TAILORING PROPHYLAXIS AND TREATMENT OF

HEMOPHILIA SANDEEP DEVABHAKTHUNI, PHARM.D.

1

TAILORING PROPHYLAXIS AND TREATMENT OF HEMOPHILIA

ACTIVITY DESCRIPTION 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.

TARGET AUDIENCE

The target audience for this activity is pharmacists,

pharmacy technicians and nurses in hospital,

community, and retail pharmacy settings.

LEARNING OBJECTIVES 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

ACCREDITATION

PHARMACY

PharmCon, Inc. is accredited by the

Accreditation Council for Pharmacy

Education as a provider of continuing

pharmacy education.

NURSING

PharmCon, Inc. is approved by the California Board of

Registered Nursing (Provider Number CEP 13649) and

the Florida Board of Nursing (Provider Number 50-

3515). Activities approved by the CA BRN and the FL

BN are accepted by most State Boards of Nursing.

CE hours provided by PharmCon, Inc. meet the ANCC criteria

for formally approved continuing education hours. The ACPE

is listed by the AANP as an acceptable, accredited continuing

education organization for applicants seeking renewal

through continuing education credit. For additional

information, please visit

http://www.nursecredentialing.org/RenewalRequirements.aspx

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

Credits: 2 contact hours (0.2 CEU)

Release Date: December 15, 2014

Expiration Date: December 15, 2016

ACTIVITY TYPE

Knowledge-Based Home Study Monograph

FINANCIAL SUPPORT BY

Baxter

2

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.

3

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

4

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 blood-

borne 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

5

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

6

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

7

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.

8

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.

9

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

10

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.

11

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

12

Despite recombinant factors being more expensive than plasma-based factors by 20-

50%, 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

13

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

14

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.

15

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 cost-

effective 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

16

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

17

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

18

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

19

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

20

(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

21

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

22

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.

23

References:

1. Mannucci PM, Tuddenham EG. The hemophilias from royal genes to gene therapy. N Engl

J Med. 2001;344:1773-1779.

2. Stonebraker JS, Bolton-Maggs PH, Soucie JM, Walker I, Brooker M. A study of variations in

the reported haemophilia A prevalence around the world. Haemophilia. 2010;16:20-32.

3. Van Dijk K, Fishcer K, van der Bom JG, Grobbee DE, van den Berg HM. Variability in clinical

phenotype of severe haemophilia: The role of the first joint bleed. Haemophilia.

2005;11:438-443.

4. Rosendaal G, Lafeber FP, Pathogenesis of hemophilic arthropathy. Haemophilia.

2006;12:117-121.

5. Mannucci PM. Back to the future: A recent history of hemophilia treatment. Haemophilia.

2008;14:10-18.

6. Plug I, van der Bom JG, Peters M, et al. Thirty years of hemophilia treatment in the

Netherlands, 1972-2001. Blood. 2004;104:3494-3500.

7. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: A systematic review.

Haemophilia. 2003;9:418-435.

8. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of

hemophilia. Hemophilia. 2013;19:e1-e47.

9. High K. The leak stops here: platelets as delivery vehicles for coagulation factors. J Clin

Invest. 2006;116:1840-1842.

10. Teitel JM, Barnard D, Israels S, Lillicrap D, Poon MC, Sek J. Home management of

haemophilia. Haemophilia. 2004;10:118-133.

24

11. Frachon X, Pommereuil M, Berthier AM, et al. Management options for dental extraction in

hemophiliacs: a study of 55 extractions (2000-2002). Oral Surg Oral Med Oral Pathol Oral

Radiol Endod. 2005;99:270-275.

12. Rattray B, Nugent DJ, Young G. Celecoxib in the treatment of haemophilic synovitis, target

joints, and pain in adults and children with haemophilia. Haemophilia. 2006;12:S14-17.

13. Hermans C, de Moerloose P, Fischer K, et al. Haemophilia Therapy Standardisation Board.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review,

European survey and recommendations. Haemophilia. 2011; 17:383-92.

14. Rattray B, Nugent DJ, Youn G. Celecoxib in the treatment of haemophilic synovitis, target

joints, and pain in adults and children with haemophilia. Haemophilia. 2006;12:514-517.

15. Tsoukas C, Eyster ME, Shingo S, et al. Evaluation of the efficacy and safety of etoricoxib in

the treatment of hemophilic arthropathy. Blood. 2006;107:1785-1790.

16. Rodriguez-Merchan EC. Musculoskeletal complications of hemophilia. HSSJ. 2010;6:37-42.

17. Mannucci P. Hemophilia: treatment options in the twenty-first century. Thromb Haemost.

2003;1:1349-1355.

18. Ludlam A, Powderly WG, Bozzetta S. Clinical perspectives of emerging pathogens in

bleeding disorders. Lancet. 2006;367:252-261.

19. Ingram C. The history of haemophilia. J Clin Pathol. 1976;29:469-479.

20. Farrugia A. Evolving perspectives in product safety for haemophilia. Haemophilia.

2002;8:236-243.

21. Pipe SW. Recombinant clotting factors. Thromb Haemost. 99:840-850.

25

22. White G, Shapiro A, Ragni M, et al. Clinical evaluation of recombinant factor IX. Semin

Hematol. 1998;35:33-38.

23. Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Recombinant factor VIII for the treatment of

previously untreated patients with hemophilia A. Safety, efficacy, and development of

inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med.

1993;328:453-459.

24. Bartorova A, Martinowitz U. Continuous infusion of coagulation factors. Haemophilia.

2002;8:170-177.

25. Kasper CK. Products for clotting factor replacement in developing countries. Seminr Thromb

Hemost. 2005;31:507-512.

26. Giangrande PL. Blood products for hemophilia: past, present and future. Bio Drugs.

2004;18:225-234.

27. Fanchini M, Salvagno GL, Lippi G. Inhibitors in mild/moderate haemophilia A: an update.

Thromb Haemost. 2006;96:113-118.

28. Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor

replacement. Curr Opin Hematol. 2006; 13:316-322.

29. Knobe KE, Sjorin E, Tengborn LI, Petrini P, Ljung RC. Inhibitors in the Swedish population

with severe haemophilia A and B: a 20-year survey. Acta Paediatr. 2002;91:910-914.

30. Kessler C, Santilli M. Understanding hemophilia: a manafed care review. CDMI Report. Fall

2013;32-38.

31. Farrugia A. Evolving perspectives in product safety for haemophilia. Haemophilia.

2002;8:236-243.

26

32. Barrow RT, Healey JF, Gailani D, Scandella D, Lollar P. Reduction of the antigenicity of factor

VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid

human/porcine factor VIII molecules. Blood. 2000;95:564-568.

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

years. Blood. 1997;90:2515-21.

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.

40. Bianchette VS. Prophylaxis in the haemophilia population. Haemophilia. 2010;16:181-188.

27

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;16:54-

60.

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-to-

moderate bleeds in hemophilia patients with inhibitors. Curr med Res Opin.

28

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.

29

Table 1. Hemophilia Severity Classification by Factor Concentration8

Classification Factor Concentration* (Units/mL)

Clinical Manifestations

Mild > 0.05 0.4 Units/mL (>5 40%)

Hemorrhage with magor trauma or surgery May go years without diagnosis

Moderate 0.01 0.05 Units/mL (1 5%)

Occasional spontaneous hemorrhages Hemorrhage with mild trauma/surgery that is prolonged

Severe < 0.01 Units/mL (

30

Table 3. Guidelines for Factor Replacement

Hemorrhage Factor VIII (% of normal)

Factor IX (% of normal)

Duration (days)

Severe

Intracranial

Retroperitoneal

Retropharyngeal

60 100 50 100 10 14

Moderate

Hemarthroses

Hematoma

Hematuria

30 60 25 50 3 7

Minor

Epistaxis

Oral (mild)

20 40 15 30 1 3

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

Factor VIII Factor IX

Initial Dose (units) Desired increase (%) x Weight (kg) x 0.5

Pediatric: Desired increase (%) x Weight (kg) x 1.4 Adult: Desired increase (%) x Weight (kg) x 1.2

Maintenance Dose (units)

50% of initial dose 50% of initial dose

Expected Response (0.02 Units/mL)

(0.01 Units/mL)

Half-life (hours) 8 15 11 27 Dosing Interval 12 24 (minor bleed)

8 12 (moderate severe bleed)

12 24

31

Table 5. Prophylactic Factor Replacement

Protocol Definition

Episodic Treatment 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

Secondary Prophylaxis Regular continuous treatment after 2 or more bleeds into large joints and before onset of joint disease

Tertiary Prophylaxis Regular continuous treatment started after onset of joint disease

Intermitent Prophylaxis Treatment given to prevent bleeding for periods not exceeding 45 weeks in a year

Table 6. Emerging Hemophilia Products in Development51,52

Product Name (Manufacturer) Product Type/Indication Distinguishing Feature

Regulatory Status

Factor VIII

BAX 855 (Baxter) Pegylated rFVIII Long acting Phase II/III

BAY 81-8973 (Bayer) BDD rFVIII 3rd generation; normal t1/2

Phase III completed March 2013

BAY 94-9027 (Bayer) Pegylated rFVIII Long acting Phase III

BIIB 031 (Blogen Idec) BDD rVIII-Fc fusion Long acting Phase III completed March 2014

CSL627 (CSL Behring) Single-chain rFVIII Improved stability during manufacturing

Phase II/III

GreenGene F (Green Cross Corporation)

rFVIII New in the United States

Phase III

Turoctocog alfa (Novo Nordisk NovoEight)

BDD rFVIII Normal t1/2 Approved 2013

NN7088 (Novo Nordisk N8-GP) Glyco-pegylated rFVIII Long acting Phase III

32

Human-cl rhFVIII (Octapharma) Hemophilia A Normal t1/2 Phase III

NecLip-pdFVIII (Recoly NV LongAte)

Plasma-derived factor VIII formulated with NecLip

Long acting Approved in Russia

Factor IX

BAX 326 (Baxter Rixubis) Third-generation rFIX First 3rd generation product

Approved June 2013

BIIB 029 (Biogen Idec/Swedish Orphan Biovitrium Alprolix)

rFIX-Fc fusion Long acting Approved March 2014

IB1001 (Cangene Corporation) rFIX Approval on hold pending data requested by FDA

CSL654 (CSL Behring) rFIX albumin fusion Long acting Phase II/III

NN7999 (Novo Nordisk N9-GP) Glyco-pegylated rFIX Long acting Phase III

Inhibitors of Factor VIIA

BAX 817 (Baxter) Hemophilia with inhibitors rFVIIa

Normal t1/2 Phase III

OBI-1 (Baxter) Hemophilia A with inhibitors or acquired hemophilia A

Recombinant (porcine)

Phase III

CSL589 rVIIa-FP (CSL Behring) Hemophilia A or B with inhibitors; rFVIIa-albumin fusion

Long acting Phase I

LA-rFVIIa (Novo Nordisk) rFVIIa Long acting Phase I/II

PF-05280602 (Pfizer/Catalyst Biosciences)

Hemophilia with inhibitors; rFVIIa

Produced by human cell line

Phase I

NecLip-rFVIIa (Recoly NV LongSeven)

Hemophilia with inhibitors; rFVIIa formulated with NecLip

Long acting Phase I/II

LR769 (rEVO biologics/LFB Biotechnologies)

Hemophilia A or B with inhibitors; transgenic rFVIIa

Produced in rabbit milk

Phase II

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

33

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

34

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

35

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.

36

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.