant FVIIa bypasses the factor deficiency and activates factor X, which can initiate
thrombin formation, and it is only active at site of tissue injury. Recombinant FVIIa can be used
for prevention and treatment of bleeding. The major limitation of this product is that it has a
very short half-life and requires redosing every 2 hours. So continuous infusion is a more
convenient and cost-effective method to administer recombinant FVIIa, and the interval can be
extended once hemostasis is achieved. There is a less risk of viral transmission and anamnestic
response compared to aPCCs. There are no routine laboratory tests that can accurately
measure the efficacy of recombinant FVIIa infusion.44-46 Recombinant FVIIa has been
demonstrated to stop bleeding episodes effectively with one dose as opposed to treatment

17

with aPCCs.47 Due to a reduced need for re-infusion of product, recombinanat FVIIa is overall
more cost-effective than aPCCs.47
Finally, the last option available to treat an acute bleed for hemophilia patients with
high titers of inhibitors is the use of porcine factor VIII. This option is only available for patients
with hemophilia A with inhibitor development. Since this is obtained from a foreign source,
there is a high risk of a severe allergic reaction when given. Because of the risk of
hypersensitivity and thrombocytopenia, porcine factor VIII is no longer commercially available,
but it can be obtained for specific patients that have no response to recombinant FVIIa or PCC
or have severe hemorrhages.44
If the hemophilia patient with inhibitors is not actively bleeding and has a low titer < 5
BU, then immune tolerance therapy is recommended so that maintenance factor replacement
is a viable option. Providing high doses of factor concentrate therapy as a regular infusion
ranging from 25 units/kg every other day to 200 units/kg daily has been shown to eradicate
inhibitors.44,46 High-dose factor treatment has been successful in 70% of patients.48 Drugs that
suppress the immune system have also been investigated for inhibitor eradication in
hemophilia patients. Rituximab is an anti-CD20 antibody that destroys existing B-cells, which
are present in immune response.49 Other immunosuppressive agents used to control inhibitors
include corticosteroids, cyclophosphamide, immunoglobulin, and prednisone.46 These drugs
can be used alone or in combination to reduce immune activity. However, these treatments
are not usually pursued because of notable adverse effects. For example, corticosteroids can
cause mood instability, weight gain, hypertension, and hyperglycemia. Because these agents
suppress the immune system, patients are higher risk for deadly infections. The process by

18

which immune tolerance is induced creates high costs, estimating up to 4 times higher than
patients without inhibitors ($697,000 vs. $155,000).30 In addition, all of these treatments
would require adequate monitoring to ensure both efficacy and safety.
Gene Therapy
In the recent years, there has been a focus on developing gene therapy for management
of hemophilia because the disease is usually caused by a single gene defect.50 The treatment
looks promising when tested in dogs and mice with knock-out mutations for the coagulation
factor gene. However, when used in human models, the same degree of coagulation factor
production was not achieved compared to animal models.17 Though gene therapy is promising,
it is currently not a viable option for mass use among hemophilia patients. Further
investigation is warranted to demonstrate universal success of gene therapy.
Hemophilia Products in Development
For the last three decades, the hemophilia market has been dominated by recombinant
clotting factors produced by specific manufacturers including Baxter, Bayer, and CSL Behring.
There have been several generations of recombinant coagulation factors. The most recent
generation (third-generation recombinant factors) lack bovine or human proteins in the
synthesis of coagulation factors or in the final products), which lowers the risk of viral
transmission. Aside from this advance in manufacturing, there have been no other major
changes that have affected management of hemophilia patients. Table 6 summarizes the
products that are currently being developed or recently approved. There are two new
recombinant products approved in 2013 (Rixubis and Alprolix) and one in 2014

19

(NovoEight).51,52 Also, there are many longer-acting versions of clotting factors in

development, which may be helpful since there has been an increased use of prophylaxis.
Comprehensive Care
Hemophilia is a rare disorder that is complex to manage and requires optimal care of
patients, especially in those with severe forms of the disease. Comprehensive care goes
beyond treatment of acute bleeds and is crucial to promote physical and psychosocial health
and quality of life and can potentially decrease morbidity and mortality. A multidisciplinary
care team is needed to address prevention and treatment, as well as vein and dental care.
Because an acute life-threatening bleed can occur anytime at any location patients should carry
easily accessible identification indicating diagnosis, type and severity of hemophilia, inhibitor
status, type of factor needed for repletion, initial dosage for treatment of mild, moderate, and
severe bleeding as well as contact information.53,54 Adequate emergency care should be
available at all times including access to a coagulation laboratory capable of performing clotting
factor assays, provision of appropriate clotting factor concentrates, blood products if factor
concentrates not available, and casting and/or splinting for immobilization and
mobility/support aids as needed.
A comprehensive care program is needed to coordinate inpatient and outpatient care
and services to patients and their family. Patients should be seen by all multisdisciplinary team
members on a yearly basis for a complete hematologic, musculoskeletal, and psychosocial
assessment.8 The management plan should be developed in collaboration with the patient and
communicated to all practitioners involved in the patients care. Communication among

20

healthcare providers is key. In addition, the patient, family members, and other caregivers
should be educated on potential consequences to ensure that optimal care is provided.
Pharmacist Role
Pharmacists play an important role in making sure that patients are receiving
appropriate care. The most important responsibility is the evaluation of factor concentrate
dosing regimens for treatment and prophylaxis. Pharmacists can also perform medication
regimen reviews to ensure that the patient is not receiving non-steroidal anti-inflammatory
drugs, aspirin, or drugs affecting platelet adhesion since these can put the patient at a higher
risk for uncontrolled bleeding. Pharmacists can also assist with insurance authorizations to
secure reimbursement for clotting factors and communicate any issues with the hemophilia
comprehensive care team. There are also specialty pharmacies that manage and coordinate
care of hemophilia patients, and this is where majority of clotting factors are dispensed.
Treatment with clotting factor requires intravenous access, and patients and their caregivers
require training on how to infuse clotting factors at home.
Pharmacists can provide hemophilia disease education to patients, families, and other
involved team members. They can assist families with making treatment decisions to provide
effective therapy with minimal side effects. They can minimize barriers to access clotting
factors, manage refills appropriately, and provide infusion training techniques and medication
education on clotting factor storage, preparation, and reconstitution. Pharmacists should take
the initiative to contact patients routinely to assess compliance, especially if patients are on
prophylaxis or immune tolerance therapy, to ensure proper adherence. Finally, pharmacists

21

can assess each patients current regimen and determine the best treatment option using
evidence-based medicine.
Conclusion
Hemophilia is a chronic illness that requires complex and comprehensive medical care
to optimize patient outcomes including extending life expectancy and improving quality of life.
Indeed, if patients receive appropriate comprehensive care at a hemophilia treatment center
and follow preventive care, these patients with hemophilia A or B can have a long life
expectancy without disability. There have been major advancements in the treatment and
prevention of bleeds that have improved quality of life for these patients. In the future, gene
therapy may serve as a cure for hemophilia, but further investigation is needed to clarify the
place in therapy. Current research is focused on improving treatment administration to
increase compliance for patients and allow them to function appropriately in society. Choosing
the appropriate therapy is dependent on several factors such as age, bleeding patterns, joint
health, and levels of physical activity) and should be determined on an individual case basis.
Multidisciplinary healthcare team coordination is necessary to ensure that patients are aware
of risks of hemophilia treatment so that they opt for safer methods of treatments. Both the
healthcare team and patients must understand the efficacy and safety of each treatment to
make an appropriate decision for management of hemophilia.

22

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32. Barrow RT, Healey JF, Gailani D, Scandella D, Lollar P. Reduction of the antigenicity of factor
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33. Castaman G. Desmopressin for the treatment of haemophilia. Haemophilia. 2008;14:15-20.
34. Manucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20
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35. Lessinger C, Becton D, Cornell C Jr, Cox Gill J. High-dose DDAVP intranasal spray (Stimate)
for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or
moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A.
Haemophilia. 2001;7:258-266.
36. Coetzee MJ. The use of topical crushed tranexamic acid tablets to control bleeding after
dental surgery and from skin ulcers in haemophilia. Haemophilia. 2007;13:443-444.
37. Hvas AM, Sorensen HT, Norengaard L, Christiansen K, Igerslev J, Sorensen B. Tranexamic
acid combined with recombinant factor VIII increases clot resistance to accelerated
fibrinolysis in severe hemophilia A. J Thromb Haemost. 2007;5:2408-2414.
38. Aronstam A, Arblaster PG, Rainsford SG, et al. Prophylaxis in haemophilia: a double-blind
controlled trial. Br J Haematol. 1976;33:81-90.
39. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to
prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535-544.
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41. Gringeri A, Lundin B, von Mackensen S, et al. ESPRIT Study Group. A randomized clinical trial
of prophylaxis in children with hemophilia A (the ESPRIT study). J Thromb Haemost.
2011;9:700-710.
42. National Hemophilia Foundation. MASAC Recommendation #179 MASAC recommendation
concerning prophylaxis (regular administration of clotting factor concentrate to prevent
bleeding).
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=100
7. Accessed 2014 November 29.
43. Astermark J, Satagostino E, Hoots KW. Clinical issues in inhibitors. Haemophilia. 2010;16:5460.
44. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic
review. Haemophilia. 2003;9:418-435.
45. Hay CR. Factor VII inhibitors in mild and moderate-severity haemophilia A.
Haemophilia. 1998;4:558-563.
46. Berntorp E, Collins P, DOrion R, et al. Identifying non-responsive bleeding episodes
in patients with haemophilia and inhibitors: a consensus definition. Haemophilia.
2011;17:e202-210.
47. Joshi AV, Stephens JM, Munro V, Mathew P, Botteman MF. Pharmacoeconomic
analysis of recombinant factor VIIa versus APCC in the treatment of minor-tomoderate bleeds in hemophilia patients with inhibitors. Curr med Res Opin.

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2006;22:23-31.
48. Manno CS. Management of bleeding disorders in children. Hematology Am Soc
Hematol Educ Program. 2005;416-22.
49. Wiestner A, Cho HJ, Asch AS, et al. Rituximab in the treatment of acquired factor
VIII inhibitors. Blood. 2002;100:3426-3428.
50. Gan SU, Kon OL, Calne RY. Genetic engineering for haemophilia A. Expert Opin
Biol Ther. 2006;6:1023-30.
51. Gouw S, van der Bom J, Ljung et al. Factor VII products and inhibitor development
in severe hemophilia A. N Engl J Med. 2013;368:231-239.
52. Clement P New factor concentrates. The future is now. Parent Empowerment
Newsletter. 2013;23:10-11.
53. Evatt BL. The natural evolution of haemophilia care: developing and sustaining
comprehensive care globally. Haemophilia. 2006;12:13-21.
54. Evatt BL, Black C, Batarova A, Street A, Srivastava A. Comprehensive care for
haemophilia around the world. Haemophilia. 2004;10:9-13.

28

Table 1. Hemophilia Severity Classification by Factor Concentration8

Classification

Factor Concentration*
(Units/mL)

Clinical Manifestations

Mild

> 0.05 0.4 Units/mL

(>5 40%)

Moderate

0.01 0.05 Units/mL

5%)

Severe

< 0.01 Units/mL (<1%)

Hemorrhage with magor trauma or

surgery
May go years without diagnosis
Occasional spontaneous hemorrhages
Hemorrhage with mild trauma/surgery
that is prolonged
Frequent spontaneous hemorrhages
Life-threatening hemorrhages

(1

*Normal plasma range = 0.5 1.5 Units/mL

Table 2. Coagulation Factors Available for Treatment of Hemophilia A and B

Recombinant
Factor VIII
Concentrates

Human Plasmaderived Factor VIII

Concentrates
Plasma-derived
Intermediate
Purity
Concentratesa

Hemophilia A Treatment
Advate (Baxter) 3rd
generation
Helixate FS (Bayer)b 2nd
generation
Kogenate FS (Bayer)b 2nd
generation
Recombinate (Baxter) 1st
generation
Xyntha (Pfizer) 3rd
generation
Hemofil M (Baxter)c
Hemofil M with nanofiltration
(Baxter)d
Monoclate P (CSL Behring)
Alphanate (Grifols)
Humate-P (CSL Behring)
Koate-DVI (Grifols)

Also contains von Willebrand Factor

Derived from human plasma

Formulation expires January 2016

New formulation September 2013

29

Hemophilia B Treatment
BeneFIX (Pfizer)
Rixubis (Baxter)

AlphaNine SD (Grifols)
Mononine (CSL Behring)

Alphante (Grifols)
Humate-P (CSL Behring)
Koate-DVI (Grifols)

Table 3. Guidelines for Factor Replacement

Hemorrhage

Factor VIII (% of
normal)
60 100

Factor IX (% of
normal)
50 100

Duration (days)

Severe
10 14
Intracranial
Retroperitoneal
Retropharyngeal
Moderate
30 60
25 50
37
Hemarthroses
Hematoma
Hematuria
Minor
20 40
15 30
13
Epistaxis
Oral (mild)
Surgery*
50 100
50 100
Up to 14
*For minor surgery, can consider lower goal of 30-60% of normal. For major surgery, can
consider higher goal of 100% before surgery begins and may repeat after 6-12 hours and
continue until healing is complete.
Table 4. Dosing of Recombinant Coagulation Factors

Initial Dose (units)

Maintenance Dose
(units)
Expected Response
Half-life (hours)
Dosing Interval

Factor VIII
Desired increase (%) x
Weight (kg) x 0.5

Factor IX
Pediatric: Desired increase (%) x
Weight (kg) x 1.4
Adult: Desired increase (%) x
Weight (kg) x 1.2
50% of initial dose

50% of initial dose

(0.02 Units/mL)
8 15
12 24 (minor bleed)
8 12 (moderate
severe bleed)

(0.01 Units/mL)
11 27
12 24

30

Table 5. Prophylactic Factor Replacement

Protocol
Episodic Treatment

Definition
Treatment given at time of clinically
relevant bleeding

Continuous Prophylaxis
Primary Prophylaxis

Regular continuous treatment in the

absence of documented osteochondrial
joint disease and started before second
clinical evident large joint bleed and age 3
years
Regular continuous treatment after 2 or
more bleeds into large joints and before
onset of joint disease
Regular continuous treatment started
after onset of joint disease
Treatment given to prevent bleeding for
periods not exceeding 45 weeks in a year

Secondary Prophylaxis

Tertiary Prophylaxis
Intermitent Prophylaxis

Table 6. Emerging Hemophilia Products in Development51,52

Product Name (Manufacturer)

Product Type/Indication

Distinguishing
Feature

Factor VIII
BAX 855 (Baxter)
BAY 81-8973 (Bayer)

Pegylated rFVIII
BDD rFVIII

Long acting
3rd generation;
normal t1/2

BAY 94-9027 (Bayer)

BIIB 031 (Blogen Idec)

Pegylated rFVIII
BDD rVIII-Fc fusion

Long acting
Long acting

CSL627 (CSL Behring)

Single-chain rFVIII

GreenGene F (Green Cross

Corporation)
Turoctocog alfa (Novo Nordisk
NovoEight)
NN7088 (Novo Nordisk N8-GP)

rFVIII
BDD rFVIII

Improved
stability during
manufacturing
New in the
United States
Normal t1/2

Glyco-pegylated rFVIII

Long acting

31

Regulatory
Status
Phase II/III
Phase III
completed
March 2013
Phase III
Phase III
completed
March 2014
Phase II/III

Phase III
Approved
2013
Phase III

Human-cl rhFVIII (Octapharma)

NecLip-pdFVIII (Recoly NV
LongAte)
Factor IX
BAX 326 (Baxter Rixubis)

Hemophilia A
Plasma-derived factor VIII
formulated with NecLip

Normal t1/2
Long acting

Phase III
Approved in
Russia

Third-generation rFIX

Approved
June 2013

BIIB 029 (Biogen Idec/Swedish

Orphan Biovitrium Alprolix)
IB1001 (Cangene Corporation)

rFIX-Fc fusion

First 3rd
generation
product
Long acting

CSL654 (CSL Behring)

NN7999 (Novo Nordisk N9-GP)
Inhibitors of Factor VIIA
BAX 817 (Baxter)

rFIX albumin fusion

Glyco-pegylated rFIX

rFIX

Long acting
Long acting

Approved
March 2014
Approval on
hold pending
data
requested by
FDA
Phase II/III
Phase III

Hemophilia with
Normal t1/2
Phase III
inhibitors rFVIIa
OBI-1 (Baxter)
Hemophilia A with
Recombinant
Phase III
inhibitors or acquired
(porcine)
hemophilia A
CSL589 rVIIa-FP (CSL Behring)
Hemophilia A or B with
Long acting
Phase I
inhibitors; rFVIIa-albumin
fusion
LA-rFVIIa (Novo Nordisk)
rFVIIa
Long acting
Phase I/II
PF-05280602 (Pfizer/Catalyst
Hemophilia with
Produced by
Phase I
Biosciences)
inhibitors; rFVIIa
human cell line
NecLip-rFVIIa (Recoly NV
Hemophilia with
Long acting
Phase I/II
LongSeven)
inhibitors; rFVIIa
formulated with NecLip
LR769 (rEVO biologics/LFB
Hemophilia A or B with
Produced in
Phase II
Biotechnologies)
inhibitors; transgenic
rabbit milk
rFVIIa
rFIII, recombinant factor VIII; BDD, B-domain deletion; t1/2, half-life; rFIX, recombinant factor
FIX; rFVIIa, recombinant factor VIIa; NecLip, non-encapsulating liposomes; FDA, Food and Drug
Administration

32

ACTIVITY TEST
1. Which of the following statements is TRUE regarding epidemiology of hemophilia?
A. Hemophilia B is the most common form counting for 80-85% of cases
B. Majority of hemophilia cases occur in females
C. Severe hemophilia is characterized by a coagulation factor level > 5 IU/dL
D. Severe hemophilia is associated with spontaneous joint and muscle bleeds.

2. Hemophilia B is caused by a deficiency of which clotting factor?

A. Factor VII
B. Factor VIII
C. Factor IX
D. Factor XII

3. Which of the following abnormal laboratory results is (are) consistent with a diagnosis of
hemophilia type B?
I. Prolonged activated partial thromboplastin time (aPTT)
II. Prolonged prothrombin time (PT)
III. Decreased factor VIII level
IV. Decreased factor IX level
A. I and III
B. I and IV
C. II and IV
D. I, II and III
E. I, II, IV

4. JK is a 10 year old boy who was recently diagnosed with hemophilia A, and his hematologist
has ordered coagulation tests to determine severity. The test results have revealed that his
factor VIII level is 0.1 Units/mL (10%). How would you classify JKs severity based on this
information?
A. Mild hemophilia A
B. Moderate hemophilia A
C. Severe hemophilia A
D. Cannot determine severity due to insufficient information provided

5. Which of the following severity of hemophilia is correctly matched with the associated
clinical manifestations?
A. Mild hemophilia occasional spontaneous hemorrhages
B. Moderate hemophilia hemorrhage with mild trauma/surgery is usually prolonged
C. Moderate hemophilia life-threatening hemorrhages
D. Severe hemophilia may go years without diagnosis

33

6. All of the following statements regarding preventive and supportive measures is true
EXCEPT:
A. Acute bleeds should be treated within 2 hours to prevent joint damage in hemophilia patients
B. Patients should be educated on home treatment since it can improve quality of life and decrease
pain and disability.
C. Immunizations against Hepatitis C and Human Immunodeficiency Virus (HIV) are necessary prior to
receiving replacement clotting factors.
D. Maintaining factor levels of at least 0.5-0.7 units/mL (50-70%) should be adequate when
performing minor surgical interventions in patients with hemophilia.

7. Assuming that there are adequate resources and cost is not an issue, which of the following
treatment options is the most appropriate treatment option for managing an acute bleed for a
patient with hemophilia B?
A. Cryoprecipitate
B. Recombinant factor IX
C. Activated prothrombin complex concentrate
D. Aminocaproic acid

8. Which of the following options is the most appropriate option to manage an acute bleed for
a patient with a history of hemophilia A, who has the presence of inhibitors (measured as 3
Bethesda Units)?
A. Cryoprecipitate.
B. Tranexamic acid
C. Recombinant Factor VIIa
D. High doses of recombinant factor VIII

9. Which of the following statements is FALSE regarding prophylactic factor replacement for
hemophilia patients?
A. The goal is to maintain the deficient factor level at a minimum of 0.01 units/mL (1%).
B. It is more beneficial to initiate prophylaxis in hemophilia patients when they reach adulthood.
C. Providing prophylactic replacement has been shown to prevent bleeding and joint destruction.
D. Providing tertiary prophylaxis (initiation after onset of joint disease) can prevent significant
progression of joint disease.

10. Other than factor replacement, which of the following treatments is the most appropriate
option for management of epistaxis in a patient with mild hemophilia A?
A. Cryoprecipitate
B. Fresh frozen plasma
C. Desmopressin
D. Aminocaproic acid

34

11. Which of the following initial dosing regimens for recombinant factor VIII concentrate
would you recommend for a patient with Hemophilia A who is experiencing an intracranial
hemorrhage (assume the goal is to increase factor level to 100% of normal)? The patients
weight is 165 pounds, and the factor VIII level is 0.007 Units/mL (0.7%).
A. 37.5 units intravenously once
B. 90 units intravenously once
C. 3750 units intravenously once
D. 9000 units intravenously once

12. Which of the following parameters would you recommend to monitor when administering
recombinant clotting factor to manage a hematoma in a patient with hemophilia B?
A. Factor VIII level 15 minutes after completed infusion
B. Hypertension
C. Thrombosis
D. Thrombocytopenia

13. Which of the following medications is correctly matched with an associated adverse effect?
A. Desmopressin hyponatremia
B. Aminocaproic acid visual disturbances
C. Recombinant Factor VIIa thrombocytopenia
D. Recombinant Factor VIII - rhabdomyolysis

14. Which of the following pharmacologic options is NOT appropriate for a hemophilia patient
who is experiencing chronic pain in his right knee due to a history of hemarthrosis (joint
bleeding)?
A. Acetaminophen
B. Ibuprofen
C. Oxycodone
D. Dexamethasone

15. Which of the following statements is TRUE when counseling a hemophilia patient on
medication management?
A. Plasma-derived coagulation factors are first line agents for factor replacement.
B. Prophylactic replacement is not recommended since it does not prevent recurrent joint bleeds.
C. You do not need to receive factor replacement if you are undergoing a dental procedure.
D. Home treatment can decrease pain and reduce risk of musculoskeletal dysfunction and long-term
disability.

35

16. Which of the following is considered a major risk factor for the development of inhibitors in
a patient with hemophilia?
A. Mild hemophilia
B. Hemophilia B
C. High-intensity factor replacement therapy
D. Bolus dosing of factor replacement therapy

17. What would be the most appropriate recommendation for managing a patient hemophilia
B found to have presence of inhibitors with a low titer of 4 BU that is not actively bleeding?
A. Cyclophosphamide
B. Immunoglobulin
C. Prednisone
D. Immune tolerance therapy with recombinant factor IX

18. If a patient with hemophilia A is found to have presence of inhibitors with a high titer of 12
BU, what would be the most appropriate recommendation for managing an acute
retroperitoneal bleed?
A. Activated prothrombin complex concentrates
B. Porcine factor VIII
C. Recombinant factor VIIa
D. High-dose replacement of recombinant factor VIII

19. Which of the following is TRUE regarding emerging therapies for hemophilia that are
currently in development?
A. Third generation recombinant clotting factors are associated with low risk since they contain
human proteins.
B. Gene therapy has been demonstrated to be effective in humans and will be available for use in the
near future.
C. Many of the new products in development are longer-acting versions of clotting factors to increase
ease of use.
D. The new products in development have been associated with a higher risk of viral transmission.

20. Pharmacists can play an important role in the coordination and management of care for
patients with hemophilia. Which of the following are responsibilities that pharmacists have
when taking care of hemophilia patients?
A. Evaluate factor concentrate dosing regimens for treatment and prophylaxis.
B. Train patients and caregivers on proper infusion technique of clotting factors at home.
C. Contact patients routinely to assess patient adherence to prescribed factor replacement regimen.
D. All of the above
Please submit your final responses on freeCE.com. Thank you.

36