Hemophilia

Author: Dimitrios P Agaliotis, MD, PhD, FACP; Chief Editor: Emmanuel C Besa, MD

Background
Making up approximately 80% of hemophilia cases, hemophilia A (HA), considered the classic form of the disease, results from a congenital deficiency of factor VIII (FVIII). Hemophilia B (HB), also called Christmas disease, is a consequence of a congenital deficiency of factor IX (FIX). These deficiencies result in an insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade. The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels, which are the most widely used criteria. Persons with less than 1% normal factor (< 0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to < 0.40 IU/mL) are considered to have mild hemophilia. Clinical bleeding symptom criteria have been used because patients with FVIII or FIX levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.

Pathophysiology
The genes for both FVIII (ie, hemophilia A) and FIX (ie, hemophilia B) are located on the long arm of chromosome X. The gene for FVIII (F8C) located within the Xq28 region, is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects. Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor. The FIX gene (F9), located within the Xq27 region, has 34 kb and composes 8 exons and 7 intervening sequences. The mature protein is composed of 415 amino acids. Point mutations and deletions in the FIX gene are the most common causes of hemophilia B. The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of FVIIa infusions in patients with acute hemarthroses and

FVIII inhibitors. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with subchondral bone-cyst formation. Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can neutralize FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that do not fix complements and do not result in the endorgan damage observed with circulating immune complexes. They neutralize the coagulant effects of replacement therapy. The inhibitors occur at a young age (about 50% by age 10 y), principally in patients with less than 1% FVIII. In the United States, levels of FVIII inhibitors are most often measured by using the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal and patient plasma in 2 hours at 37C. FIX inhibitors can produce anaphylaxis and nephrotic syndrome in individuals with complete gene deletions. Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This condition can be idiopathic (occurring in people >50 y), it can be associated with collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be associated with lymphoproliferative malignancies.[1]

Epidemiology
Frequency
United States The annual incidence of hemophilia A in Europe and North America is approximately 1 case per 5000 male births. It is the most common X-linked genetic disease, and the second most common factor deficiency after von Willebrand disease (VWD). The incidence of hemophilia B is estimated to be approximately 1 case per 30,000 male births. In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease. International The worldwide incidence of hemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history. Hemophilia B occurs in 1 case per 25,000 male individuals and represents one fourth to one fifth of all patients with hemophilia. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4-14.5 cases per 100,000 male individuals. The prevalence of hemophilia B varies from 0.9-3.2 cases per 100,000 male individuals.

Mortality/Morbidity
Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic therapies with lyophilized concentrates that eliminate bleeding episodes help

prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y). Life expectancy has increased from 11 years before the 1960s for patients who were severely affected to older than 50-60 years by the early 1980s.[2, 3] Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the rate is increased 4-6 times. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia A is 1.2 times that of the healthy male population.[4, 5]

Viral complications became a problem during the replacement era. o The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early 1980s. Rates of seroconversion were more than 75% for severe disease, 46% for moderate disease, and 25% for mild disease. In severe hemophilia B, seroconversion was observed at a rate of 46%. More than 50% of patients with hemophilia were infected with HIV by 1983. o In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis. o The most common cause of death in patients with severe hemophilia is AIDS. Life-threatening hemorrhage is also a significant problem. o Intracranial hemorrhage is a life-threatening hemorrhage with a lifetime risk of 2-8%, accounting for one third of deaths due to hemorrhage. o Other life-threatening hemorrhages include soft-tissue hemorrhages that obstruct airways or damage the internal organs. The life expectancy of patients with inhibitors is only slightly higher than the life expectancy of people without inhibitors. Fewer patients with inhibitors than patients without inhibitors have seroconversion for HIV. o Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%. See also Complications below.

Race
Hemophilia A and hemophilia B are observed in all ethnic and racial groups.

In general, the demographics of hemophilia follow the racial distribution in a given population with a multiracial background as observed in the United States.

Sex
Both forms of hemophilia are sex-linked coagulopathies because they are inherited as Xlinked traits; therefore, the disease primarily affects male individuals. Female individuals who carry the affected genes usually do not have bleeding manifestations. Lyonized females (ie, those with unequal inactivation of FVIII or FIX alleles and with hemizygosity of all or part of the X chromosome) may be symptomatic.

Female patients may have clinical bleeding due to hemophilia if 1 of 3 conditions is present: (1) extreme lyonization, (b) homozygosity for the hemophilia gene (eg, father with hemophilia and mother who is a carrier), or (3) Turner syndrome (XO) associated with the affected hemophilia gene (on average, only the X chromosome). Mild hemophilia may be more common in girls than previously recognized. In 1 study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.[6

History

Ask about the patient's family history and bleeding symptoms. o Male patients with severe hemophilia present at circumcision. o Easy bruising may occur at the start of ambulation or primary dentition. o The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues. o A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia. Physiologically low levels of all vitamin Kdependent procoagulant factors may complicate the early diagnosis of hemophilia B. The principal sites of bleeding in patients with hemophilia are as follows: o For joints, weight-bearing joints and other joints are affected. o Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve. o In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. o In the GI tract, bleeding may complicate common GI disorders. o Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.

Physical

Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted.

Causes

Hemophilia A and hemophilia B are a consequence of a congenital deficit of FVIII and FIX, respectively. The defect results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade.

This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding.

Differentials

Ehlers-Danlos Syndrome Factor V Factor VII Factor XI Deficiency Glanzmann Thrombasthenia Platelet Disorders von Willebrand Disease

Laboratory Studies

The plasma concentration of FVIII or FIX determines the severity of hemophilia. o Levels of these factors are assayed against a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII or FIX 1 U/mL. Patients' tested values ranging from 50-150% are considered in the normal range of variance. o Aging, pregnancy, contraceptives, and estrogen replacement therapies are associated with increased levels. o In term and healthy premature neonates, FIX values are lowered (20-50% of the normal level) and rise to normal levels after 6 months (hepatic immaturity). FVIII levels are normal during that period of life. o Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals with activity (25% normal), and mild in individuals with factor levels greater than 5%. Hemophilia A and hemophilia B protein deficiencies of the intrinsic pathway result in abnormal whole-blood clotting times, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs). o FVIII and FIX activities are usually determined by using the 1-stage assay based on the aPTT. o Chromogenic assays or 2-stage assays have also been used to determine FVIII levels. Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia. Laboratory confirmation of a FVIII or FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. o For autoantibody and alloantibody inhibitors, obtain a repeat measurement of the patient's prolonged aPTT after incubating the patient's plasma with normal plasma at 37C for 1-2 hours. o If the prolonged aPTT is not corrected, use the Bethesda method to titrate the inhibitor biologic concentration. By convention, more than 0.6 BU is considered a positive result for an inhibitor, less than 5 BU is considered a low

titer of inhibitor, and more than 10 BU is a high titer (neutralizing effectiveness of factor concentrate therapy to control bleeding).

Imaging Studies

Radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progress with subchondral bone cyst formation, which may occur in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages. Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. MRI is useful in the evaluation of the cartilage, synovium, and joint space.

Procedures

Specific orthopedic procedures may be required in chronic, neglected cases with irreversible joint or muscular deformities. Patients with portal hypertension due to hepatic cirrhosis secondary to chronic hepatitis have undergone portocaval shunt procedures or variceal sclerotherapy, with good palliative results.

Histologic Findings
Recurrent joint bleeds result in synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage.

Staging
Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to stage 5, which consists of advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[7]

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

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: o FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. o 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. o Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a hemophilia A factor level of 30% and a hemophilia B factor level of 20%. o 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%. o 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. o Preclinical studies in mice and dogs with hemophilia have resulted in longterm correction of the bleeding disorders and, in some cases, a permanent cure. The induction of neutralizing antibodies often precludes stable phenotypic correction. o 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. o Safe analgesics include acetaminophen, oxycodone, and pentazocine. o Avoid all aspirin products. The treatment of patients with inhibitors of FVIII is difficult. o 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] o Porcine FVIII, which has low cross-reactivity with human factor VIII antibody, has also been administered. o FVIII inhibitor-bypassing agents (FEIBA), including FIX complex, activated prothrombin complex concentrate (aPCC), and activated FVII has also been used. o Plasmapheresis, IVIG, or immunosuppressive therapy with cyclophosphamide and prednisone, have showed some success in achieving long-term control. o 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 Summary
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 Kdependent glycoprotein that is structurally similar to human plasmaderived 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

Class Summary

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

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

Recombinant factor VII

Class Summary
This activated recombinant FVII increases local formation of FXa, thrombin, and fibrin, to facilitate the formation of a hemostatic plug.
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Factor VIIa, recombinant (Novo Seven)

Binds to exposed tissue factor and also directly activates FX

Antifibrinolytic agents
Class Summary

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).
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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.
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Tranexamic acid (Cyklokapron)

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

Further Inpatient Care

Hospitalizing patients with internal bleeding, with uncontrollable bleeding, and before elective surgery or other invasive procedures is advised.

Further Outpatient Care

Monitor patients with hemophilia in an outpatient setting for bleeding episode frequency, use of home-administered replacement factors, dental status, and joint and muscle problems. If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.

Inpatient & Outpatient Medications

See Medication.

Transfer
Patients whose condition and bleeding are stabilized should be transferred to a specialized center for further treatment and monitoring because a multidisciplinary approach by specialists experienced in hemophilia may be required.

Deterrence/Prevention

Prophylactic replacement of FVIII or FIX is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and breaking the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[14] o This goal is achieved by administering factor 2-3 times a week. o The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years. 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. o Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. o Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period. o Phenotypic and genotypic (ie, restriction fragmentlength polymorphism) methods have advantages and disadvantages. 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.[15, 16, 17] o The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. o This technique circumvents pregnancy termination. In summary, data suggest that genetic correction of the hemophilias is feasible. o Future prospects for RNA repair, use of gene-modified endothelial progenitors, and gene-modified stem-cell therapy are being investigated. o Patients report decreasing bleeding episodes; this observation suggests that reasonable factor levels can be reached and encourage further research in this type of hemophilia treatment. o Gene transfer for the treatment of hemophilia requires a combination of vector delivery systems, animal models, and clinical models and/or studies to prove its practical utility.

Complications

Infection is the most important complication of hemophilia therapy. o As many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate. o The preferred source of factor are recombinant preparations, which do pose a risk of transmitting infectious disease, which is still theoretically possible with plasma-derived concentrates. o Virally attenuated products have reduced the risk of hepatitis observed in most patients receiving early-developed products. o Products that are not heat treated result in 90% positivity rates for hepatitis B surface antibody and hepatitis C virus. Therefore, their use is not recommended (or generally available) for routine management. o More than 50% of patients with severe hemophilia who have used older products have elevations in liver enzyme levels.

Outbreaks of hepatitis A infection in Europe and the United States have prompted more vigorous monitoring of product safety than before. o HIV infection has been the most serious complication of hemophilia to date. In the United States, as many as 90% of adults with severe hemophilia are HIV-positive. 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 transient remissions. AntiHIV medications and splenectomies may result in long-term improvement of thrombocytopenia. Allergic reactions are occasionally reported with the use of cryoprecipitate, freshfrozen plasma (FFP), and factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem. Thrombosis or even acute myocardial infarctions have been encountered in patients using PCC products, especially patients with concurrent liver disease or those taking multiple doses, as during surgery. A highly purified FIX product that is preferred. The cost of treatment of an average adult patient is more than $100,000 per year. o Costs are increased for the treatment of patients with inhibitors. o The use of prophylactic factor has resulted in short-term increases in cost, though the long-term economic benefit of reducing the incidence of joint disease is expected to outweigh the initial expense. See also Mortality/Morbidity above.
o

Prognosis

Prophylactic use of antihemophilic factors and early treatment with replacement therapy with factors that are safe from infections have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. o In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. o The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to more than 50-60 years by the early 1980s. o Viral complications occurred during the factor replacement era. See Morbidity/Mortality. Intracranial hemorrhages and hemorrhages of the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. o The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. o The life expectancy of patients receiving inhibitors may be slightly shorter than that of patients not receiving inhibitors. o Approximately one quarter of children and adolescents with severe hemophilia aged 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.[18]

Patient Education

Patient and family education about early recognition of hemorrhage signs and symptoms is important to institute or increase the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease that may vary from life-threatening events to quality-of-lifeimpairing events. In addition, educating patients or family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia. Employing results from 67 male patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al assessed the efficacy of VERITAS-Pro (Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis).[19] The patient/parent questionnaire uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. The authors validated their results by using subjective adherence ratings from patients and providers and by assessing through log entries the number of recommended infusions that were administered. The investigators found a strong correlation between adherence assessments derived from VERITAS-Pro scores and those obtained through the validation measures. Based on the above data, Duncan and colleagues stated that VERITAS-Pro is a better tool than a global or informal adherence rating is, concluding that it provides a quantified and validated means of assessing adherence from the patient's perspective, and that it delivers enough information to reveal specific nonadherence-related patient issues. For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.