Hemophilia A is an X-linked, recessive disorder caused by deficiency of clotting factor VIII. It may be inherited or arise from spontaneous mutation. The development of inhibitory antibodies to factor VIII can result in acquired hemophilia A or can complicate the treatment of genetic cases.
Depending on the level of factor VIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage.
Severe disease presents in children younger than 1 year and accounts for 43-70% of hemophilia.
Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 males
Hemophilia A occurs in all races and ethnic groups.
Hemophilia B and C are deficiencies of ….. respectively. They are discussed separately.
Pathophysiology of Hemophilia A
Hemophilia is caused by an inherited or acquired genetic mutation that results in dysfunction or deficiency of factor VIII.
Inadequate factor VIII results in the insufficient generation of thrombin by the factor IXa and factor VIIIa complex by means of the intrinsic pathway of the coagulation cascade.
[Read about coagulation cascade]
Hemophilia A is inherited in an X-linked recessive pattern.
However, combined factor V and factor VIII deficiency is an autosomal recessive disorder.
Factor VIII is mainly produced by the liver and the reticuloendothelial system.
Factor VIII circulates in plasma in a noncovalently bound complex with von Willebrand factor which vWF stabilizes factor VIII and protects it from degradation.
The gene for factor VIII is located on the long arm of chromosome X, within the Xq28 region.
Factor VIII deficiency leads to the disruption of the normal intrinsic coagulation cascade, resulting in excessive bleeding.
The bleeding sites include joints, muscles, CNS and the gastrointestinal, genitourinary, pulmonary, and cardiovascular systems.
The hallmark of hemophilia is hemorrhage into joints.
High levels of tissue factor pathway inhibitor [causes factor Xa inhibition] predisposes hemophilic joints to bleed.
Joint bleeding may lead to synovial inflammation predisposing the joint to further bleeds. Knee is most commonly involved joint.
Repeated hemarthroses lead to progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and degenerative changes in the joint.
Clinical Presentation of Hemophila
Often, there is a history of bleeding disproportionate to trauma and/or spontaneous hemorrhage. History of bleeding disorders in the family may be present.
Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision.
Easy bruising may occur at the start of ambulation or primary dentition.
Older patients may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, and have spontaneous bleeding in soft tissues.
Mild or moderate may go unnoticed till adult age some trauma brings attention ton it.
Weight-bearing joints and other joints [knee, ankle, hip] are main sites of bleeding. Flexors of the arms and gastrocnemius of the legs are main muscles affected.
Hematuria may occur in as many as 90% of patients.
30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding. Bleeding then is usually seen in toddlers, when trauma-related soft-tissue hemorrhage occurs.
Eruption of teeth may be associated with oral bleeding.
As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis.
Petechiae usually do not occur in patients with hemophilia as petechiae are manifestations of capillary blood leakage.
In acute bleeding patient may have tachycardia, tachypnea, hypotension etc. There would be organ specific signs. For example, joint pain or muscle pain in bleeding in joints and muscles. Central nervous system bleed may present with altered neural findings.
Hemophilia is classified according to clinical severity as mild, moderate, or severe.
|Classification||Factor Activity, %||Cause of Hemorrhage|
|Mild||>5-40||Major trauma or surgery|
Patient must be examined for musculoskeletal deformities, jaundice and other signs of liver failure.
Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They may be noted in the buttock, pelvis, and thighs.
- Acquired Hemophilia
- Ehlers-Danlos Syndrome
- Factor XI Deficiency
- Glanzmann Thrombasthenia
- Hemophilia C
- Hemophilia, Type B
- Child Abuse
- Platelet Disorders
- von Willebrand Disease
- Acquired multiple-factor coagulopathies due to liver disease
- Warfarin excess
- Coagulopathy of dysproteinemias
Laboratory studies for suspected hemophilia include a
- Complete blood cell count
- Coagulation studies
- Factor VIII assay.
Hemoglobin/hematocrit assay are normal or low values. Platelet count is normal.
Bleeding time and prothrombin time are normal but usually, the activated partial thromboplastin time (aPTT) is prolonged.
For factor VIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:
- Mild: >5%
- Moderate: 1-5%
- Severe: < 1%
Increased factor VIII levels are seen with aging, oral contraceptive use, estrogen replacement therapy and in pregnancy.
Post natal diagnosis can be made from assaying factor VIII as it does not cross placenta.
For differentiation from von Willebrand disease levels of von Willebrand factor antigen should be measured.
Imaging choices are guided by clinical suspicion and the anatomic location of involvement.
Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage.
Perform magnetic resonance imaging (MRI) on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space.
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions.
Testing for Inhibitors
Test for factor VIII inhibitor is important when a bleeding episode is not controlled despite infusion of adequate amounts of factor concentrate. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method.
> 0.6 Bethesda units (BU) is considered a positive result for an inhibitor.
Patients with low-titer inhibitors may respond to higher doses of Factor VIII concentrate.
Patients with high-titer inhibitors require treatment with agents that bypass factor VIII and consideration for induction of immune tolerance.
Carrier Testing and Fetal Testing
Screening for carrier status can be performed by measuring the ratio of factor VIII coagulant activity to the concentration of vWF antigen. A ratio that is less than 0.7 suggests carrier status.
Direct genetic testing for known gene mutation is more accurate.
For prenatal testing, carriers whose mutation has been identified can have chorionic villus sampling.
Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who have been untreated or inadequately treated or in those with recurrent joint hemorrhages.
Treatment of Hemophilia
Approach to Treatment
The treatment of hemophilia may involve
- Management of bleeding episodes
- Treatment of factor VIII inhibitors
- Treatment and rehabilitation of hemophilia synovitis/arthritis.
Treatment of patients with hemophilia should be done at a specialized center. Home treatment or ambulatory replacement therapy for bleeding episodes is advised for preventing chronic arthropathy and deformities.
Following targets of factor VIII should be attained
- Factor VIII activity level of 30-40% for most mild hemorrhages
- 50% for
- Severe bleeds (eg, trauma)
- Prophylaxis of major dental surgery or major surgery
- 80-100% in life-threatening hemorrhage.
Patients can be treated with prophylaxis or with intermittent, on-demand therapy for bleeding. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.
In countries with access to recombinant product, primary prophylaxis is started in patients as young as 1 y and continues into adolescence
In case of patients with inhibitors, in patients with low-titer inhibitors (< 5 Bethesda units can occasionally be overcome with high doses of factor VIII. In other cases following options can be tried
- Porcine FVIII, which has low cross-reactivity with human FVIII antibody
- Agents that bypass factor VIII like activated FVII
- Activated prothrombin complex concentrate (PCC)
- large doses of FVIII along with steroids or intravenous immunoglobulinand cyclophosphamide
- Success rates of 50-80%
- Immune tolerance induction
In patients who develop synovitis from joint bleeds
- Injection of radioisotopes into the joint to ablate the synovium (radiosynovectomy)
- Unresponsive cases – arthroscopic synovectomy or arthroplasty.
To counter associated osteopenia, regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake are recommended, along with prophylactic factor replacement therapy in severe hemophilia.
Management of bleeding episodes
Achieve hemostasis and correct coagulopathy immediately. Include a diagnostic workup for hemorrhage.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously.
Epistaxis and moderately severe hematuria require factor VIII levels in the range of 30-50%.
Joint bleeds with intense pain require narcotic analgesics and adequate factor replacement.
Life-threatening bleeding episodes demands factor VIII levels of approximately 100%, until the clinical situation improves to bring reduction in dosage.
Other measures for bleeding should be done according to the site of injury.
Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.
Oral bleeding is aggravated by the increased fibrinolytic activity of saliva. An antifibrinolytic agent (epsilon-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity should be used along with factor replacement.
GI hemorrhage may require repeated or continuous infusions to maintain nearly normal circulating levels of FVIII.
Factor VIII Concentrates
Various FVIII concentrates are available to treat hemophilia A [ Fresh frozen plasma and cryoprecipitate are no longer used because risk of disease transmission
Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission [ heat treatment, cryoprecipitation, and chemical precipitation]
Many recombinant factor VIII concentrates are currently available.
As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours.
Desmopressin is vasopressin analog, that is used in the treatment of mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. It stimulates a transient increase in plasma factor VIII levels.
It is given usually as intravenous preparation. An intranasal spray is also available.
Hyponatremia due to water retention is a potentially serious adverse effect.
Nonsteroidal anti-inflammatory drugs can be effective in managing acute and chronic arthritic pain.
Avoid aspirin because of its irreversible effect on platelet function.
Routine immunizations to hemophiliacs may be given by means of a deep subcutaneous rather than deep intramuscular injection.
In severe hemophilia, prohylaxis should be considered.
Carrier testing may prevent births of individuals with major hemophilia.
Persons with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma
Regular dental evaluation is recommended.
Patient and family should be educated about hemorrhage signs and symptoms for early recognition. They can also be taught about factor replacement at home reducing the need for emergency department visits.
Prognosis of Hemophilia
With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with factor VIII concentrate have dramatically improved the prognosis of patients with severe hemophilia.
Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population.
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