See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/308792978

Diagnosis and Management Guidelines of Hemophilia in Saudi Arabia

Article · June 2011

CITATIONS READS

2 2,918

1 author:

Abdulkareem M Almomen
Security Forces Hospital Program
124 PUBLICATIONS   1,640 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Beta thalassemia management View project

Trace elements View project

All content following this page was uploaded by Abdulkareem M Almomen on 03 October 2016.

The user has requested enhancement of the downloaded file.

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]

review
Diagnosis and Management Guidelines of
Hemophilia in Saudi Arabia
Ahmad M. Tarawah,a Tarek Owaidah,b Mahasen Saleh,b Fawaz Al-Kasim,c Thekra Al-Khaial,d
Hazzaa Al-Zahrani,b Azzah Al-Zahrani,c Mohammad Zolaly,a Mohammad Al-Shahrani,c Fawzi
AlJassir,e and Abdulkareem Almomen

a
Maternity and Children Hospital, King Abdullah
Medical City, Madinah, bKing Faisal Specialist
The current medical practice is evidence based. The use of evidence-based Hospital and Research Centre, cRiyadh Military
guidelines in the management of medical conditions can result in harmonisa- Hospital, dKing Saud Medical City, eKing Khalid
University Hospital, Center of Excellence for
tion among care providers with regard to diagnosis, and selection of therapeutic Thrombosis and Homeostasis
products to treat haemophilia.These guidelines are designed to fit the needs and
Corresponding author:
special conditions of patients in Saudi Arabia, and include details of the therapeu- Ahmad M.Tarawah, MD
tic products available in Saudi Arabia. Consultant, Pediatric Hematology and Oncology
Maternity and Children Hospital
King Abdullah Medical City
KEYWORDS: hemophilia, Saudi Arabia, treatment, diagnosis Madinah, Saudi Arabia
T: +966505302750
tarawah@yahoo.com, atarawah@hotmail.com

H emophilia is not an uncommon disease in

Saudi Arabia. This guideline has been devel-
oped to fulfil practitioners’ increasing needs
for guidance regarding hemophilia treatment.
This guideline has been developed based on 201-20
well-known standard and international guidelines with
slight modification to suit practice in Saudi Arabia.
The guideline has been designed to provide a prac-
tical and accessible guidance for health care practi-
tioners. The responsibility for the care and choice of
treatment of patients with hemophilia lies with the at-
tending doctor and it should not be a substitute for the
attending doctor’s clinical judgment. Our guidelines
have addressed important issues regarding the com-
prehensive management of hemophilia patients with
emphasis on the treatment of special situations like
dentistry, orthopaedics, and circumcision. We hope
these guidelines will continue to be of value to phy-
sicians, nurses, laboratory scientists, and other health
care providers.
Hemophilia overview
Hemophilia is an inherited bleeding disorder caused
by a congenital deficiency or complete absence of co-
agulation factor VIII (FVIII; hemophilia A) or coagu-
lation factor IX (FIX; hemophilia B).
Hemophilia A has a prevalence of about 1 in
10,000 males, while hemophilia B is about 1 in 35,000-
50,000 males. Unfortunately, no current local data are
available.
The FVIII and FIX genes are located on the long
arm of the X chromosome. Hemophilia almost ex-
clusively affects men, but women are the carriers.
However, in about 30% of the new cases, there is no
known person with hemophilia in the family.
Clinical presentations depend on hemophilia sever-
ity. While mild hemophiliacs may delay presentation
till adulthood, severe hemophiliacs may present as
early as the neonatal period and most are diagnosed
during the first 2 years (Table 1). The factor levels can
be affected by age, and consideration of physiologi-
cal changes in factors levels must be considered in the
diagnosis of factor deficiency (Table 2).
If hemophilia patients are not well treated, se-
rious damages may occur in the form of deformed
joints with severe movement limitations, contractures,
chronic pain, and muscle atrophy (Table 3).
Hemophilia diagnosis
Accurate diagnosis of hemophilia is essential before
starting any therapy, and should be done as soon as
clinical manifestations appear or whenever there is
a family history of hemophilia. Careful history and
physical examination are important.
Hemophilia should be suspected in patients pre-
senting with:
• Family history of bleeding, particularly in males
with a lifelong history of bleeding
• Spontaneous bleeding (particularly into the joints
and soft tissue)

Journal of Applied Hematology 2011 171

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]

review SAUDI HEMOPHILIA GUIDELINES

Table 1. International Society on Thrombosis and Hemostasis

Once the screening tests show suspected hemophilia,
Clotting factor level
Severity Bleeding episodes
% activity (IU/mL)
1. In the case of prolonged aPTT, a mixing test
Spontaneous bleeding, should be done.
Severe <1 (<0.01) predominantly in joints
and muscles 2. If there is complete or partial correction of
aPTT, a factor assay should be done, starting with a
Occasional
spontaneous bleeding. factor VIII/IX assay.
Moderate 1-5 (0.01-0.05)
Severe bleeding with 3. If both values are normal, test for factors XI,
trauma, surgery X, and V.
Severe bleeding with 4. If aPTT and PT are normal and PFA-100 is pro-
Mild 5-40 (0.05-0.40) major trauma or
surgery longed, testing for vWF antigen and ristocetin co-
factor can identify cases of von Willebrand disease.
5. If the vWF antigen and function were normal
Table 2. Normal factor VIII and factor IX level by age. with prolonged PFA-100, consider testing for
Day 1 Day 5 Day 30 Day 90 Day 180 Adult platelet disorders.
(IU/mL) (IU/mL) (IU/mL) (IU/mL) (IU/mL) (IU/mL) 6. Patients with complete or partial aPTT correc-
FVIII 0.5-1.78 0.5-1.54 0.5-1.57 0.5-1.25 0.5-1.09 0.5-1.49
tion should be worked up for inhibitors.

FIX 0.15-0.91 0.15-0.91 0.21-0.81 0.21-1.13 0.36-1.36 0.55-1.63 Special conditions

Table 3. Most common bleeding site.
Joints (haemarthroses)
Muscle bleeding
Other bleeding sites (intracranial,
gastrointestinal or renal)
Diagnosis of hemophilia during the neonatal period
can be challenging. Cord blood (preferred) or a pe-
ripheral blood sample can be used. Diagnosis of mild
70–80% -
10–20%
cause the newborn normally has low levels of FIX co-
agulant activity (a vitamin K-dependent factor). Low
levels of FIX may persist for up to 6 months. The
5–10%

Molecular studies at special centres can be done

• Excessive bleeding following circumcision, trau-
ma, surgery, or tooth eruption or extraction
• Easy bruising in early childhood
The bleeding history should be detailed and should
include inquiries relating to the age bleeding started
and the site, type (induced or spontaneous), and extent
(immediate or delayed).
Sample collection
Sample quality is very important in coagulation testing.
Patients need to be well rested (Anxiety may falsely
elevate von Willebrand factor [vWF] and factor VIII
[FVIII] levels.). It is important that the sample be ob-
tained by non-traumatic collection drawn into the ap-
propriate amount of citrate anti-coagulant. The blood
should be centrifuged promptly to obtain plasma,
which should remain at room temperature if the as-
says are to be completed within 4 hours.
Screening tests
The initial work up should include complete blood
count (CBC), prothrombin time (PT), activated partial
thromboplastin time (aPTT), and PFA-100®.
for carrier detection, prenatal diagnosis, and prenatal
-
mophiliac, family members need to be screened using
factor assays.
Available treatment options for hemophilia A
and B
Patients with hemophilia A now receive excellent
treatment with very safe and effective anti-haemophil-
ic products that can result in excellent quality of life.
I. Factor VIII concentrate
There are 2 available types of factor VIII concentrates
depending on the factor source:
a. Recombinant factor VIII concentrates (rFVIII)
b. Plasma-derived factor VIII concentrates (pdF-
VIII)
Use of recombinant FVIII is preferred, particularly
if a patient has never been exposed to plasma prod-
ucts (pdFVIII, fresh frozen plasma [FFP] or cryopre-
cipitate). However, both current pdFVIII and rFVIII
Infusion of 1 IU/kg of pdFVIII or rFVIII will in-

172 Journal of Applied Hematology 2011

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
SAUDI HEMOPHILIA GUIDELINES
crease in vivo FVIII level by 2%. The half-life of the
infused FVIII is approximately 8-12 hours.
The formula for calculating the dosage is the pa-
tient’s weight (kg) multiplied by the factor level desired
multiplied by 0.5.
Example: 50 kg × 40 (% level desired) × 0.5 =
1,000 units of factor VIII
• Factor VIII should be infused by slow IV push
at a rate not to exceed 3 mL/min in adults and 100
U/min in young children.
• When a patient’s body weight exceeds 10 kg, al-
ways give the entire content of each vial of factor
VIII, even if it exceeds the calculated dosage (wast-
age should be avoided).
• For patients in whom factor VIII inhibitor status
is unknown or suspected, determination of fac-
tor recovery within 1-2 hours after the infusion by
measurement of factor VIII levels is advisable.
• For continuous infusion of factor VIII, a 50 U/
kg bolus followed by 3-5 U/kg/h of factor VIII
will provide a factor VIII level of approximately
80-100% in a patient with severe hemophilia, and
daily factor levels must be monitored.
II. FIX concentrates
a. Recombinant factor IX concentrates (rFIX)
b. Plasma-derived factor IX concentrates (pdFIX)
• Each FIX U/kg body weight will raise the
plasma FIX level by approximately 1%, although
different preparations have different increment
rates. The half-life is about 18-24 hours.
The formula for calculating the dosage is weight
(kg) multiplied by the desired factor level.
Example: 50 kg × 40 (% level desired) = 2,000 U
of FIX
• FIX should be infused by slow iv push at a rate
not to exceed a volume of 3 mL/min.
• For patients in whom FIX inhibitor status is un-
known, determination of factor recovery in 1-2
hours after infusion by measurement of FIX levels
is advisable
kg/h.
• pdFIX is a prothrombin complex concentrate
(PCC) containing other vitamin K-dependent fac-
tors (II, VII, and X). Large doses of PCCs may be
associated with thrombosis or disseminated intra
vascular coagulation (DIC).
III. Desmopressin acetate (1-desamino-8-d-arginine vasopressin
(DDAVP)
DDAVP is a synthetic vasopressin analogue that re-
Journal of Applied Hematology 2011
review
leases stored FVIII into the circulation, increasing
its level 2-10 times. DDAVP is the drug of choice
for the treatment of patients with mild hemophilia
A. However, its use is not recommended in patients
<3 years of age. Repetitive use will lead to tachy-
phylaxis.
Prior to therapeutic use, DDAVP should be evalu-
ated using a responsiveness assessment as follows:
measure the FVIII level pre-infusion; slowly infuse
DDAVP (0.3 µg/kg body weight; maximum 20 µg
diluted in 30-50 cc of normal saline) over a 15-30-
min period; and measure FVIII level 30-60 min post-
DDAVP. Adequate response is considered when FVIII
level is increased 2-3 times from baseline.
It should be noted that DDAVP nasal preparations
(with concentration of 10 µg) that are used for diabe-
tes insipidus and enuresis are not suitable for hemo-
philia A treatment.
Dosages
• Subcutaneous or iv: 0.3 µg/kg
• Intranasal: 300 µg for adults and 150 µg for children
DDAVP is equivalent.
nausea; abdominal cramps; tachycardia; and, un-
commonly, hypertension or hypotension. Water
intoxication with extreme hyponatraemia is rarely
seen. Myocardial infarction and stroke have been
reported among elderly patients with atherosclero-
sis. Blood pressure, serum sodium level, and urine
output should be monitored.
products for invasive dental work or for the treatment
of mouth bleeds; however, their use is contraindicated
in the treatment of renal bleeding.
Dosages
• Oral: 25 mg/kg every 8 hours
• IV: 10 mg/kg every 8 hours. IV preparations can
be used as oral washes.
V. Bypassing Agents
For the treatment of bleeding in patients with inhibitors
a. Recombinant activated factor VII (rFVIIa)
Dosages
• 90-120 µg/kg every 2-3 hours until haemostasis
is achieved or treatment is considered ineffective
• Recent evidence suggests that single larger doses
(e.g. 270 µg/kg) may be as effective as 3 separate
doses (e.g., 90 µg/kg each)
b. Activated prothrombin complex concentrate (aPCC)
173
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
review
Dosage
• 50-100 U/kg every 12-24 hours (maximum daily
dose should not exceed 200 U/kg)
VI. Fibrin glue
Fibrin glue is a topical agent that is used to accelerate
hemostasis and wound healing. It is made of a mixture
of platelet-rich plasma and thrombin that is applied to
wounds at a concentration of 0.2 mL/cm2.
Management of bleeding episodes
A. General treatment principles
• Bleeding episodes should be treated immediately
with factor replacement therapy. Do not wait for
signs or investigations.
• Treat suspected life-threatening hemorrhages im-
mediately.
• Treat veins with care. Use of 23- or 25-gauge but-
• When intramuscular injections are given, contact
sports should be avoided.
• Exercise (e.g., swimming) should be encouraged.
• Helmets and car safety belts should be used.
• Rest, ice, compression, immobilisation, and eleva-
tion are important adjunctive management factors
for muscle and joint bleeding.
• Exercises (initially static) must be started as soon
as the pain subsides to maintain muscle function
and strength.
• Maintain dental hygiene.
• Keep immunizations up to date.
• Avoid using products that cause platelet dysfunction.
• When a patient with a bleeding disorder requires
an anti-coagulant for problems such as deep vein
thrombosis or myocardial infarction with stent
FVIII) and then use anti-coagulant or anti-platelet
agents.
• If the bleeding does not resolve, review for ade-
quate treatment, check for clotting factor level, and
monitor the inhibitor level if low.
• Patients should be encouraged to keep a record of
all bleeding episodes.
-
cation indicating their diagnosis, severity, inhibitor
status, type of product used, and treating physi-
cian/clinic contact information.
I. Joint hemorrhage (hemarthroses)/muscle hemorrhage
Hemarthroses are the most common type of bleeds.
174
SAUDI HEMOPHILIA GUIDELINES
They can affect the knees, elbows, ankles, shoulders,
wrists, and hips (in that order). These bleeds are de-
a single joint. There is a poor correlation between
normal joint physical activity and bleeding frequency.
This bleeding can be spontaneous or post-traumatic.
Management of each episode requires careful deter-
mination of the factor level.
a. Spontaneous mild bleed
• The factor level needs to be raised to 30-40%.
• A second dose given 12-24 hours later should
be considered.
• If bleeding (i.e., swelling and/or pain) is not im-
proved, the factor level needs to increase to 40-
50% every 12 hours for hemophilia A and every
24 hours for hemophilia B until symptoms settle.
b. Traumatic/major bleeds (excluding knees/hips)
• The factor level needs to be at least 40-50% with
• A second infusion to raise the factor level to
40-50% in 24 hours (hemophilia A) or 48 hours
(hemophilia B)
• A third infusion to raise the factor level to 40-50%
(hemophilia A) in 72 hours is recommended in chil-
dren and may be needed in adults if symptoms persist
c. Target joint or major traumatic bleeds and major
hip, knee, or shoulder bleeds
• The factor level needs to be at least 80-100%
• A second infusion to raise the factor level to
40-50% in 12-24 hours (hemophilia A) or 24-48
hours (hemophilia B)
• A third infusion to raise the factor level to 40-
50% in 48 hours (hemophilia A) or in 72 hours
(hemophilia B)
• If symptoms persist, continue infusion to raise
the factor level to 40-50% every 12-24 hours (he-
mophilia A) or 24-48 hours (hemophilia B) until
symptoms settle.
II. Iliopsoas hemorrhage
Diagnosis
Computed tomography (CT) scan or ultrasound
Treatment
• Immediately raise the factor level to 80-100%.
• Hospitalisation
• Maintain factor levels >50% until hemorrhage re-
solves (may take more time).
• Consider use of a continuous infusion.
• Limit activity until pain resolves. Physiotherapy
is helpful.
Journal of Applied Hematology 2011
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]

SAUDI HEMOPHILIA GUIDELINES review

Ultrasonography, CT scan, MRI, endoscopy, radi-
III. Head injury ography
• Any head injury to a hemophiliac should be con- Treatment
sidered serious. • Raise the factor level to 80-100%.
• Factor level should be raised to 100% immediately. • Hospitalisation
• Admit patient. • Maintain at least a 50% factor level until the aeti-
• Observe for at least 24 hours.
• A CT scan or magnetic resonance imaging (MRI) • Tranexamic acid may be used in cases except for
may be necessary depending on the case and the renal hemorrhage.
attending physician’s decision.
VIII. Genitourinary hemorrhage
IV. Life-threatening hemorrhages; central nervous system hem- Diagnosis
orrhages; compartment syndrome; and eye, throat, and neck Urinalysis/culture, ultrasonography
hemorrhages Treatment
Diagnosis • Use of tranexamic acid is contraindicated.
Do not wait for investigation; use CT scan, MRI, • Painless haematuria should be treated with bed
or ultrasonography rest and intensive hydration (1-1/2 times mainte-
Treatment nance) for 48 hours.
• Immediate prompt treatment • In cases of pain or persistent gross haematuria,
• Hospitalisation raise the factor to 50%.
• Raise factor level to 100%
• Monitor factor levels to maintain trough factor Management of chronic synovitis and target
levels >50% joints
• Hemophilia A: raise factor level to 100% every 8 Chronic synovitis is characterised by synovial hyper-
hours for 3 days trophy with formation of new blood vessels. These
• Hemophilia B: raise factor level to 100% every vessels are prone to increased bleeding, resulting in
12-24 hours for 3 days more severe synovitis and bleeding.
• Continuous infusion is appropriate. Clinical features
• Continuous factor infusion at reduced dose for • Recurrent joint bleeds not adequately responsive
3 weeks to factor replacement
o 100% for 3 days • Painless joint swelling
o 80% for 4 days • Joint will bleed spontaneously
o 50% for 2 weeks • Radiograph of chronic synovitis may not show
o Long-term prophylaxis often needed. joint arthropathy.
Management
V. Oral hemorrhage • Management of chronic synovitis should be con-
• Bleeding may be controlled with the use of sidered at a specialised centre.
tranexamic acid alone. • Medical management
• Fibrin glue may help. o FVIII 15-20 U/kg (30-40%) daily or FIX 20-
• If bleeding is not controlled, raise the factor level 30 U/kg (20-30%) daily for 2 weeks, then review.
to 20-40% using tranexamic acid. o Continue factor infusion 3 times weekly.
• Consult an oromaxillary/dental specialist. o Prednisone 1 mg/kg for 5 days
o Immobilisation
VI. Epistaxis • In cases of failure to respond within 10-12 weeks,
• Factor replacement therapy is usually not required. stop medical therapy and refer to an expert ortho-
• Place patient’s head forward to prevent the swal- paedic surgeon.
lowing of blood. • Synovectomy
o Arthroscopic chemical synovectomy (treat with
• The use of tranexamic acid may be advisable. rifampicin)
o Radionucleotide synovectomy
VII. Gastrointestinal/acute abdominal hemorrhage * Usually in patients >10 years of age with
Diagnosis mild-moderate (not advanced) arthritis

Journal of Applied Hematology 2011 175

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
review
* Pre-synovectomy
* Factor concentrate to give factor level >30%
for 48 hours
* For inhibitor patients, use a single dose of
FVIIa (Novo Seven) or FEIBA
• Treatment regimen
o 5-7 mCi Yttrium by intra-articular injection.
Xylocaine and dexamethasone by intra-articular
injection through the same intra-articular needle
o Splint the joint or place in plaster cast to im-
mobilise for 48-72 hours.
o Repeat injections may be necessary to the max-
imum of 14 mCi per patient
Immunisations
The standard routine vaccination schedule for chil-
dren should be followed.
• Vaccination can be given without factor concen-
trate prophylaxis.
• Application of ice and prolonged pressure for
5-10 min is recommended.
• Sub-cutaneous rather than intra-muscular admin-
istration is recommended to avoid muscle hemor-
rhage.
• Hepatitis A vaccine should be given to all newly
diagnosed patients.
• Family members involved in factor replacement
therapy in the home who test negative should also
receive the Hepatitis A and B vaccine series.
Management of hemophilia patients
undergoing surgery
• Ensure adequate supplies of factor replacement
are available.
• Surgery should be undertaken in a hospital associ-
ated with a hemophilia service.
• Surgery should be scheduled early in the week and
early in the day for optimal laboratory and blood
bank support if needed.
I. Pre-surgery preparations
• Determine factor level.
• Complete a factor inhibitor screen prior to the
scheduled surgery.
• Do PT, PTT, mixing study, and inhibitor screen
before surgery.
• Measurement of serial factor levels during the
surgical procedure.
II. Minor surgery
• Raise factor level to 50-80% 30-60 min pre-sur-
176
SAUDI HEMOPHILIA GUIDELINES
gery and 6 hours post-surgery.
• Maintain a factor level >50% for 5-7 days. Check
pre-dose factor level at least twice a week.
III. Major surgery/arthroplasty
(Including circumcision and adenotonsillectomy in
children)
• Raise the factor level to 80-100% 30-60 min pre-
surgery and 6 hours post-surgery.
post-operative days (factor infusion every 12 h for
hemophilia A and 24 hours for hemophilia B)
• Continuous factor infusion may be appropriate.
• Maintain a factor level >50% for 1-2 weeks de-
pending on surgery type. Check pre-dose factor
level at least twice a week.
• Short-term prophylaxis 2-3 times a week for up to
6 weeks for orthopaedic procedures
• For hemophilia patients undergoing circumci-
sion, start tranexamic acid 12 h pre-surgery and
continue for 3 days post-surgery.
IV. Invasive procedures (e.g. lumbar puncture, liver biopsy, and
endoscopy)
• Raise factor level to 50-60% before procedure.
• Repeat dose at 24 hours and as required.
• Tranexamic acid may be used when appropriate.
• For liver biopsy, maintain factor level at >50% for
at least 3 days.
Dental care in hemophilia patients
A. General measures
• Good oral hygiene for hemophiliacs should be
encouraged to prevent the need for dental work-
up.
• Teeth should be brushed at least twice daily for
plaque control.
• After tooth extraction, a diet of cold liquids
and minced solids should be taken for 5-10 days.
Smoking should be avoided.
or hoarseness must always be reported to the
dentist/haematologist immediately.
• Antibiotic prophylaxis should be administered
to patients with prosthetic joint replacements.
• Regular follow-up every 3 months is warranted.
• Routine dental care should be performed for all
hemophiliacs.
• Nerve blocks are not contraindicated provided
satisfactory factor levels are achieved.
• Consult a haematologist.
Journal of Applied Hematology 2011
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
SAUDI HEMOPHILIA GUIDELINES
I. Low-risk procedures (e.g., restorative procedures)
• Generally can be performed without raising
factor levels
the pre-dental work-up and continued later to
alleviate the bleeding risk.
- where high-risk obstetric and haemophilic services are
tor level to at least 50%.
• Local measures to control or prevent bleed-
ing should be used.
II. High-risk procedures (e.g., extractions, oral surgery, etc.)
• Extensive procedures may require hospitali-
sation.
• Raise the factor level to 50-100% and contin-
ue factor coverage for 1-2 days after if needed.
concomitantly.
- Early post-partum hemorrhage should be managed
ued for 7-10 days after procedures.
• Third molars should be evaluated during
the teenage years. If extractions must be per-
formed, infuse factor for several days in addi-
• Local measures to control or prevent bleed-
ing should be used.
hemophilia A patients.
III. Primary teeth eruption/exfoliation
Pressure and ice should be enough to con-
trol bleeding after primary tooth eruption. If
used. In rare instances, factor may be need-
ed. For patients with a history of prolonged
bleeding, it may be appropriate for the den-
tist to extract the tooth after proper factor
infusion.
IV. Mild hemophilia A
Scaling and some minor surgery may be pos-
sible under DDAVP with no factor require-
ment. Local measures are important. DDAVP
IV 0.3-0.5 µg/kg before surgery repeated
every 12 h for up to 4 days or intranasal 300
µg. DDAVP is not effective for hemophilia B
(even mild cases).
V. Hemophilia with FVIII inhibitor
An aggressive preventive program should be
carried out and a haematologist should be con-
sulted. Recombinant FVIIa is the treatment
for dental bleeds in hemophilia patients with
inhibitors. Tranexamic acid and other local
measures are very important.
Journal of Applied Hematology 2011
review
Pregnancy and delivery
A. During pregnancy
trimester.
B. Labour and delivery
Delivery should ideally be conducted in a hospital
available. Vaginal delivery is preferred unless contrain-
dicated for obstetric reasons. However, vaginal deliv-
ery of a breech baby, prolonged labour, vacuum ex-
traction, use of forceps, foetal scalp blood sampling,
and scalp electrodes should be avoided.
C. Post-partum care
It is generally recommended that factor levels be kept
>50% for 3-4 days after a vaginal delivery and up to 7
days after a caesarean section.
D. Post-partum hemorrhage
by factor replacement therapy or DDAVP. Late post-
partum hemorrhage can be managed with tranexamic
acid and, oral contraceptives.
E. Management of neonates
Cord blood samples should be taken for factor levels.
Intra-muscular injections should be avoided.Vitamin
K is often given orally or sub-cutaneously. Trans-
fontanel ultrasonography should be performed soon
-
philia. Prophylactic factor replacement should not be
given due to the potential risk of inhibitor develop-
ment.
F. Management of bleeding in neonates
Neonates known (or suspected) to have hemophilia
and who have evidence of either intra-cranial bleed-
ing or severe bleeding elsewhere should receive im-
mediate factor replacement. If the hemophilia type is
unknown, then both FVIII and FIX (75 U/kg and 150
U/kg, respectively) should be given to raise factor lev-
els to 100%. Factor levels should be maintained in the
normal range for at least 7-10 days. Prophylaxis should
Prophylaxis for patients with severe
hemophilia A and B
Since the 1960s, studies have shown that use of pro-
phylaxis therapy compared with on-demand treatment
results in a reduction in the frequency of haemarthroses
and protects joints from the development and progres-
sion of arthropathy. Subsequently, patients experience
improved quality of life. Recent controlled randomised
effective, especially when started at younger ages.
177
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
review
Studies of young adult patients have indicated that
the annual factor consumption in patients who are
currently and have always been treated on demand is
no different from the consumption in those on long-
term intermediate-dose prophylaxis.
A. Prophylactic regimens in children
• Prophylaxis should be commenced by the sec-
• Prophylaxis may be introduced by initially ad-
ministering factor concentrate once weekly but
escalating treatment rapidly to more frequent
administration as venous access permits in order
to prevent the occurrence of joint or soft tissue
bleeds.
• Prophylaxis should consist of a FVIII concentrate
dose (25-50 U/kg) administered ideally every 48
hours.
• The minimum dosage of factor concentrate
that prevents breakthrough bleeds should be
the amount of concentrate required to prevent
bleeds and maintain trough factor levels >1% and
should be considered in very active older boys or
where breakthrough bleeds are occurring on a
less frequent prophylactic regimen.
• Prophylaxis should be administered ideally in
the morning to optimize FVIII levels.
• Children and neonates with severe hemophilia
who have had a spontaneous central nervous
system bleed should continue long-term prophy-
laxis following initial treatment of the bleeding
episode.
• Insertion of an indwelling venous access device
should be considered if venous access and/or ad-
• The prophylaxis dose should be rounded up to
the nearest whole vial size.
• Sngle-dose prophylaxis where factor concen-
trates may be given prior to an event (e.g., sports).
B. Prophylactic regimens in adult patients
• Adolescent and adult patients with severe he-
mophilia should be encouraged to continue reg-
ular prophylaxis at least until they have reached
physical maturity.
• Holding prophylaxis may be considered in some
individuals who have less frequent bleeds, but
in such cases, there must be an agreed plan for
monitoring and reintroducing prophylaxis if nec-
essary.
• Prophylaxis should, in particular, be restarted if
bleeding interferes with education or employment.
• The dose and frequency of infusions should be
178
SAUDI HEMOPHILIA GUIDELINES
adjusted based on bleeding phenotype and ide-
ally individual pharmacokinetics. The minimum
amount of concentrate should be used to prevent
haemarthroses irrespective of trough levels.
• Pharmacokinetic studies may help dose adjust-
ment.
• Patients on long-term prophylaxis should have
their regimens critically reviewed at least every
6 months. If no breakthrough bleeds have oc-
curred, a trial dose reduction is appropriate, espe-
cially if the trough level >1 U/dL.
• Short- or long-term secondary prophylaxis
should be considered in patients with advanced
-
cantly interfere with work or mobility.
• Long-term secondary prophylaxis is indicated
following intracranial hemorrhage if no underly-
ing cause can be corrected.
• Secondary prophylaxis can be given intermit-
tently prior to activities that are likely to cause
bleeding.
• Continuous secondary prophylaxis without a
C. Monitoring
I. Clinical monitoring
Regular physical assessment of the patient and an
accurate evaluation of breakthrough bleeds in-
cluding the number of breakthrough bleeds, the
nature and cause of the bleeds, the number of
days taken off of school or work and the days
away from regular physical activities. The number
and quantity of extra treatments given for break-
through bleeds are recorded.
II. Laboratory monitoring
As one of the principal purposes of prophylaxis is
to convert the severity of hemophilia from severe
to moderate (factor level >1 U/ml), trough levels
of FVIII should be monitored (pre-dose level) at
1-2-month intervals. Inhibitor screening should be
considered when the 48-hour trough FVIII level
is <1 U/ml.
Maintenance of trough levels >1 U/ml is not al-
ways necessary.
III. Radiological monitoring
There is no requirement for radiological surveil-
-
cal indication.
D. Management of breakthrough bleeding
• Breakthrough bleeds should be treated accord-
ing to site and severity until completely resolved.
• The prophylaxis regimen should be reviewed ac-
cordingly.
Journal of Applied Hematology 2011
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]

SAUDI HEMOPHILIA GUIDELINES review

Management of hemophilia patients with
inhibitors -
Approximately 25% of patients with severe hemo- tor that will neutralize 50% of one unit of added
philia A develop inhibitors after initial treatment with FVIII in 2 hours at 37 °C.
FVIII concentrates. Approximately half of these ap- • Patients being treated on a regular basis with
pear transient and disappear with continued FVIII coagulation concentrate should be tested for in-
therapy. The incidence of inhibitors in those with hibitors at least annually.
severe hemophilia B is much less common (3%).
Inhibitors of both IgG1 and IgG4 subclass inhibit concentrate, levels should be tested every 5-10
FVIII function directed to the C2, A2, and A3 do- infusions or every 3-6 months.
mains of the FVIII protein. C. Treatment of bleeding episodes
Genetic factors and family history of inhibitors are • Anamnestic response usually begins 3-7 days
the most important risk factors for FVIII inhibitor after factor infusion with a peak at 14 days.
development. Other factors include age at initial treat- Treatment of the bleeding episodes depends on
ment, treatment intensity, and type of clotting factor the titre and the response of the patient.
replacement. I. Low titre inhibitor/low responder (Figure 1)
Clinical manifestations that draw attention to the • Human FVIII/FIX (recombinant or plas-
possibility of inhibitors include bleeding that does ma-derived) can be used in higher doses at
not respond as expected to factor concentrate, bleed- 2-3-fold.
ing that stops after only higher than expected doses • The recommended dose for minor bleeds or
of substitution therapy or bleeding that occurs despite minor surgeries
previously effective prophylactic therapy. o FVIII is 50-100 IU/kg repeated every 8-12
hours.
I. Low titre/low responding inhibitor o FIX of 100-150 IU/kg every 12-24 hours
• Inhibitor titre does not rise above 5 BU after may be used in patients with low titre FIX
factor exposure. inhibitors and no or limited allergic reac-
• Inhibitors may be transient. tions to FIX.
• Inhibitor level ≤5 BU
• No anamnestic response to FVIII after immu-
nologic challenge.
II. Low titre/high responding inhibitor
• Inhibitor level ≤5 BU
• Inhibitor can become low titre if the patient is
not exposed to factor for long periods of time.
III. High titre/high responding inhibitor
• Inhibitor level (>5 BU)
IV. Transient inhibitors
Low titre inhibitors (<5 BU) that disappear
spontaneously with continuation of the same
replacement therapy within 6 months from oc-
currence
B. Diagnosis
The amount of antibodies or hemophilia factor in-
hibitors can be measured using 2 methods:
• Enzyme-linked immunosorbent assay (ELISA). If
-
cause of the possible presence of non-neutralising
antibodies.
• BETHESDA ASSAY or MODIFIED
BETHESDA (Nijmegen), where the source
of FVIII is pooled normal plasma for anti-hu-
man titres and Porcine concentrate diluted in Figure 1. Management of hemophilia patients with inhibtors and low responders.

Journal of Applied Hematology 2011 179

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
review
Figure 2. Management of hemophilia patients with low titre inhibitors and high
response.
• The recommended dose for minor bleeds or
minor surgeries
o FVIII is 100-150 IU/kg repeated every 8-12
hours.
o FIX of 150-200 IU/kg every 12-24 hours.
o Factor level through maintained >50%
until healing has completed
• Clinical assessment.
• Factor level monitoring
• If hemostasis is not obtained, use a bypass-
ing agent (rFVIIa/aPCC)
• Consider continuous infusion (10 IU/kg/h))
II. Low-titre inhibitor and history of high response
(Figure 2)
• rFVIIa or FEIBA should be considered
• If adequate hemostasis is not achieved, con-
sider switching to the alternative bypassing
agent.
• Concurrent use of rFVIIa and tranexamic
acid may be considered, especially with muco-
cutaneous bleeding.
• Concurrent use of aPCC and tranexamic
180
SAUDI HEMOPHILIA GUIDELINES
acid is not recommended.
III. High-titre inhibitor (Figure 3)
• rFVIIa or aPCC should be considered.
• If adequate hemostasis is not achieved, con-
sider switching to the alternative bypassing
agent.
• Concurrent use of rFVIIa and tranexamic
acid may be considered, especially with muco-
cutaneous bleeding.
• Concurrent use of aPCC and tranexamic
acid is not recommended.
D. Surgery
• Experienced surgeon and haematologist should
take care of surgery in hemophilia patients with
inhibitors.
• Ensure availability of diagnostic/therapeutic fa-
cilities for at least 14 days.
• Human FVIII/FIX can be used in higher doses
2-3-fold in low-titre inhibitor/low responders.
• rFVIIa or aPCC should be considered in high
responders.
• If adequate hemostasis is not achieved, consider
switching to the alternative bypassing agent.
• Concurrent use of rFVIIa and tranexamic acid
may be considered, especially with mucocutaneous
surgery.
Prophylaxis in patients with inhibitors
In hemophilia patients with inhibitors who are on fac-
tor prophylaxis before inhibitor development and still
need to be on prophylaxis, rFVIIa may be used as pro-
phylaxis at a dose of 270 µg/kg every other day.
As aPCC contains residual FVIII and may cause an
anamnestic response in the inhibitor titre, aPCC is not
be used as second-line prophylaxis at a dose of 50 µg/
kg 3 time per week. If no response is seen, the dose
may be increased to 85 µg/kg. If no response is seen,
stop therapy.
Home therapy
Hemophilia patients must be well educated/knowl-
edgeable about hemophilia and hemophilia man-
agement. Home therapy allows immediate access to
treatment and, hence, optimal early treatment. This is
ideally achieved with clotting factor concentrates that
are safe and can be stored in a domestic fridge and
easily reconstituted. Home treatment must be super-
vised closely by the comprehensive care centre and
be started after adequate education and preparative
teaching, which should include recognizing a bleed
and its common complications, dosage calculation,
Journal of Applied Hematology 2011
[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]

SAUDI HEMOPHILIA GUIDELINES review

preparation, storage, and administration of clotting
factor, aseptic technique, venipuncture (or access of
central venous catheter), record keeping, proper stor-
age and disposal of needles, and handling of blood
spills. Encouragement, support, and supervision are
the keys to successful home therapy and periodic reas-
sessment of educational needs, techniques and com-
pliance must be performed.
• Home care can be started on young children with
adequate venous access by motivated family members
who have undergone adequate training.
• Older children and teenagers can learn self-infu-
sion with family support.
• An implanted venous access device (Port-A-Cath)
can make injecting treatment much easier. However,
they can be associated with local infection and throm-

weighed and discussed with the patient and/or their

parents.

Management of HIV and hepatitis C

Management of HIV and hepatitis C should be per-
formed in collaboration with specialized HIV medi-
cine/infectious disease/hepatology/gastroenterology.
A. Hemophilia patient with hepatitis C
Many of the hemophiliacs receiving pooled plasma
concentrates prior to the late 1980s were infected with
- FVIII and FIX are produced in the liver. HIV co-
veloping complications (e.g. cirrhosis, haematoma).
Liver biopsy can be performed safely in hemophiliacs
if appropriate hospitalisation and factor replacement
are undertaken. Hepatitis C is more susceptible to
the hepatotoxic effects of other drugs. Persons with
chronic hepatitis C can have a more severe illness
should they contract hepatitis A or B; consequently,
persons with hepatitis C infection should be screened
for hepatitis A and B and offered a vaccine should
they be non-immune.
• Liver biopsy
o Hospitalisation for 48 h
o Before liver biopsy, factor levels should be raised
to 70–100%.
o Levels should be maintained at 70-100% by either
intermittent bolus infusions or continuous infusion
for 3 days.
o Reduction of factor replacement to maintain lev-
els of 30% should be considered for the next 2 days.
o Post-biopsy ultrasonography can be considered.
• Liver transplantation
o Liver transplant may be considered for hepatitis
C or its complications.
o Liver transplantation cures hemophilia as both
Figure 3. Management of hemophilia patients with high titre inhibitors.
infection is not a contraindication to liver transplant.
B. Hemophilia patient with HIV
• Increased bleeding tendency or atypical bleeds
in hemophilia patients on protease inhibitor ther-
apy has been reported.
• All hemophilia patients on protease inhibitor
therapy should be closely observed for atypical
bleeds.
• Septic arthritis, which may be afebrile, should be
considered in any joint bleed that is unresponsive
to factor replacement.
C. Hemophilia patient with HIV/HCV co-infection
• HIV has been shown to accelerate the course of
HCV chronic liver disease and HCV, which ap-
pears to worsen the prognosis of HIV.
Acquired hemophilia
Acquired hemophilia is caused by autoimmune auto anti-
bodies—predominantly of the IgG4 subtype—to FVIII
against epitopes in the A2 domain, which results in FVIII
-
quired hemophilia is approximately 1–2 million/year.
Most cases are idiopathic in nature but they may be due
to secondary, post-partum, other autoimmune diseases,

Journal of Applied Hematology 2011 181

[Downloaded free from http://www.jahjournal.org on Friday, September 23, 2016, IP: 95.219.97.103]
review
- ceed a total of 200 U/kg/day)
ry disorders, dermatologic diseases, infections (hepatitis
B or C) or adverse effect of medications.
A. Diagnosis
• Clinical presentation. Patients usually present
with bruising, soft tissues, muscle bleeding, gas-
trointestinal and genitourinary bleeding.
• Prolonged aPTT
• Low FVIII level
• Mixing studies demonstrate the presence of a
time-dependent inhibitor of FVIII (1-2 hours in-
cubation at 37 °C).
• It is important to distinguish anti-FVIII inhibi-
tors from the more commonly encountered anti-
phospholipid antibodies where aPTT will be pro-
longed at 0 and 1-2 hours time.
• Factor VIII inhibitors (Bethesda)
B. Management of acute hemorrhage
• Treatment of bleeding
o FVIII at high dose 100-200 IU/kg is rapidly
inactivated but may be tried in cases of minor
bleeds and low inhibitor level (<5 BU)
o rFVIIa at 90-120 µg/kg given every 2-3 hours
until hemostasis is achieved or until treatment is
considered ineffective
o FEIBA 50-100 U/kg iv infusion (not to ex-
References
1. Guidelines for the Management of Hemophilia. Published By The World Fed-
eration Of Hemophilia, 2005. www.wfh.org
2. Protocols for the Treatment of Hemophilia And Von Willebrand Disease,
2009. www.hog.org
3. A Guide to the Management of Patients with Inhibitors to Factor VIII and Fac-
tor IX. Published by The Association Of Hemophilia Clinic Directors Of Canada,
2010. www.ahcdc.ca
4. Standards for Comprehensive Care of Hemophilia in Canada. Published by
The Association of Hemophilia Clinic Directors of Canada, last update 2010.
www.ahcdc.ca
5. Canadian Comprehensive Care Standards for Hemophilia and Other Inher-
ited Bleeding Disorders. Published by The Association Of Hemophilia Clinic
Directors Of Canada, 2007. www.ahcdc.ca
6. Hemophilia and von Willebrand’s disease: diagnosis, comprehensive care and
assessment, last update 2010. Published by The Association Of Hemophilia
Clinic Directors Of Canada, 2007. www.ahcdc.ca
7. Guideline for the Management of Patients with Hemophilia Undergoing Sur-
gical Procedures. Published by Australian Hemophilia Centre Directors’ Organi-
zation, 2010. www.ahcdo.org.au
8. Guidelines for the Treatment of Inhibitors in Hemophilia A and Hemophilia
B Australian Hemophilia Centre Directors. Published by Australian Hemophilia
Centre Directors’ Organization, 2010. www.ahcdo.org.au
9. Guidelines for Management of Pregnancy and Delivery in Women Who Are
Either Carriers or Patients with Bleeding Disorders. Published by Australian He-
mophilia Centre Directors’ Organization, 2007. www.ahcdo.org.au
10. A Consensus Statement on the Dental Treatment of Patients with Inherited
Bleeding Disorders. Published by Australian Hemophilia Centre Directors’ Or-
ganization, 2010. www.ahcdo.org.au
11. A Consensus Statement on the Dental Treatment of Patients with Inherited
182
View publication stats
SAUDI HEMOPHILIA GUIDELINES
o Immunoadsorption followed by FVIII/FIX
concentrate may be the ultimate choice if the
other alternatives of treatment have failed
C. Treatment of acquired hemophilia (eradication)
• Immunosuppressives should be initiated as
soon as the diagnosis is established:
o Prednisolone (prednisone) at a dose of 1 mg/
kg combined with cyclophosphamide 50-100
mg/day orally for 6 weeks
o Prednisolone combined with azathioprine 2
mg/kg once daily for 6 weeks may be preferred
for women of child-bearing age.
o Rituximab 375 mg/m2 intravenous infusions
weekly for 4 weeks. Rituximab is a second-line
therapy.
a. Large-volume adsorption 2.5-3 times the
total plasma volume on days 1-5
b. IVIG 0.3 g/kg on days 5-7
c. Prednisolone 1 mg/kg and cyclophospha-
mide 1-2 mg/kg daily until remission
d. FVIII concentrate infusion in a dosage of
100-200 IU/kg every 6 h that is reduced when
satisfactory response was achieved.
Bleeding Disorders. Published by Australian Hemophilia Centre Directors’ Or-
ganization, 2008. www.ahcdo.org.au
12. Guideline for the Treatment of Hemophilia in South Africa, J Mahlangu, A
Gilham, SAMJ, 2007
13. National guidelines, management of hemophilia, published by Medical Ad-
visory Committee of Hemophilia Foundation of New Zealand, 2004. www.
hemophilia.org.nz
14. Swedish Guidelines for the Care and Treatment of Hemophiliacs. Published
by The Swedish Hemophilia Society, 2003. www.fbis.se
15. Guidelines for Treatment of Patients with Hemophilia and Inhibitors A.
Gringeri for the Italian Association of Hemophilia Centres, Springer-Verlag Ber-
lin Heidelberg, 2005.
16. Guideline on the Selection and Use of Therapeutic Products to Treat He-
mophilia and Other Hereditary Bleeding Disorders. A United Kingdom He-
mophilia Center Doctors’ Organisation (Ukhcdo) Guideline Approved by the
British Committee for Standards in Haematology, D. KEELING, C. TAIT, and M.
MAKRIS, Hemophilia, 2008.
17. The Diagnosis and Management of Factor VIII and IX Inhibitors: a Guideline
from the UK Hemophilia Centre Doctors’ Organization (Ukhcdo), British Jour-
nal of Haematology, 2000.
18. A United Kingdom Hemophilia Centre Doctors’ Organization Guideline
Approved by the British Committee for Standards in Haematology: Guideline
on the Use of Prophylactic Factor VIII Concentrate in Children and Adults with
Severe Hemophilia A, M Richards, M Williams, E Chalmers, BJH, 2010.
19. Acquired Hemophilia. Published By The World Federation Of Hemophilia,
2005. www.wfh.org
20. Acquired Hemophilia Nordic Guidelines for Diagnosis and Treatment. Pub-
lished by Working Group on Acquired Hemophilia of the Nordic Hemophilia
Centres, 2009. www.nordhemophilia.org
Journal of Applied Hematology 2011