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.

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.

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.

• 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

• 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 

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.

• 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

• 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 

• CT scans or sonography diagnose abdominal hematomas or hemorrhages 
• CT scan or MRI for intracranial bleeding 
• MRI for joint hemorrhage 

• Bethesda assay quantifies the amount of inhibitor present in patients with antibodies to replacement factors 

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.

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.

• 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 

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).

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.

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.

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).

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).

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).

• Close monitoring with 6- to 12-month evaluations identifies and reduces complications.
• Comprehensive care treatment centers provide multidisciplinary treatment and patient education.

• 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. 

• 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 

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.

• Rare associated risk as most females are only carriers
• Prenatal diagnosis—factor assays and genetic testing available

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