eMedicine Specialties > Pediatrics: General Medicine > Hematology
Hemophilia A and B: Treatment & Medication
Updated: Dec 2, 2008
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Treatment
Medical Care
Current treatment of patients with hemophilia requires a comprehensive multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Comprehensive care clinics are supported by evidence of better access to care, less morbidity, and better overall outcome.
Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability. For most mild hemorrhages, dose calculations are directed toward achieving a factor VIII (FVIII) activity level of 30-40% or factor IX (FIX) activity level of 30% and clotting factor activity of at least 50% in severe bleeds (eg, major dental surgery, major surgery, trauma) and 80-100% in life-threatening hemorrhage.
Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work. Patients are treated with prophylaxis or intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.2,3
In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity.4 In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has been established to prevent worsening of the joint) is instituted for a defined period. Dosing is designed to maintain trough levels greater than 2%. This usually requires the administration of FVIII 3 times per week or FIX 2 times per week. Individualized therapy to individual patients (tailored prophylaxis) has been also used with success; the best approach has yet to be determined.
The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis.
Management of hemostasis
Hemostasis is achieved with replacement therapy aimed at correcting the coagulation factor deficiency. The dose and frequency of administration are calculated as outlined in Table 2.
Table 2. Replacement Therapy Dose Calculations
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Table
Factor | Half-Life, h | Increase After 1 U/kg, % | Required Activity for Common Bleeding, % |
VIII | 8-12 | 2 | 40 |
IX | 24 | 1 | 30 |
Factor | Half-Life, h | Increase After 1 U/kg, % | Required Activity for Common Bleeding, % |
VIII | 8-12 | 2 | 40 |
IX | 24 | 1 | 30 |
Management of bleeding episodes
- Musculoskeletal bleeding
- The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.
- Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.
- Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.
- Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply.
- Aseptic necrosis of the femoral head can be complications in hip joint hemorrhages. Administer adequate replacement therapy for at least 3 days.
- Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.
- Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension.
- Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.
- Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII or FIX.
- Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.
- Oral bleeding
- Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.
- Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.
- Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.5
- Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.
- Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.
- GI bleeding
- GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause.
- Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII coagulant or FIX.
- Intracranial bleeding
- Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare.
- If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.
- All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI.
- Prophylactically infuse the factor.
- In addition, if the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.
Factor replacement products and medications
- FVIII products
- Various products are available for replacement therapy. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia A and B because of the lack of safe viral elimination and concerns regarding volume overload. Many plasma-derived FVIII concentrates are commercially available.
- Various purification techniques are used to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation.
- Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. Third-generation products without any exposure to animal proteins are now available to further decrease this risk. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of the presence of inhibitor appear to be unwarranted.
- With wider availability of improved products (stability, purity), use of continuous infusion of factors has incrementally increased. Continuous administration of antihemophiliac factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods of time.
- Besides improved hemostasis, continuous infusions decreases the amount of factor used, which can result in significant savings.
- The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery.
- In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.
- Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP)
- DDAVP is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia.
- It stimulates a transient increase in plasma FVIII levels and results in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. Other possible mechanisms of action are noted.
- A test dose should be performed. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting.
- Its peak effect is observed in 30-60 minutes.
- A concentrated DDAVP intranasal spray is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.
- Patients should be advised to limit water intake during treatment and to avoid 3 consecutive daily doses to a prevent hyponatremia. Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed.
- The major adverse effects of DDAVP include asymptomatic facial flushing and hyponatremia.
- Antifibrinolytics
- Aminocaproic acid (Amicar), or EACA, is administered to patients with hemophilia to control mucosal bleeding, such as oral or nasal and menstrual bleeding or bleeding after dental extractions. It must avoided in patients with hematuria.
- It neutralizes fibrinolytic activity in the saliva.
- Gene therapy
- With the cloning of FVIII and FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived.
- Several human trials have been performed in patients with hemophilia A and patients with hemophilia B; however, stable production of the coagulation protein has not been achieved. This is still an area of intense investigation.
Table 3. Replacement Therapy for Hemorrhage in Hemophilia A and B
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Table
Site of Bleeding | Required Factor Level, % | Dose in Hemophilia A | Dose in Hemophilia B |
| Joint | 30-50 | ... | 30-40 U/kg q2d |
| Muscle | 40-50 | 20-40 U/kg/d | 40-60 U/kg q2d |
| Oral mucosa | 50, add EACA | 25 U/kg | 50 U/kg |
| Epistaxis | 80-100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg/d | 80-100 U/kg, then 70-80 U/kg q2d |
| GI tract | 100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg | 80-100 U/kg, then 70-80 U/kg q2d |
| Genitourinary tract | 100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg/d | 80-100 U/kg, then 70-80 U/kg q2d |
| CNS | 100, then 50-100 for 10-14 d | 50 U/kg, then 25 U/kg q12h or continuous infusion | 100 U/kg, then 50 U/kg/d |
| Trauma or surgical site | 100, then 30-50 until healed | 50 U/kg, then q12h or continuous infusion | 100 U/kg, then qd |
Site of Bleeding | Required Factor Level, % | Dose in Hemophilia A | Dose in Hemophilia B |
| Joint | 30-50 | ... | 30-40 U/kg q2d |
| Muscle | 40-50 | 20-40 U/kg/d | 40-60 U/kg q2d |
| Oral mucosa | 50, add EACA | 25 U/kg | 50 U/kg |
| Epistaxis | 80-100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg/d | 80-100 U/kg, then 70-80 U/kg q2d |
| GI tract | 100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg | 80-100 U/kg, then 70-80 U/kg q2d |
| Genitourinary tract | 100, then 30 until healed | 40-50 U/kg, then 30-40 U/kg/d | 80-100 U/kg, then 70-80 U/kg q2d |
| CNS | 100, then 50-100 for 10-14 d | 50 U/kg, then 25 U/kg q12h or continuous infusion | 100 U/kg, then 50 U/kg/d |
| Trauma or surgical site | 100, then 30-50 until healed | 50 U/kg, then q12h or continuous infusion | 100 U/kg, then qd |
Prophylactic factor infusions
Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic regimes of factor concentrate infusions that take place at home and are usually given by a parent.
The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to the joint. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method. But this approach is not universally accepted, with only about one half of children with hemophilia A and one third of children with hemophilia B receiving this treatment modality in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability, repeated venipunctures, cost, and others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects.
Treatment in patients with factor inhibitors
Inhibitors to FVIII develop in 25-35% of children with severe hemophilia A; inhibitors to FIX develop in 1-3% in children with hemophilia B. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII. Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development (FVIII and FIX). Also, inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development. As for recombinant FVIII products, no new inhibitors have been known to develop in previously treated patients, and inhibitors develop in as many as 30% of previously untreated patients (PUPs). In PUPs, the titer of the inhibitors is low in half and transient in one third.
In the treatment of patients with low-titer FVIII inhibitors (<5 Bodansky units [BU]), bleeding can be controlled with human FVIII administered at standard or higher doses. In patients with high-titer inhibitors, immune tolerance induction (ITI) may be used to reduce or suppress the inhibitor. Therapeutic options include standard or activated prothrombin complex concentrate (PCC); recombinant factor VIIa (NovoSeven); and porcine FVIII (Hyate:C), if no cross-reacting antibodies are present. Recombinant factor VII has become the first choice of bypassing agents.6 In patients with high-titer FIX inhibitors, ITI is less successful compared with that in patients with FVIII inhibitors. Therapeutic options are the same for these patients as for those with FVIII inhibitors, with the same doses. Patients with hemophilia B and inhibitors can have anaphylactic reactions to FIX infusions.
Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in patients with hemophilia A and in patients with hemophilia B and high titer inhibitors.7
Gene transfer therapy
Previous clinical trials have suffered from transient, subtherapeutic expression of human FVIII transgenes. More recently, porcine factor VIII retroviral gene was successfully transferred into genetically immunocompetent hemophilia A mice. FVIII expression was sustained beyond 10 months. Also, for severe hemophilia B, an adenoassociated viral vector trial is underway.
Consultations
A genetic counselor may be consulted. Genetic testing for hemophilia A and B is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.
Annual dental evaluation is recommended. A neurologist and neurosurgeon should be consulted when necessary, and consultation with an orthopedic surgeon should be considered in situations involving significant or repeated hemarthrosis.
Activity
Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning.
Medication
Hemostatic agent
These are used in the treatment of excessive bleeding in the oral mucosa that results from local fibrinolytic activity.
Aminocaproic acid (Amicar)
Competitively inhibits activation of plasminogen, reducing fibrinolysin without inhibiting clot lysis. Widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal.
Adult
5 g PO first h followed by 1-1.25 g/h for about 8 h or until bleeding stops
4-5 g IV first h followed by continuous infusion at 1-1.25 g/h; continue for 8 h or until bleeding stops
Pediatric
100-200 mg/kg PO initially, followed by a maintenance dose of 100 mg/kg q6h; not to exceed 30 g
100 mg/kg or 3 g/m2 IV initially, followed by continuous infusion of 33.3 mg/kg/h or 1 g/m2/h; not to exceed 18 g/m2/d
Coadministration with estrogens may increase in clotting factors, leading to a hypercoagulable state
Documented hypersensitivity; evidence of active intravascular clotting process; can be lethal in patients with DIC (important to differentiate hyperfibrinolysis and DIC)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Do not administer unless diagnosis of hyperfibrinolysis is definite; caution in cardiac, hepatic, or renal disease
Antihemophilic agent, hemostatic agent, vasopressin analog, synthetic
These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.
Desmopressin (DDAVP, Stimate)
Main effect is enhancement of water reabsorption in the kidney and smooth muscle constriction. Causes dose-dependent increase in plasma FVIII and plasminogen activator.
Adult
IV: 0.3 mcg/kg slow infusion 30 min before procedure
Intranasal: 300 mcg (1 spray per nostril [ie, 2 sprays total]) 2 h before surgery; may repeat use, depending on clinical situation
Pediatric
0.3 mcg/kg IV slow infusion; may repeat prn; administer 30 min before procedure; maximum dose is 20 mcg.
>12 years:
<50 kg: 150 mcg intranasally (1 spray intranasally)
>50 kg: 300 mcg intranasally (1 spray in each nostril [ie, 2 sprays total])
Repeat use is determined by clinical situation; administer 2 h before surgery
No known interactions related to antihemophilic effect
Documented hypersensitivity; avoid in type IIB or platelet-type von Willebrand disease, hemophilia A (<5%), hemophilia B; avoid intranasal route with mucosal changes (congestion, obstruction, scarring)
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Predisposition to thrombus formation; conditions associated with fluid and electrolyte imbalance (eg, cystic fibrosis)
Antihemophilic agent; blood product or recombinant DNA derivative
These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.
Antihemophilic factor Human plasma derived:(Alphanate, Hemofil M, Koate-DVI). Recombinant: (Recombinate, Kogenate, Helixate, Refacto, Advate)
FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.
Adult
20-50 U/kg/dose
IV q12-24h; higher doses may be used (eg, 50-75 U/kg with high inhibitor titers); individualize doses according to clinical situation; may administer more frequently in special circumstances
Pediatric
Administer as in adults
None reported
Documented hypersensitivity; documented hypersensitivity to mouse proteins
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Viral contamination and infection remotely possible but unlikely because of prescreening; risk of hemolysis with anemia in blood groups A, B, and AB is due to trace amounts of A and B isohemagglutinins
Antihemophilic agent; blood product derivative or recombinant DNA derivative
These used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.
Plasma-derived prothrombin complex concentrates/Factor IX complex concentrates (Bebulin, Profilnine SD, Proplex T), Anti-inhibitor coagulant complex (FEIBA VH), Plasma-derived coagulation factor IX concentrate (Alpha Nine SD, Mononine). Recombinant factor IX (BeneFIX)
Replaces deficient FIX and other factors in the complex. AlphaNine and Mononine contain only FIX. BeneFIX is a recombinant product.
Adult
20-50 U/kg IV; individualize doses according to clinical situation; may administered higher doses and qd or more frequently in special cases Patients who are also receiving FVIII: 75-100 U/kg IV q6-12h
Pediatric
Administer as in adults
Increased risk of thrombosis (FIX complex) with aminoproic acid (delay aminocaproic acid dose by 8 h)
Documented hypersensitivity; liver disease, DIC, fibrinolysis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Viral contamination and infection remotely possible but unlikely because of prescreening; caution in liver disease
Recombinant factor VII (NovoSeven, NiaStase)
Indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. Promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, FIX to factor IXa, and factor II to factor IIa.
Adult
90 mcg/kg IV q2h until hemostasis is achieved or treatment is judged inadequate; for patients with or without inhibitors; may use 35-120 mcg/kg, depending on the severity of the clinical situation; duration of administration has not been well established
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Viral contamination and infection remotely possible but unlikely because of prescreening
More on Hemophilia A and B |
| Overview: Hemophilia A and B |
| Differential Diagnoses & Workup: Hemophilia A and B |
 Treatment & Medication: Hemophilia A and B |
| Follow-up: Hemophilia A and B |
| Multimedia: Hemophilia A and B |
| References |
| « Previous Page | Next Page » |
References
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Further Reading
Keywords
hemophilia a, hemophilia b, factor VIII deficiency, FVIII deficiency, factor VIII hemophilia, factor IX deficiency, FIX deficiency, factor IX hemophilia, Christmas disease, angiostaxis, coagulation disorder, coagulation deficiency, bleeding disorder, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus infection, HIV, hemarthrosis, hematomas, petechiae, vasculitis
