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Overview |
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Definition |
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Proper blood coagulation is a rapid, efficient, localized reaction, requiring
normal hemostasis. Abnormalities of certain blood coagulation factors result in
either delay of clot formation or premature fibrinolysis; these bleeding
disorders are classified as hemophilia. Hemophilia A (factor VIII deficiency)
and B (factor IX deficiency) are the most common serious hereditary coagulation
factor deficiencies. They are both X-linked, recessive congenital disorders that
primarily affect males, with females being the carriers. Hemophilia A and B have
identical clinical symptoms; severity corresponds to the degree of factor
deficiency. Hemophilia A comprises about 80% of cases (10 in 100,000 versus 2 in
100,000 for type B; this translates to 1 in 10,000 males with factor VIII
deficiency or dysfunction and 1 in 100,000 males with factor IX deficiency or
dysfunction). About two-thirds of hemophilia A and one-half of hemophilia B
patients have moderately severe to severe disease. |
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Etiology |
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As stated in the Overview, Hemophilia A and B are recessive, X-linked
congenital disorders. The DNA codon for hemophilia A is located on the long arm
(q) of the X chromosome. The locus of the gene controlling for factor IX in
hemophilia B is more remote than for type A. Males who lack a normal allele will
have hemophilia. |
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Risk Factors |
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Hemophilia occurs in all ethnic groups. Risk factors include the
following:
- All daughters of affected males will be carriers, with most being
clinically unaffected unless they inherit an abnormal allele from a carrier
mother, giving them a 50% risk of having hemophilia if the mother is a carrier.
Affected males cannot transmit the disorder to sons. True female hemophiliacs
are generally only seen in the case of consanguinity or concomitant Turner's
Syndrome (XO).
- Half of sons of carrier females will have hemophilia; half of
daughters will be carriers.
- High mutation rate for hemophilia A makes negative family history less
relevant in excluding the diagnosis; also may result in female
hemophilia.
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Signs and Symptoms |
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- Level of factor deficiency correlates to symptoms: severe or
classic—level <1 U/dl;
moderate—1 to 5 U/dl, less frequent bleeding, less
severe hemarthrosis; mild—5 to 30 U/dl, symptoms often
absent exclusive of surgery or traumatic injury
- Symptoms often precede objective evidence of bleeding
- Hemarthrosis—develops into crippling
arthropathy without factor replacement therapy; pain, which can be excruciating;
knees and elbows most frequently affected
- Hemorrhage—may be excessive or prolonged
bleeding from apparent or imperceptible trauma or injury; start of bleeding into
muscles, joints, or body cavities may be delayed—e.g.,
hours to days following an injury and may last days to weeks
- Large ecchymoses
- Subcutaneous and intramuscular hematomas with leukocytosis, fever,
skin discoloration, and significant pain; often in muscles and soft tissue
- Chronic inflammation and pain in synovial membranes
- Abdominal hemorrhaging—internal fascial
spaces, muscles, retroperitoneum, intraperitoneum
- Life-threatening bleeding into central nervous system or airway; CNS
bleeding may occur without preceding trauma or lesion
- Hemorrhaging of mouth and gums, deciduous tooth loss
- Hematuria in the absence of genitourinary pathogens is common;
generally self-limited and may not require treatment
- Gastrointestinal involvement
- Epistaxis
- 30% of cases diagnosed at time of circumcision due to excessive
bleeding leading to suspicion; in utero bleeding possible in severe cases; more
cases become apparent when a child becomes
active
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Differential
Diagnosis |
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- von Willebrand's disease (vWD) is the most common bleeding disorder
affecting 1% of population; often confused with type A hemophilia because factor
VIII also reduced with vWD
- Other platelet disorders including thrombocytopenia and idiopathic
thrombocytopenic purpura (ITP)
- Vascular disorders including thrombotic thrombocytopenic purpura
(TTP), hemolytic uremic syndrome (HUS), and Henoch-Schönlein purpura
- Protein C and S deficiencies
- Liver disease and other causes of vitamin K deficiency
- Disseminated intravascular coagulation (DIC)
- In the case of deep hematomas—suppurative
conditions are considered
- In the case of joint bleeding, consider tuberculosis, arthritis, or
Legg-Calvé-Perthes' disease
- Soft tissue hemorrhage—sarcoma
- Hemorrhage in gastrointestinal or genitourinary tracts lead to
consideration of the following depending on respective location: appendicitis or
appendiceal abscess, peptic ulcer, bowel obstruction, kidney
tumor
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Diagnosis |
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Physical Examination |
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History is frequently very revealing. Symptoms frequently precede bleeding;
therefore, it is important to rely on the patient's report, not just the
physical exam. Determination of mucocutaneous or deep bleeding is important to
diagnosis. In the case of hemarthrosis, the joint is warm, grossly distended,
and generally discolored; muscle spasms and limited joint motion are also
apparent. Soft tissue hematomas appear indurated and raised. A purplish-black
color decreases in intensity as it moves from the site of origin.
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Laboratory Tests |
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- Partial thromboplastin time (PTT)—prolonged
when factor VIIIc is <25% of normal; prolonged, but difficult to detect when
factor IX is mild (i.e., 20% to 30%); normal range varies among laboratories
- Clotting factor assays for factors VIII and
IX—large potential for error with type A, sensitive
assays exist for type B; can be performed on fetal blood; distinguishes between
types A and B; normal range is 50 to 150 U/dl
- Platelet count
- Bleeding time assesses function of platelets; difficult test to
standardize
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Pathology/Pathophysiology |
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- Hemorrhage from synovial vessel into joint cavity or the diaphysis or
epiphysis of the bone; synovial space becomes distended with blood, muscle spasm
contributes to increased pressure
- Incomplete absorption of extravasated blood causes synovial membrane
inflammation; recurrences cause thickening, folds, and villi to form and distend
the joint (chronic proliferative synovitis)
- Loss of hyaline cartilage and cavitation in joints
- Diffuse demineralization of bones
- Arthropathy—fibrous or bony ankylosis in
large joints, complete destruction of
articulations
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Imaging |
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- CT scans or sonography diagnose abdominal hematomas or
hemorrhages
- CT scan or MRI for intracranial bleeding
- MRI for joint hemorrhage
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Other Diagnostic
Procedures |
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- Bethesda assay quantifies the amount of inhibitor present in patients
with antibodies to replacement
factors
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Treatment Options |
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Treatment Strategy |
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Early treatment is more effective, less costly, and can be lifesaving since
symptoms frequently precede evidence of bleeding. The mainstay of treatment for
hemophilia is replacement therapy, which replaces the deficient factor VIII or
IX with a factor that has been produced from normal human or animal blood
products or, more recently, from recombinant coagulation proteins. Various
adjunct therapies may be used, including aspiration and analgesics (no
aspirin-containing or non-steroidal anti-inflammatory medications). Orthopedic
devices and physiotherapy supports joint healing and function. Surgery is
performed for disabling sequelae. |
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Drug Therapies |
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Factor replacement therapy:
- Factor VIII (maintain 25 to 30 U/dl) or factor IX (maintain 15 to 30
U/dl) replacement therapy; administered intravenously based on body weight,
plasma volume, and influenced by severity of bleed
- Cryoprecipitate—a fraction of plasma
containing high concentrations of factor VIII; used for less severe episodes of
bleeding than factor replacement
- Purified concentrates for factors VIII and
IX—allow large-scale production; serologic testing and
solvent-detergent treatment or heat sterilization greatly decrease viral
transmission in concentrates; avoids thrombotic potential of prothrombin complex
concentrates for factor IX
- Monoclonal affinity purification for factor
IX—purifies factor IX from other vitamin K factors,
which removes the thrombotic potential; simultaneously, this process essentially
removes risk of viral contamination
- Recombinant factor VIII and IX—avoids
infection risk by not using human plasma; recombinant factor IX (available since
1997) safer as it does not contain albumin; factor VIIIc preparation being
developed with B domain of the gene being removed before transfection of hamster
cells, which will also eliminate requirement of serum albumin for stabilization
Topical hemostatics, such as microfibrillar collagen, may arrest bleeding at
accessible sites.
DDAVP—1-deamino-8-D
arginine-vasopressin:
- Useful for mild hemophilia A; transiently increases factor VIII;
consider use prior to dental work or minor surgeries
- 0.3 mcg/kg/IV up to 24 mcg; nasal spray, 1.5 mg/ml
- No viral contamination, but thrombosis risk
Tranexamic acid and epsilon-aminocaproic acid
(EACA)—help to stabilize clots forming after
replacement therapy; adjunct therapies for mucosal bleeding and dental work;
thromboembolism risk makes it contraindicated with factor IX replacement; can be
used as a mouthwash – 4 to 6 grams qid for 72 to 96
hours following a dental procedure.
Activated prothrombin complex
concentrates—efficacious for patients who develop
antibodies to the replacement factor; for example, FEIBA (factor VIII inhibiting
bypass activity), with factors II, VII, IX, and X, bypasses the need for factor
VIII, although the mechanism of action remains unknown. |
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Surgical Procedures |
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- Pre-op: Hemophiliacs without antibodies to replacement factor should
receive factor infusion prior to surgery; daily monitoring to maintain levels
above 50% following surgery should take place for 3 weeks following orthopedic
procedure, 10 to 14 days for other surgeries.
- Synovectomy for repeated hemarthrosis causing chronic hypertropic
synovial enlargement; perform before articular cartilage is completely
destroyed
- Radionuclide synovectomy: radioactive isotopes shrink outer synovium;
reduces pain, bleeding, recurrence
- Osteotomy for severe soft-tissue contracture or bony
deformity
- Arthroplasty for severely arthritic joints
- Removal of uncontrollable, expanding hematoma
- Amputation for chronically infected or infarcted
extremities
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Complementary and Alternative
Therapies |
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Conventional evaluation, treatment, and follow up for patients with
hemophilia is extremely important and should never be delayed in the case of
symptoms or bleeding. There are a few CAM therapies, though, which show promise
as adjunctive care to help alleviate the occurrence of certain symptoms and
sequelae of hemophilia. The degree of spontaneous bleeding may be linked to
emotional and psychological stress; modalities that are based on the mind-body
connection, incorporating techniques for managing stress, are likely to be
effective in relieving the associated stress and anxiety. Studies even suggest
that hypnosis may reduce the need for blood transfusions in hemophiliacs.
Self Hypnosis
In two studies, a 9-month pilot study with 7 patients and a subsequent
30-month controlled experiment with 20 patients, those who learned self-hypnosis
significantly decreased their need for blood products over a 3-year period. Case
studies and anecdotal reports corroborated the benefits of hypnosis in
increasing coagulability and reducing the need for transfused blood products
(LaBaw 1992).
Relaxation, Group Support, Education & Self Hypnosis
Swirsky-Sacchetti and Margolis subsequently undertook a more rigorous
investigation. Their randomized, controlled study evaluated the effects of a
comprehensive training program on the amount of factor concentrate used to
control spontaneous bleeding. The training program included self-hypnosis,
education, support, and relaxation training. Thirty male hemophiliacs receiving
home therapy, whose condition was determined to be severe (i.e., less than 1%
clotting factor present in the blood), were assigned to a treatment or control
group. After completing six weekly sessions, patients were followed for 18
weeks. The treatment group experienced:
- Significant reduction in factor usage.
- Lower subjective levels of distress
The researchers concluded that a comprehensive training program, including
hypnosis, support, education, and relaxation training, may be a useful adjunct
to medical management for severely affected hemophiliacs (Swirsky-Sacchetti and
Margolis 1986). |
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Nutrition |
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The relationship between nutrition and hemophilia has not been explored in
scientific studies. Vitamin E and fish oil appear to increase bleeding time by
inhibiting platelet aggregation; therefore, patients with hemophilia will be
well advised to avoid these nutrients. Vitamin K is a cofactor in normal
clotting and may be a useful dietary source or supplement; although, again,
research is needed in this area. |
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Herbs |
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In practice, herbs that strengthen vascular tissues and have astringent
properties are considered by some clinicians to try to lessen severity of
bleeding or enhance vascular integrity (Blumenthal et al. 2000):
- Hawthorn berry (Crataegus monogyna)
- Bilberry fruit (Vaccinium myrtillus)
- Grape seed extract (Vitis vinifera)
- Yarrow (Achillea millefolium)
- Witch hazel (Hamamelis virginiana)
- Horse chestnut (Aesculus hippocastanum)
However, the use of these agents for hemophilia specifically has not been
evaluated.
Ginkgo (Ginkgo biloba) reduces platelet aggregation and should
be avoided in the case of hemophilia. |
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Homeopathy |
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Six case histories of patients with hemophilia were analyzed to assess the
possible benefit of homeopathy. A review of four different reference texts
(Kent, Boericke, Lilienthal, and Boenninghausen) was used to identify the
remedies most likely to be helpful. Using this method, the first line remedies
were found to be (Hunton 1991):
- Lachesis - thought to be useful for hemorrhages that are dark
in color
- Phosphorus - prescribed when hemorrhages are frequent and
profuse
- Crotalus horridus - used by homeopaths when there is
bleeding into the muscles and blood appears thin and
dark
Secondary remedies as follows:
- Secale
- Arnica
- Millefolium
- Carbo vegetabilis.
- Hamamelis . . .
Review of the six cases revealed a consistent decrease in the need for factor
VIII; there is also some evidence of a decreased number of bleeds following
individualized homeopathic treatment. The results are very intriguing, although
not necessarily generalizable, given the size and design of the study (Hunton
1991). |
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Acupuncture |
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According to a report of two cases in Australia, acupuncture may be effective
for relieving joint arthropathies secondary to hemophilia. Acupuncture in this
population should be used only as a last resort, when other treatments have
failed or when symptoms persist. Guidelines and precautions for using
acupuncture in hemophilia should be closely observed (Koh 1981).
According to the recommendations of some practitioners:
- Cryoprecipitate should be easily available and precede acupuncture
needling
- Factor VIII activity should be raised at least 15% prior to the
process to account for the minor trauma involved in acupuncture
- Needles should be used sparingly in as few points as possible
- Pressure should be applied for longer periods after removal of needles
- Treatments should be limited in number
- Acupuncture around cranial, lingual, laryngeal, pericardial, and
pleural cavities should be strictly avoided due to potential lethality in
hemophiliac patients
- Insert needles cautiously near blood vessels such as B 54 (popliteal),
L 9 (radial), or K 3 (posterior tibial).
In spite of its dangers, acupuncture may relieve pain when other treatments
have failed. It may also be an effective substitute for medications whose side
effects include gastrointestinal bleeding (Koh 1981). |
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Physical Medicine |
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Physiotherapy may play an important role in reducing the incidence of chronic
joint arthropathy secondary to recurrent hemorrhage in a joint. Therapeutic
modalities that can be used to halt the cycle of recurrent hemarthroses in
addition to prophylactic factor replacement therapy include:
- Isometric, isotonic, and dynamic exercises
- Isokinetic and proprioception training
- Stretching exercises
A complete physiotherapy program may also include:
- Splints
- Ice
- Pulsed high frequency diathermy
- Therapeutic ultrasound
- Transcutaneous nerve stimulation
- Hydrotherapy.
This regimen should be used on an ongoing basis for at least 6 to 9 months in
order to treat chronic synovitis and prevent excessive bleeding (Buzzard
1997). |
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Patient Monitoring |
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- Close monitoring with 6- to 12-month evaluations identifies and
reduces complications.
- Comprehensive care treatment centers provide multidisciplinary
treatment and patient education.
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Other
Considerations |
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Prevention |
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- All aspirin-containing products and non-steroidal anti-inflammatory
medications should be avoided.
- Viral contamination rate has been significantly reduced by the
development of synthetic blood products, heat treatment of factor VIII (licensed
in 1983), HIV screening (instituted in 1985), and development of monoclonal
antibodies to factor VIII.
- Patients, including infants, should receive hepatitis B inoculation.
- Self-administration of factor VIII or IX delays progression of
degenerative arthritis; prophylactic use through adolescence prevents
significant arthropathy.
- Polymorphic DNA probes identify 90% of affected families and 96% of
carriers and can be used for neonatal diagnosis.
- Some recommend that male infants of known carriers not be circumcised
until hemophilia in the infant has been excluded.
- Patients should carry hemophilia
identification.
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Complications/Sequelae |
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- Without replacement therapy, sequelae include atrophy and necrosis of
the bone, cyst formation, stunted growth, and overgrowth of the epiphyses.
- HIV—resulting from replacement therapy using
plasma; first reported in 1981; more common in severe hemophilia, less common
with type B; high prevalence, but new incidence uncommon given new technological
advances as described in section entitled Prevention, as well as greatly
improved HIV detection since 1985
- Hepatitis—types B and C, resulting from
replacement therapy using plasma; correlates to long-term morbidity and
mortality
- Inhibitors—factor-specific antibodies
directed against the active clotting site can develop; desensitization is
sometimes effective; approximately 5% of patients receiving repeated
cryoprecipitate
- Chronic joint destruction
- Bleeding into muscles can cause compartment syndrome, necrosis, and
even damage to nerves—e.g., femoral neuropathy from
retroperitoneal hematoma
- Iliac hemophilic pseudotumor
(cysts)—life-threatening complication with factor VIII
deficiency; usually in femur or pelvis
- Pseudotumor in soft tissue mistaken for sarcoma
- Airway may be rapidly compromised by bleeding into the tongue, throat,
neck
- Gangrene—from pressure to arteries
- Ischemic contractures—especially in forearms,
calves
- Peripheral nerve lesions—especially femoral
nerve from retroperitoneal bleed
- Intracranial bleeding—common cause of death
- Chronic epistaxis, which may cause mild iron deficiency anemia;
otherwise, iron deficiency anemia is rare because bleeding is generally internal
and iron is recycled
- Hemolytic anemia possible following reception of large doses of
purified factor VIII
- Thrombosis is a potential complication for the type B hemophiliac
receiving purified concentrates following surgery
- Psychological—including risk-taking, suicide
attempts, spontaneous bleeding with emotional stress
- Aspirin decreases platelet aggregation and must be avoided
- Female carriers with factor VIII levels below 50% may have heavy
menses and increased bleeding from surgical
procedures
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Prognosis |
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Improved replacement therapy techniques have reduced the risk of contracting
HIV viral infection, thus prolonging lives. Median life expectancy for
hemophiliacs was 68 years before AIDS epidemic, reduced to 49 years from 1981 to
1990. Life expectancy now is anticipated to return to pre-1981 levels for those
not infected with HIV. Hemophilia does not protect against thromboembolic
disorders or atherosclerosis. Liver transplantation for hepatic failure may cure
hemophilia. |
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Pregnancy |
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- Rare associated risk as most females are only carriers
- Prenatal diagnosis—factor assays and genetic
testing available
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References |
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Behrman RE, ed. Nelson Textbook of Pediatrics. 15th ed. Philadelphia,
Pa: W.B. Saunders Co; 1996.
Blumenthal M, Goldberg A, Brinckmann J, et al., eds. Herbal Medicine:
Expanded Commission E Monographs. Newton, Mass: Integrative Medicine
Communications; 2000.
Buzzard BM. Physiotherapy for prevention and treatment of chronic hemophilic
synovitis. Clin Orthop. 1997;343:42-46.
Hoots WK. Hemophilia and related conditions. In: Rakel RE, ed. Conn's
Current Therapy. 51st ed. Philadelphia, Pa: W.B. Saunders; 1999.
Hunton M. Homoeopathy in the treatment of haemophilia. Br Homeopath J.
1991;80:82-100.
Koh TC. Acupuncture therapy in hemophilia. Am J Acupunct.
1981;9(3):269-270.
LaBaw W. The use of hypnosis with hemophilia. Psychiatr Med.
1992;10(4):89-98.
Lee GR, ed. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md:
Williams & Wilkins, Inc.; 1999.
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. N Engl J Med.
1993;328(7):453-459.
Swirsky-Sacchetti T, Margolis CG. The effects of a comprehensive
self-hypnosis training program on the use of Factor VIII in severe hemophilia.
Int J Clin Exp Hypn. 1986;34(2):71-83.
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Copyright © 2000 Integrative Medicine
Communications This publication contains
information relating to general principles
of medical care that should not in any event be construed as specific
instructions for individual patients. The publisher does not accept any
responsibility for the accuracy of the information or the consequences arising
from the application, use, or misuse of any of the information contained herein,
including any injury and/or damage to any person or property as a matter of
product liability, negligence, or otherwise. No warranty, expressed or implied,
is made in regard to the contents of this material. No claims or endorsements
are made for any drugs or compounds currently marketed or in investigative use.
The reader is advised to check product information (including package inserts)
for changes and new information regarding dosage, precautions, warnings,
interactions, and contraindications before administering any drug, herb, or
supplement discussed herein. | |