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Hemophilia A Treatment & Management

  • Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
 
Updated: Feb 29, 2016
 

Approach Considerations

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of hemophilia synovitis. Use of factor replacement products and other medications, including pain medications, is typically required.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers, which are found in many US cities, follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have 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.

Dose calculations are directed toward achieving an FVIII activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large-soft tissue bleeds; retroperitoneal hemorrhage or other internal bleeding; and hemorrhage related to head injury, surgery, or dental work.

Patients can be treated with prophylaxis or with 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.[24, 25] According to a review of 6 randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, resulting in decreased overall joint deterioration and improved quality of life.[26]

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.[27] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, to prevent worsening of the joint) is instituted for a defined period.

For prophylaxis, dosing is designed to maintain trough levels greater than 2%. This usually requires the administration of FVIII 3 times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined.

The treatment of patients with inhibitors of FVIII is difficult. Bleeding episodes in patients with low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[28] Options in other cases include a variety of agents that bypass FVIII, such as activated FVII; desensitization; and immune tolerance induction.

In patients who develop synovitis from joint bleeds, injection of radioisotopes into the joint to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Unresponsive cases may require arthroscopic synovectomy or arthroplasty.[29]

Increasing evidence associates hemophilia with low bone mineral density; consequently, careful assessment and management of fracture risk are recommended. Regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake are recommended, along with prophylactic factor replacement therapy in severe hemophilia.[21]

Please see the following for more information:

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Prehospital Care

Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:

  • Apply aggressive hemostatic techniques
  • Assist patients capable of self-administered factor therapy
  • Gather focused historical data if the patient is unable to communicate
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Emergency Department Care

Before a patient with hemophilia is treated, the following information should be obtained:

  • The type and severity of factor deficiency
  • The nature of the hemorrhage or the planned procedure
  • The patient's previous treatments with blood products
  • Whether inhibitors are present and if so, their probable titer
  • Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome.

Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated, because these procedures may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding.

Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeds frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and reduce usage of expensive factor replacement product by approximately 30%.

If admission is indicated, disposition (intensive care unit vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose the attending service based on the etiology and site of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory.

Patients whose condition and bleeding are stabilized should be transferred to a comprehensive hemophilia care center for further treatment and monitoring. These centers offer a multidisciplinary approach by specialists experienced in hemophilia.

Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic. These patients require monitoring of their CD4 count, observation for adverse effects of anti-HIV treatment, and monitoring for and treatment of possible opportunistic infections.

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Factor VIII Concentrates

Various FVIII concentrates are available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques 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 potential problem.

Many recombinant FVIII concentrates are currently available. The advantage of such products is the elimination of viral contamination. Third-generation products with no exposure to animal proteins further decrease this risk. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of inhibitor development appear to be unwarranted.

With wider availability of improved products (ie, better stability, purity), use of continuous infusion for administration has incrementally increased. Continuous infusion of antihemophilic 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.

Besides improved hemostasis, continuous infusion 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.

Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. Target levels by hemorrhage severity are as follows:

  • Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
  • Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of 50%
  • Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII level of 80-90%; after stabilization, maintain levels above 40-50% for a minimum of 7-10 days

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia (Open Table in a new window)

Indication or Site of Bleeding Factor level Desired, % FVIII Dose, IU/kg* Comment
Severe epistaxis; mouth, lip, tongue, or dental work 20-50 10-25 Consider aminocaproic acid (Amicar), 1-2 d
Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h
Soft tissue or muscle 20-40 10-20 No therapy if site small and not enlarging (transfuse if enlarging)
Muscle (calf and forearm) 30-40 15-20 None
Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 Transfuse, repeat at 24 h, then as needed
Neck or throat 50-80 25-40 None
Hematuria 40 20 Transfuse to 40% then rest and hydration
Laceration 40 20 Transfuse until wound healed
GI or retroperitoneal bleeding 60-80 30-40 None
Head trauma (no evidence of CNS bleeding) 50 25 None
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) 100 50 Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented
Trauma with bleeding, surgery 80-100 50 10-14 d

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. Obtain factor level assays daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

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Desmopressin

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase in plasma FVIII levels. Other possible mechanisms of action are noted.

DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. A test dose should be performed before prophylactic use. 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.

If the test dose produces an appropriate rise in the FVIII level, at least 1 week should elapse before performance of any procedures. This allows time for replenishment of endogenous stores of FVIII, so that an adequate DDAVP-induced rise in FVIII is obtained for the procedure.

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.

Hyponatremia due to water retention is a potentially serious adverse effect. Patients should be advised to limit water intake for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes, and should avoid three consecutive daily doses. In addition, patients should be alerted to the distinct drop in urine output they will experience after DDAVP administration, and the subsequent increase when the antidiuretic effect of DDAVP wanes.

Tachyphylaxis may occur even after first dose, but the drug can be effective again after several days. A minor adverse effect of DDAVP is facial flushing.

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Management of Bleeding Episodes by Site

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 initial symptoms of a joint bleed 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. Arthrocentesis is indicated if septic arthritis is suspected.

Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. 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. 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 saliva. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Combine adequate replacement therapy with an antifibrinolytic agent (epsilon-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.[30]

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.

Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, to achieve a peak level of approximately 30%, along with a single 20 mg/kg dose of EACA.[31] Routine practice is to continue antifibrinolytic therapy in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.

Gastrointestinal bleeding

GI bleeds are much less common in persons with hemophilia than in those 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.

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. 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.

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Treatment of Patients with Inhibitors

Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.

Rarely, inhibitors can develop in individuals without genetic hemophilia (eg, elderly persons, pregnant women). These occasionally are responsive to immunosuppressive therapy (eg, prednisone).

The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[28] There is no established treatment for bleeding episodes in patients with high-titer inhibitors.

Other approaches to treating patients with FVIII inhibitors include the following:

  • Porcine FVIII, which has low cross-reactivity with human FVIII antibody
  • Activated prothrombin complex concentrate (PCC)
  • Activated FVII
  • Desensitization
  • Immune tolerance induction (ITI)

Recombinant activated factor VII

Recombinant activated FVII (FVIIa; Eptacog Alfa or NovoSeven) has become the first choice of bypassing agents.[32] Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[33] It is manufactured by using DNA biotechnology.

Intravenous recombinant FVIIa has been studied for the treatment of bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis.[32] Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

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

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[34]

Desensitization

Desensitization in nonemergency situations also may be feasible. This approach comprises 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 ITI, tolerance to FVIII is induced by means of regular exposure to FVIII over several months to years.[28, 35] The overall likelihood of success with ITI is 70% ± 10%.

Factors associated with successful outcome of ITI include the following[36] :

  • Historical inhibitor titers < 200 BU and immediate pre-ITI titers < 10 BU
  • Younger age at ITI initiation
  • An interval of < 5 years between inhibitor diagnosis and ITI start
  • ITI interruption < 2 weeks in duration

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20 that rapidly and specifically depletes B cells, has been used with success in ITI.[37, 38] A 4-week course of weekly rituximab, with or without prednisone and/or cyclophosphamide, has shown durable and complete responses in several small trials in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.[39] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[40, 41]

The choice of FVIII dosing regimen for ITI has ranged from 50 IU/kg 3 times weekly to 300 IU/kg/d. An international study in patients with severe hemophilia and high-titer inhibitors found no significant difference between low-dose and high-dose ITI in terms of the percentage of subjects achieving tolerance (70%) or in the time taken to achieve tolerance. However, the study was stopped early because of safety considerations involving bleeding (significantly more common early on in the low-dose arm) and lack of statistical power.[36]

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Prophylactic Factor Infusions

Most of the care for children with severe hemophilia now takes place at home, in the community, and at school, allowing these children to participate in normal activities that are otherwise impossible. This approach resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated venipunctures, and cost, among others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule.

In December 2013, the US Food and Drug Administration (FDA) expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis in patients with hemophilia A or B who have developed inhibitors. Approval was based on data from a pivotal phase III study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate compared with on-demand treatment.[42] An earlier study showed a 62% reduction in all bleeding episodes with prophylaxis versus an on-demand regimen.[43]

In June 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis, rVFIIIFC is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days.[44, 45]

The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG1, which allows a naturally occurring pathway to prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients receiving on-demand treatment.[44, 45]

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries).[46]

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Pain Management

Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.

Hemophilic chronic arthropathy is painful. Narcotic agents have been used, but their benefit for long-term therapy is limited by side effects, the development of tolerance, and the risk of addiction.

Nonsteroidal anti-inflammatory drugs can be effective in managing acute and chronic arthritic pain. Although they pose a risk of gastrointestinal bleeding, their effects on platelet function are reversible. Avoid aspirin because of its irreversible effect on platelet function. Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

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Complications

HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces only transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.

Allergic reactions are occasionally reported with the use of factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.

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Deterrence/Prevention

Do not circumcise boys born to mothers who are known or thought to be carriers of hemophilia unless disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous (rather than deep intramuscular) injection with a fine-gauge needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[47] This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.

Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because plans for delivery and neonatal management can be made.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[48, 49, 50] The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination. However, it is expensive and has limited success rates, with a 22% chance for a live birth.[23]

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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 improves psychosocial functioning. Kumar et al reported that aerobic exercise on a stationary cycle resulted in significant improvement in hemostatic indices in post-adolescent patients with mild to moderate hemophilia A.[51]

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 during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.

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Gene Therapy

With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived.[52] Possible approaches to gene therapy for hemophilia A include the following[53] :

  • Ex vivo gene therapy, in which cells to be transplanted are genetically modified to secrete factor VIII and then are reimplanted into the recipient
  • In vivo gene therapy, in which a vector (typically a virus altered to include FVIII DNA) is directly injected into the patient
  • Nonautologous gene therapy, in which cells modified to secrete FVIII are packaged in immunoprotected devices and implanted into recipients

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. Preliminary results in human trials of gene therapy for hemophilia B have yielded encouraging results, but hemophilia A has proved more problematic, given the much larger size of FVIII DNA and the frequent development of neutralizing antibodies.[54] Implantation of liver-derived stem cells that have been expanded in vitro is under consideration, as these could theoretically induce a steady-state production of quantities of factor sufficient to prevent spontaneous bleeding.[55]

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Consultations

Management should be provided in coordination with a comprehensive hemophilia care center. Specific consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

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, as may occur 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.

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Radiosynovectomy

In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Yttrium-90 and rhenium-186 have proved equally effective for radiosynovectomy.[56] A review by Rodriguez-Merchan et al concluded that radiosynovectomy is effective, safe, and well tolerated.[56]

The review by Rodriguez-Merchan included 500 synovectomies in 443 joints of 345 patients with chronic hemophilic synovitis. One to three injections were administered, with a 6-month interval between injections. On average, the number of hemarthroses decreased by 64.1%, articular pain decreased by 69.4%, the degree of synovitis decreased by 31.3%, and the World Federation of Haemophilia score improved by 19%. Only four complications (0.9%) occurred. In 28 joints (6.3%), arthroscopic synovectomy or total knee replacement was eventually required.[29]

 

 

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Contributor Information and Disclosures
Author

Robert A Zaiden, MD Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Florida at Jacksonville College of Medicine

Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine

Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Acknowledgements

Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System

Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, and Florida Medical Association

Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver

Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee

Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital

Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi

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William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center

William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine

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Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute

Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

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Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

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Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center

Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

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Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute

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Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

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Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, and American Society of Hematology

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Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi

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Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Acknowledgments

The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from Chicago, Margaret Telfer, MD. The authors would also like to acknowledge Professor K.N. Subramanian (Department of Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure and mutation of the FVIII gene.

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Coagulation pathway.
The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
Possible genetic outcomes in individuals carrying the hemophilic gene.
Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.
Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.
Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
Large amount of vascular synovium removed at surgery.
Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
Large pseudocyst involving the left proximal femur.
Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Dissection of a pseudocyst.
Transected pseudocyst with chocolate brown-black old blood.
Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Coagulation Cascade
Table 1. Severity, Factor Activity, and Hemorrhage Type
Classification Factor Activity, % Cause of Hemorrhage
Mild >5-40 Major trauma or surgery
Moderate 1-5 Mild-to-moderate trauma
Severe < 1 Spontaneous
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
Indication or Site of Bleeding Factor level Desired, % FVIII Dose, IU/kg* Comment
Severe epistaxis; mouth, lip, tongue, or dental work 20-50 10-25 Consider aminocaproic acid (Amicar), 1-2 d
Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h
Soft tissue or muscle 20-40 10-20 No therapy if site small and not enlarging (transfuse if enlarging)
Muscle (calf and forearm) 30-40 15-20 None
Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 Transfuse, repeat at 24 h, then as needed
Neck or throat 50-80 25-40 None
Hematuria 40 20 Transfuse to 40% then rest and hydration
Laceration 40 20 Transfuse until wound healed
GI or retroperitoneal bleeding 60-80 30-40 None
Head trauma (no evidence of CNS bleeding) 50 25 None
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) 100 50 Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented
Trauma with bleeding, surgery 80-100 50 10-14 d
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