Primary and
Secondary
Prophylaxis
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A. Rationale, Definition and Goals
In hemophilia care, prophylaxis refers to the regular infusion of clotting factor concentrate
to prevent bleeding episodes and related morbidity. This contrasts with episodic care in
which bleeding episodes are treated on-demand to achieve hemostasis. The World Health
Organization, the World Federation of Hemophilia, and the National Hemophilia
Foundation recommend that primary prophylaxis be considered as first-line therapy for
those with severe hemophilia. The ultimate goal is to prevent bleeding episodes and
disease sequelea.1,2 In patients with hemophilia, both primary and/or secondary
prophylaxis can be utilized and are discussed below and outlined in Table 1.
Bleeding into joints and muscles can typically be prevented if a severely deficient patient's
nadir level does not fall below 1%. Prevention of bleeding into joints and muscles leads to
preservation of a "normal" musculoskeletal state and prevention of a disability.
Maintaining a normal musculoskeletal state provides optimal therapy.
Prophylaxis is considered optimal therapy and should be instituted early, often beginning
at 1-2 years of age and prior to the onset of frequent bleeding, with the aim of keeping
trough levels ≥1% between doses.1 This can be accomplished by giving 25-50 IU/kg factor
VIII three times a week or every other day; or by giving 40-100 IU/kg factor IX two to three
times a week.1 The National Hemophilia Foundation recommends that individuals treated
on prophylaxis receive routine follow-up to document joint condition, complications, and
the frequency of breakthrough bleeding. To-date there is no definitive guideline on when to
stop prophylaxis1 and patients should work with their hemophilia treatment center (HTC)
to determine their individualized plan. Those with pre-existing joint arthropathy may
benefit from life-long prophylaxis.
a. Primary Prophylaxis: Primary prophylaxis is the initiation of infusion therapy on a
regular basis with the purpose of preventing hemorrhagic episodes for a prolonged,
if not indefinite period of time. Primary prophylaxis can be technically defined in
two ways:
A) Continuous therapy after the first joint bleed or before age 2 years;
B) Continuous therapy started before age 2 years and before a joint bleed has
occurred (Table 1).3,4
b. Secondary Prophylaxis: Secondary prophylaxis is aimed at interrupting a bleeding
pattern or preventing the advancement of joint disease. Secondary prophylaxis is
often used for a defined period with the purpose of interrupting an established
bleeding pattern, or providing coverage in order to “rest” an affected joint.4
Secondary prophylaxis can be:
A) Continuous (long-term);
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B) Intermittent (short-term).
The amount of long-term damage a joint develops however, may not be completely altered
by secondary prophylaxis. The frequency of infusion therapy required may be every other
day to effectively prevent recurrent bleeding; a higher nadir level than that required in
primary prophylaxis is often required to interrupt a bleeding pattern or rest a joint (Table
1).
Table 1. Definitions of Prophylaxis Therapy4,5
Type of Therapy
Definition
Primary prophylaxis A
Continuous therapy after first joint bleed or before age 2
years
Primary prophylaxis B
Continuous therapy started at age 2 before a joint bleed
Secondary prophylaxis A
Continuous therapy started after ≥2 bleeds or at an age
≥2 years
Secondary prophylaxis B
Intermittent therapy due to frequent bleeds
B. History of Prophylaxis
Primary prophylaxis is based upon the observation that moderate deficient patients bleed
less frequently than severe deficient patients and usually in association with some
intercurrent injury. Prophylaxis therefore aims to take a severe deficient patient and allow
them to maintain coagulation factor levels equivalent to a moderate deficient patient (i.e.
keep nadir levels prior to each infusion equal to or greater than 1%). The goal of this
method of infusion therapy is to prevent the sequelea of severe hemophilia, specifically
joint and muscle damage. Secondary prophylaxis has been employed since the advent of
reasonable replacement therapy and primarily has been used in countries where
replacement therapy has been instituted after bleeding episodes have been experienced
(definition of episodic care).
Published data regarding prophylaxis largely comes from studies performed in Sweden and
the Netherlands. Although two studies highlighted the importance and benefits of
prophylaxis on hemophilic arthropathy, they did not make comparisons to on-demand only
treatment.6,7 Others have published results detailing the benefits of prophylaxis and have
documented not only prevention of joint arthropathy, but also demonstrated an improved
quality of life for those receiving preventative care.8-12
Most recently, Manco-Johnson et al. published the first U.S. prospective, randomized study
in the New England Journal of Medicine comparing prophylactic therapy (n=32) to
enhanced episodic infusion therapy (n=33) in boys (1-21/2 years old) with severe factor VIII
deficiency.13 The study continued until the boys reached six years of age and results
showed that although those on prophylaxis consumed up to three times as much factor VIII
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concentrate than those using enhanced on-demand therapy, the prophylaxis group
experienced a median of 1.2 hemorrhages/year compared to 17.1 hemorrhages/year in the
episodic treatment arm. As a result, the on-demand group had a six-fold higher relative
risk of joint damage (p<0.001) as assessed by X-ray, MRI and physical examination.
Additionally, three of the 33 patients in the on-demand group experienced a serious lifethreatening hemorrhage compared to none in the prophylactic treatment arm (p=0.24).
The primary conclusion of this study is that prophylaxis not only prevents joint damage but
also decreases the frequency of hemarthrosis and serious non-joint hemorrhage.
C. Prophylaxis Considerations: Central Venous Access Devices
Independent of patient choice of treatment regimens, prophylactic or on-demand, there are
certain aspects of care that must be taken into consideration. One of the most important of
these considerations, specifically in very young children, is venous access.
a. Venous Access Devices: The use of peripheral veins to infuse clotting factor
concentrate is the method of choice; however, if this method is not possible, a
central venous access device (CVAD) may be used as a bridge. CVADs are typically
used in young patients who require clotting factor concentrate but are unable to
obtain venous access regularly at home.14-17 They are used in about 30% of those on
every-other-day prophylaxis and in 90% of those receiving daily immune tolerance
induction therapy.18 CVADs have benefits and risks and their use should be
discussed with the patient and/or family to determine the most appropriate
treatment option (Table 2). CVADs should only be used as long as medically
necessary.
i. Internal Catheter/Ports: Typically, an internal port is comprised of a
subcutaneous reservoir that is surgically implanted into either the chest
(Port-A-Cath) or in the arm (PassPort). The port appears as a bump under
the skin.14 A radio-opaque catheter (not transparent to X-rays or other
radiation) is attached to the reservoir with the free catheter end projecting
into the junction between the superior vena cava and the right atrium. Ports
are often used in those who may easily displace an external CVAD (i.e.
children).16 Ports require a needle to puncture the skin to access the
reservoir which can cause pain, anxiety and skin breakdown. They are
typically inserted in an operating room or radiology suite. A benefit of this
device, especially for children who enjoy swimming or are learning to swim,
is that this device allows for full submersion under water and has an
associated lower risk of infection compared to an external catheter.
ii. External Catheter: External catheters exit the skin through a subcutaneous
tunnel or directly at the site of entry into the skin. For tunneled catheters, a
tunnel is created under the skin through which the catheter is positioned.
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The distal end of the catheter is located between the superior vena cava and
the right atrium. An X-ray will verify the location of the catheter tip. The
proximal end of the catheter exits the skin and is typically located in the
chest region.16
Nontunneled catheters are secured in place at the insertion site. With this
treatment, the catheter and attachments protrude directly from the skin.
Patients with an external catheter cannot be submerged in water.
iii. Peripherally Inserted Central Catheter (PICC): A PICC line is a central
catheter that is inserted into a vein in the arm. This catheter enters the vein
and continues through the venous system until the tip reaches the superior
vena cava. A guide wire located in the catheter line allows for the movement
of the line through the veins. Just as with an external catheter, those with a
PICC line cannot be submerged in water.
Table 2. Commonly Used CVADs and Brief Descriptions
CVAD
Description
Potential Duration
of Use
Internal Cather/Port
• Surgically implanted under the skin usually in the
chest above the heart
• Patient places needle into a reservoir connected to the
catheter to infuse
Several years
External Catheter
• Surgically implanted under the skin and commonly
inserted into a vein in the neck or chest
• Patient infuses through the external end of the
catheter
• Inserted into a vein in the arm
•Patient infuses through the external end of the catheter
≥1 year
• Located in a vein near the heart, usually through the
chest
• Patient infuses into a cap near the end of the tube
The external catheter
is changed frequently
to keep the area sterile
(Tunneled)
Peripherally Inserted
Central Catheter
Weeks to months
(PICC)
External Catheter
(Nontunneled)
b. Benefits of CVADs: The three most common benefits of CVADs in hemophilia are:
1) the ease with which clotting factor concentrate can be infused; 2) the ability to
institute early prophylaxis and independent home infusion therapy; and 3) the
reduction in the risk of long-term peripheral vein damage.19 CVADs allow patients
and their families the freedom to infuse at home when peripheral venous access is
not possible, particularly in very small children, and thus reduces the number of
hospital, physician, and clinic visits.
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c. Risks of CVADs: The two most common risks associated with the use of a CVAD are
infection and thrombosis. Other less common risks include hemorrhagic
complications and occlusive complications caused by the device itself.
i. Infectious Complications: The placement of indwelling venous access
devices interrupts the body’s normal defense mechanisms to prevent
infection (bacteria) from entering the blood-stream. Individuals with any
CVAD are subject to experiencing a bacterial infection in the blood
(bacteremia or sepsis). These infections may be severe or life-threatening if
prompt attention is not sought or provided. It is estimated that between 855% of patients with a CVAD get an infection.20-22 Infections are most
common in patients under two years of age who require frequent infusions
and in those with inhibitors.
Signs of an infection include fever, reddening of the skin at the point of entry
or along the catheter tract, and/or drainage at the insertion site. Antipyretic
medication may be given as outlined in Table 3; however, the patient should
be immediately evaluated by a physician. Blood cultures should be taken
from the CVAD, and peripherally if possible. Blood cultures are permitted to
grow for 72 hours. In the interim, a dose of broad spectrum antibiotics
should be administered as a precautionary measure through the CVAD. If a
culture tests positive for bacteria, sensitivity testing will be performed to
determine the appropriate antibiotic treatment regimen.
Table 3. Antipyretic Dosage
Medication
Pediatric Dosage
Adult Dosage
Acetaminophen
10-15 mg/kg, every 4-6 hours*
325-500 mg, every 4-6 hours^
Non-steroidal antiinflammatory (e.g.,
Ibuprofen)Δ
10 mg/kg, every 6-8 hours
200-400 mg, every 4-6 hours
Due to the potential for liver damage:
*No more than 5 doses of acetaminophen in a 24 hour period; maximum daily dose should not exceed 90
mg/kg/day
^Maximum daily dose should not exceed 4 g/day
ΔNon-steroidal anti-inflammatory medications should only be taken in individuals with bleeding disorders if
directed by a physician
Gram-positive and Gram-negative bacteria are types of organisms that are
common in CVADs (Table 4). They are distinguished by their ability to retain
a crystal violet stain. This technique was developed in the 1800’s and is
called Gram staining.23 Gram-positive bacteria retain the crystal violet stain
while Gram-negative bacteria do not. Most pathogens in humans are Gram-
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positive organisms and usually eradicated with antibiotic therapy. Gramnegative organisms tend to be more virulent and difficult to eradicate due to
having an outer endotoxic layer that triggers an immune response. Bacteria
in or around a catheter also form a slimy matrix, called biofilm, that can
inhibit successful clearing with antibiotics.24 In this case, antibiotic lock
therapy, a method of allowing an antibiotic to sit within the catheter for up to
48 hours, may be indicated. Different fungal species can also cause CVAD
infection.
Table 4. Types of Organisms Typically Found in CVADs
Pathogen Name
Type of
pathogen
Coagulase-negative Staphylococcus
epidermidis and Staphylococcus saprophyticus
Gram-positive
Comments




Coagulase-positive Staphylococcus aureus
Gram-positive

Enterococcus species
Enterobacter species, E. coli, K. pneumonia,
P. aeruginosa
Gram-positive
Gram-negative
Fungus (yeast)
Requires aggressive treatment as
organism is highly virulent
May clear with 4 weeks of systemic
antibiotics and antibiotic lock
therapy; however, clearance of
infection may require catheter
removal
Known to cause infective
endocarditis


Causes 10% of all infections
Likely to be cleared with use of
ampicillin; or vancomycin for
ampicillin-resistant strains

Propensity to form a biofilm in the
catheter, making it difficult to clear
the infection
Need to be aggressive with first
round of antibiotic treatment to
prevent recurrence of infection
To prevent antibiotic resistance,
therapy should be continued for at
least 7-14 days


Candida species
Most common cause of catheterrelated infection
Likely to be cleared if treated with a
10-14 day antibiotic regimen



Low success rate of clearing infection
High associated mortality and
morbidity
May require removal of the central
line
Other risk factors for infection include: poor oral hygiene and/or the
presence of dental cavities or abscesses; and medical conditions that
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compromise the immune system.19 Infections can also occur due to poor
sterile technique when accessing the CVAD. If more than one infection
occurs in a device, a follow-up investigation is warranted and the medical
provider should discuss techniques to lessen future risk of infection if
continued CVAD use is required. Current Centers for Disease Control and
Prevention strategies to prevent catheter-related infections can be found at:
http://www.cdc.gov/hicpac/pdf/guidelines/bsi-guidelines-2011.pdf.
ii. Thrombosis: Thrombosis is the development of a blood clot that obstructs
the flow of blood through a vessel. Patients with hemophilia can develop
blood clots most commonly when a CVAD is present.19 The clot can form
within the reservoir, within the catheter tube, or directly inside the lumen of
a blood vessel. Clots that form within the reservoir or catheter may be caused
by inappropriate flushing or anticoagulation. A fibrin sheath may also form
around the catheter leading to fluid leakage or complete blockage at the
catheter tip. It is also possible for the catheter to irritate the lumen of the
vessel, leading to thrombus formation. The long-term consequences from
CVAD-related thrombosis in children with hemophilia are not completely
known at this time.
To dissolve a clot, thrombolytic therapy may be used. If clot dissolving
medications prove ineffective, the catheter may require removal and/or
replacement. Depending upon patient symptoms, the utility of the existing
line, and the extent of clot formation, a patient may need to have the CVAD
removed.
iii. Hemorrhagic Complications: Individuals with hemophilia may have low
enough factor levels, prior to the next infusion, such that the placement of the
needle into the port may precipitate the development of a hematoma around
the port reservoir. This may in turn lead to the development of a problem
with the port or a theoretical increased risk of infection. A blow to a CVAD
may also precipitate a bleeding episode despite the use of primary
prophylaxis.
iv. Other Complications: Although uncommon, it is possible for the line of the
catheter to fracture and travel to another part of the body such as the heart
or lungs.19 The catheter can also separate from the reservoir causing
infiltration of clotting factor concentrate into the surrounding tissue without
delivery into the blood stream. Finally, an opening can form in the skin
covering the reservoir from skin dehiscence. These complications require
corrective action.
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d. Removal of a CVAD: A CVAD should be removed as soon as is feasible due to the
inherent risks of these devices. Circumstances that may warrant immediate removal
include: an infection cannot be cleared; catheter occlusion; line fracture; or if a
thrombosis has occurred in a vessel. The optimal method of factor infusion is
peripheral venipuncture; this should be used as soon as the patient or family is able
to master this technique.
D. Dental Prophylaxis
Dental treatment can be risky and cause bleeding which can be severe or even fatal in
individuals with bleeding disorders. Therefore, dental care and prevention should be
stressed by an HTC. Preventative actions will help maintain good oral health. In those with
bleeding disorders, teething alone rarely causes bleeding; however, if minor bleeding
occurs, the HTC should be notified to take the appropriate measures. Steps should also be
taken to ensure the individual’s dentist has the following information on file:
•
•
•
•
•
Type and severity of the bleeding disorder
Presence of inhibitor or venous access device
List of current medications
Knowledge of appropriate pre-dental treatment requirements
HTC contact information
Dental procedures in those with hemophilia can be divided into two broad categories: lowrisk and high-risk. Low-risk procedures do not require special medical recommendations
and include the placement of sealants, incipient restorations and restorations that do not
require block injections, including root canal therapy on the upper teeth. High-risk
procedures require dental prophylaxis and are described below. Ideally, these procedures
are performed on the day of regularly scheduled prophylaxis; alternatively individuals are
infused on the day of treatment if utilizing an on-demand regimen.
a. Tooth Extractions: Individuals with hemophilia that require a dental extraction
should be infused with an 80-100% correction prior to extraction.25 A full-mouth
extraction should be performed in one to two appointments. Additionally,
antifibrinolytic therapy should be started on the day of treatment and continued for
ten days.
b. Block Injections: If a block injection is required, a 40% factor correction is
recommended.25 Alternatively, desmopressin may be used when appropriate.
c. Oral Surgery: Oral surgery in an individual with a bleeding disorder requires
formulation of a surgery plan. The plan should be communicated to all of those
participating in the patient’s care. Topics of discussion include whether clotting
factor concentrate and/or antifibrinolytics are required and the dosage, the type
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and location of anesthetic coverage, and whether antibiotic coverage is
recommended.
The American Academy of Pediatric Dentistry (AADP)
recommendations for antibiotic coverage are listed in Table 5.26
Table 5. AADP Antibiotic Coverage Recommendations
Situation
Agent
Adults
Pediatrics
Oral
Amoxicillin
2g
50 mg/kg
Unable to take oral
medication
Ampicillin,
Cefazolin or Ceftriaxone
2 g IM or IV
1g IM or IV
50 mg/kg IM or IV
50 mg/kg IM or IV
Allergic to
penicillin or
ampicillin – oral
Cephalexin,
Clindamycin,
Azithromycin or Clarithoromycin
2g
600mg
500mg
50 mg/kg
20 mg/kg
15 mg/kg
1g IM or IV
600mg IM or IV
50mg/kg IM or IV
20mg/kg IM or IV
Allergic to
penicillin or
ampicillin and
unable to take oral
medication
Cefazolin or Ceftriaxone,
Clindamycin
d. Periodontal Treatment: Individuals with severe periodontal disease may require
surgery. Patients on a regular clotting factor concentrate or prophylaxis schedule
are encouraged to have the surgery performed on the same day as they are
scheduled to infuse. Patients using on-demand therapy require a 40-80%
correction prior to surgery. Antifibrinolytic agents may be used to stabilize the clot
following surgery.
e. Dental Emergencies: Dental emergencies in individuals with a bleeding disorder
require immediate attention and the patient should be seen by a dentist as soon as
possible. Examples of dental emergencies include: discoloration of soft tissue;
broken teeth or black areas on the tooth; swollen, puffy or inflamed gums; dental
abscesses; frenulum tear; liver clot; eruption hematoma; and evulsed or broken
teeth.
For more information on Dental Management for individuals with bleeding disorders refer
to the IHTC manual entitled Management Issues: Hemophilia and von Willebrand Disease
(Section 15).
E. Compliance with Home-Based Prophylaxis Therapy
The institution of either primary or secondary prophylaxis requires a compliant
patient/family situation, especially if an indwelling venous access catheter is used. Not all
patients/families are optimal candidates. The caregiver should adequately explain the
need for compliance, the medical follow-up required and provide sufficient education so
that the patient and family are equipped to handle their care. Families with no family
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history, or experience with hemarthrosis and other complications may have some difficulty
realizing the life-long benefits of prophylaxis.27
In a recent European study, reasons cited for low compliance to a prophylactic regimen
included: disappearance of symptoms; forgetfulness; lack of time; and inconvenience of
treatment.28 This study also cited the most common reasons for positive compliance as:
young age, time spent in a hemophilia treatment center, and the quality of the relationship
with the medical team.28 Acceptance of the diagnosis and difficulties with venous access
have also been cited as reasons for low compliance.29 Ultimately, to achieve optimal
compliance, a caregiver must understand the patient’s and family’s needs, desires,
expectations, social environment, self-image, and desire for quality of life.27
F. Infusion Logs
Infusion logs are an important tool for patients, families and HTCs. Infusion logs allow
HTCs to manage a patient’s care more accurately and effectively, and enable patients to
take a more proactive approach to their own healthcare. Logs track clotting factor
concentrate infusion date and time, purpose, site of infusion, and outcome. Some insurance
companies require patients to keep infusion logs for claim reimbursement. Infusion logs
can be kept on paper, through phone applications, or via other electronic records such as
that provided by the American Thrombosis and Hemostasis Network (ATHN) called
ATHNadvoy.
G. Financial Issues
Hemophilia therapy is an expensive medical condition with the primary cost arising from
factor replacement.30 The cost of primary or secondary prophylaxis is more per year as
compared to on-demand therapy; however, the health-related quality of life and medical
outcomes in patients on prophylaxis is consistently better. 31 Additionally, expenses
incurred from surgery and loss of work days is lower in those on prophylaxis. 10 The cost of
the long-term sequelea of hemophilia such as disability or need for joint replacement need
to be weighed when considering these infusion programs. One is essentially placing the
cost of hemophilia care "up-front" when instituting primary prophylaxis for patients. The
National Hemophilia Foundation strongly encourages primary prophylaxis as a first-choice
of therapy in severe deficient hemophilia A and B. Patients and families must be informed
about issues related to cost. Optimally, insurers should be educated and "buy-in" to the
concept of primary prophylaxis.
H. Product Availability
Patients on prophylactic therapy consume more clotting factor concentrate per year than
those using on-demand therapy. The optimal treatment today is the use of recombinant
clotting factor concentrate. A theoretical unlimited supply of recombinant product should
be available as recombinant clotting factor concentrate does not rely on human plasma for
its production.
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I. Psychosocial Implications
Many publications have documented the psychosocial implications associated with chronic
disease and hemophilia in the U.S. as well as abroad (refer to the IHTC Manual:
Management Issues: Hemophilia and von Willebrand Disease for more detailed
information).32 Prior to prophylaxis, school absenteeism was common due to the
frequency of bleeding episodes and joint problems; however, school integration and
attendance is less of a problem since the advent of prophylaxis and home treatment. 33-35
Prophylaxis in patients with hemophilia may also protect these individuals from
psychosocial complications sometimes seen in patients with other rare bleeding
disorders.36 The exact reason for this correlation is not well understood but is
hypothesized to be due to allowing children to lead more “normal” lives. This may be due to
the observation that prophylaxis leads to improved social and academic participation and
improves subsequent work opportunities in those with severe hemophilia.
J. Future of Prophylaxis
Given the convincing evidence documented on the benefits of prophylaxis compared to ondemand therapy, and due to the recommendations by the National Hemophilia
Foundation1, the hemophilia field has now focused on identifying the optimal prophylactic
regimen rather than further delineating the differences between prophylaxis and ondemand treatment. An “optimal” regimen takes into account: whether or not the primary
goal is only to maintain joint function or to maintain near-normal hemostasis and thus
participation in normal daily activities. Furthermore, methods to decrease the expense of
prophylaxis are being investigated. In regard to the latter, studies from Malmö, Sweden
have shown that patients using daily prophylaxis for one year consumed 30% less clotting
factor concentrate (p<0.04) than those using the standard prophylactic regimen (i.e.,
either every other day or three times/week) or pharmacokinetic-specific dosing.37
However, the total number of bleeding events increased in some patients utilizing the daily
prophylaxis regimen. This was associated with a decreased quality of life. Further studies
are needed to determine the cause of increased bleeding, and hence optimal regimens.
K. References:
1.
Medical and Scientific Advisory Council (MASAC) recommendation #179: MASAC
recommendation concerning prophylaxis (regular administration of clotting factor concentrate to
prevent
bleeding).
2007.
(Accessed
January
7,
2010,
at
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=1007.)
2.
Berntorp E, de Moerloose P, Ljung RC. The role of prophylaxis in bleeding disorders.
Haemophilia 2010;16 Suppl 5:189-93.
3.
Petrini P, Lindvall N, Egberg N, Blombäck M. Prophylaxis with factor concentrates in
preventing hemophilic arthropathy. Am J Pediatr Hematol Oncol 1991;13:280-7.
4.
Ljung R. Prophylactic therapy in haemophilia. Blood Rev 2009;23:267-74.
5.
Donadel-Claeyssens S, Management EPNfH. Current co-ordinated activities of the PEDNET
(European Paediatric Network for Haemophilia Management). Haemophilia 2006;12:124-7.
2012 Copyright Indiana Hemophilia & Thrombosis Center, Inc. Primary and Secondary Prophylaxis
| 12
6.
Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of
prophylactic treatment in severe haemophilia A and B. J Intern Med 1992;232:25-32.
7.
van den Berg HM, Fischer K, Mauser-Bunschoten EP, et al. Long-term outcome of
individualized prophylactic treatment of children with severe haemophilia. British Journal of
Haematology 2001;112:561-5.
8.
Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes
for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med
1994;236:391-9.
9.
Fischer K, Astermark J, van der Bom JG, et al. Prophylactic treatment for severe
haemophilia: comparison of an intermediate-dose to a high-dose regimen. Haemophilia
2002;8:753-60.
10.
Steen Carlsson K, Höjgård S, Glomstein A, et al. On-demand vs. prophylactic treatment for
severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome.
Haemophilia 2003;9:555-66.
11.
Brackmann HH, Eickhoff HJ, Oldenburg J, Hammerstein U. Long-term therapy and ondemand treatment of children and adolescents with severe haemophilia A: 12 years of experience.
Haemostasis 1992;22:251-8.
12.
Carlsson M, Berntorp E, Björkman S, Lindvall K. Pharmacokinetic dosing in prophylactic
treatment of hemophilia A. European Journal of Haematology 1993;51:247-52.
13.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to
prevent joint disease in boys with severe hemophilia. The New England Journal of Medicine
2007;357:535-44.
14.
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for use of
central venous access devices in haemophilia. Haemophilia 2004;10:629-48.
15.
Ljung R. The risk associated with indwelling catheters in children with haemophilia. Br J
Haematol 2007;138:580-6.
16.
Komvilaisak P, Connolly B, Naqvi A, Blanchette V. Overview of the use of implantable venous
access devices in the management of children with inherited bleeding disorders. Haemophilia
2006;12 Suppl 6:87-93.
17.
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for use of
central venous access devices in haemophilia. Haemophilia 2004;10:629-48.
18.
Valentino LA, Kawji M, Grygotis M. Venous access in the management of hemophilia. Blood
Rev 2011;25:11-5.
19.
Medical and Scientific Advisory Council (MASAC) document #115- MASAC recommendation
regarding central venous access devices including ports and passports. 2001. (Accessed at
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=297.)
20.
Medeiros, Miller, Rollins, Buchanan. Contrast venography in young Haemophiliacs with
implantable central venous access devices. Haemophilia 1998;4:10-5.
21.
Liesner RJ, Vora AJ, Hann IM, Lilleymann JS. Use of central venous catheters in children with
severe congenital coagulopathy. Br J Haematol 1995;91:203-7.
22.
Blanchette VS, Al-Musa A, Stain AM, Ingram J, Fille RM. Central venous access devices in
children with hemophilia: an update. Blood Coagul Fibrinolysis 1997;8 Suppl 1:S11-4.
23.
Austrian R. The Gram stain and the etiology of lobar pneumonia, an historical note. Bacteriol
Rev 1960;24:261-5.
24.
Talsma SS. Biofilms on medical devices. Home Healthc Nurse 2007;25:589-94.
2012 Copyright Indiana Hemophilia & Thrombosis Center, Inc. Primary and Secondary Prophylaxis
| 13
25.
Brewer A, Correa M. Guidelines for dental treatment of patients with inherited bleeding
disorders.
Treatment
of
Hemophilia.
http://www.lhsc.on.ca/Health_Professionals/Bleeding_Disorders/TOH-40_Dental_treatment.pdf.
2006.
26.
American Academy of Pediatric Dentistry (AAPD). Guideline on Antibiotic Prophylaxis for
Dental Patients at Risk for Infection. Clinical Guidelines Reference Manual 2011;33:265-9.
27.
Coppola A, Cerbone AM, Mancuso G, Mansueto MF, Mazzini C, Zanon E. Confronting the
psychological burden of haemophilia. Haemophilia 2011;17:21-7.
28.
De Moerloose P, Urbancik W, Van Den Berg HM, Richards M. A survey of adherence to
haemophilia therapy in six European countries: results and recommendations. Haemophilia
2008;14:931-8.
29.
Santagostino E, Mancuso ME. Barriers to primary prophylaxis in haemophilic children: the
issue of the venous access. Blood Transfus 2008;6 Suppl 2:s12-6.
30.
Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia
patients with inhibitors: costly can be cheaper. Blood 2000;96:1698-702.
31.
Royal S, Schramm W, Berntorp E, al e. Quality-of-Life differences between prophylaxis
treatment and on-demand factor replacement therapy in European haemophilia patients.
Haemophilia 2002;8:44-50.
32.
Psychosocial Care for People with Hemophilia- The World Federation of Hemophila. 2007.
(Accessed at
33.
Plug I, Peters M, Mauser-Bunschoten EP, et al. Social participation of patients with
hemophilia in the Netherlands. Blood 2008;111:1811-5.
34.
Markova I, MacDonald K, Forbes C. Integration of haemophilic boys into normal schools.
Child Care Health Dev 1980;6:101-9.
35.
Shapiro AD, Donfield SM, Lynn HS, et al. Defining the impact of hemophilia: the Academic
Achievement in Children with Hemophilia Study. Pediatrics 2001;108:E105.
36.
Clemente C, Tsiantis J, Sadowski H, et al. Psychopathology in children from families with
blood disorders: a cross-national study. Eur Child Adolesc Psychiatry 2002;11:151-61.
37.
Lindvall K, Astermark J, Bjorkman S, et al. Daily dosing prophylaxis for haemophilia: a
randomized crossover pilot study evaluating feasibility and efficacy. Haemophilia : the official
journal of the World Federation of Hemophilia 2012.
2012 Copyright Indiana Hemophilia & Thrombosis Center, Inc. Primary and Secondary Prophylaxis
| 14