eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Hemophilia, Overview: Treatment & Medication

Author: Dimitrios P Agaliotis, MD, PhD, FACP, Consulting Staff, Department of Medicine, Baptist Health System
Coauthor(s): Robert A Zaiden, MD, Fellow, Department of Hematology and Medical Oncology, University of Florida at Jacksonville; Saduman Ozturk, PA-C, Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Contributor Information and Disclosures

Updated: Nov 24, 2009

Treatment

Medical Care

Before a patient with hemophilia is treated, the following information should be obtained: (1) the type and severity of factor deficiency, (2) the nature of the hemorrhage or the planned procedure, (3) the patient's previous treatments with blood products, (4) the presence and possible titers of inhibitors, and (5) the patient's previous history of desmopressin acetate (DDAVP) use (eg, in mild hemophilia A only) with the degree of response and clinical outcome.

Various FVIII and FIX concentrates are now available to treat hemophilia A and hemophilia B. Reductions in infectious complications and improved purity are the main advantages of these concentrates. During production, a specific viral-inactivation stage, either solvent-detergent treatment or liquid-phase heat treatment, is implemented to inactivate viruses, such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a problem.

Recombinant FVIII and FIX are now commercially available. They have lowered the risk of viral contamination.

General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia

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^* Dosing intervals are based on a half-life for FVIII of 8-12 h (2-3 doses/d) and half-life of FIX of 18-24 h (1-2 doses/d). Maintenance doses of one half the initial dose may be given at these intervals.

^† Continuous factor infusions may be administered. After the initial loading dose, continuous infusion at a dose of 3 IU/h is given. Subsequent doses are calculated according to the plasma factor levels.

• For dosage calculations, these general guidelines may be applied:
  • FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours.
  • FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.
• Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels.
  • Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a hemophilia A factor level of 30% and a hemophilia B factor level of 20%.
  • Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an hemophilia A factor level of 50% and a hemophilia B factor level of 40%.
  • Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain a hemophilia A factor level of 80-90% and a hemophilia B factor level of 60-80%. Plasma levels are maintained higher than 40-50% for a minimum of 7-10 days.
• Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.
• In dental procedures, antifibrinolytic drugs and local hemostatic techniques, such as topical thrombin and cellulose bandaging, may be useful.
• Substantial progress has been made in the development of gene therapy for hemophilia A and hemophilia B.⁸ This advancement reflects technical improvements of existing vector systems and the development of new delivery methods.
  • Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. The induction of neutralizing antibodies often precludes stable phenotypic correction.
  • On the contrary, certain promoters are prone to transcriptional inactivation in vivo, resulting in failure of long-term FVIII or FIX expression. Several phase I trials of gene therapy are ongoing in patients with severe hemophilia. Some individuals report fewer bleeding episodes than before, and low levels of clotting factor activity are occasionally detected.
• Pain medications are used for acute bleeding or chronic arthritis.
  • Safe analgesics include acetaminophen, oxycodone, propoxyphene, and pentazocine.
  • Avoid all aspirin products.
• The treatment of patients with inhibitors of FVIII is difficult.
  • Attempts to overwhelm the inhibitor with large doses of human FVIII have been tried in attempts to induce immune tolerance, especially if inhibitor concentrations are below 5 BU.⁹
  • Porcine FVIII, which has low cross-reactivity with human factor VIII antibody, has also been administered.
  • FVIII inhibitor-bypassing agents (FEIBA), including FIX complex, activated prothrombin complex concentrate (aPCC), and activated FVII has also been used.
  • Plasmapheresis, IVIG, or immunosuppressive therapy with cyclophosphamide and prednisone, have showed some success in achieving long-term control.
  • Rituximab with prednisone plus or minus the addition of mycophenolate mofetil when standard therapy has failed.

Consultations

• Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.
• Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.
• Management should be coordinated in coordination with a comprehensive hemophilia center.

Activity

• Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously.
• Any physical activity may trigger bleeding in soft tissues.
• Prophylactic factor replacement early in life may help prevent bleeding, as well as chronic arthritic and muscular damage and deformity.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.

Recombinant activated FVIIa

Recombinant activated FVIIa (Eptacog Alfa or Novo Seven) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.¹⁰ It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.

Recombinant FVIIa is effective and well tolerated in patients with hemophilia A and hemophilia B with inhibitors, in those with acquired hemophilia, or in those with Glanzmann thrombasthenia. Recombinant FVIIa (Eptacog Alfa) is the treatment of choice in patients with hemophilia B with high-responding inhibitors and in patients with FVII deficiency.

To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with inhibitors for FVIII or FIX; when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding.

In summary, recombinant activated FVIIa is a valuable treatment choice in patients with hemophilia with inhibitors, in those with platelet-refractory Glanzmann thrombasthenia, or in those with congenital FVII deficiency.

Desensitization

Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FVIII along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy.

Immune tolerance induction

In immune tolerance induction (ITI), a person is rendered tolerant to FVIII or FIX by means of repeated daily exposure to FVIII or FIX over several months to years.⁹

First described by Backmann in 1977, ITI has been used, with variations in the dosing schedule for FVIII and in the presence or absence of immunosuppressive therapy. A characteristic of most recent protocols that use FVIII alone has been the avoidance of immunosuppression (steroids, cyclophosphamide) because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia.

The success of rituximab in eliminating refractory FVIII inhibitors may be a valid subject of further investigation. Reports describe durable complete responses with a brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.¹¹ According to hematology workers (personal communication with Dr. Troy H. Guthrie, Jr. MD, Medical Director Baptist Cancer Institute, Jacksonville, Florida), Rituximab is more effective in treating patients with acquired inhibitors than in patients with hereditary hemophilia that develop inhibitors during their course of the disease.¹²

Attenuation of B-cells essential to the development of an acquired immune response, or autoimmunization seen in patients with refractory FVIII inhibitors, with a 4-week course of every week rituximab has shown durable and complete responses in several small trials. The addition of prednisone with or without cyclophosphamide has increased response rates.

The overall likelihood of success with ITI is 70% ± 10%.

An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high-dose ITI. For information, please see the study Web site Immune Tolerance Induction Study.

Posterior pituitary hormones

These agents raise endogenous FVIII levels in mild hemophilia A. Increases as much as 3-fold from the baseline are observed, with peak responses at 30-60 minutes after infusion.¹³

Desmopressin acetate (DDAVP)

Increases cellular permeability of collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur even after first dose, but drug can be effective again after several days.

Targeted/biologic therapy

This agent is a monoclonal antibody directed against the CD20 antigen on B-cells. it is recommended as second-line therapy, especially in cases with high inhibitor titers.

Rituximab (Rituxan)

Binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.

Recombinant factor VII

This activated recombinant FVII increases local formation of FXa, thrombin, and fibrin, to facilitate the formation of a hemostatic plug.

Coagulation factor VIIa (recombinant) (Novo Seven)

Binds to exposed tissue factor and also directly activates FX

Antifibrinolytic agents

These agents are used in oral surgery or bleeding. Their use should be avoided in cases of genitourinary bleeding (ie, obstructive uropathy) and in combination with prothrombin complex concentrate (PCC).

Aminocaproic acid (Amicar)

Inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. Main problem is thrombi formed during treatment not lysed, and effectiveness uncertain. Has been used to prevent recurrence of subarachnoid hemorrhage.

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

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