Hemophilia B (Factor IX Deficiency)

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century.  The newspaper item below demonstrates what appears to be a late 18th-century record of hemophilia passed from mother to sons.

Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.

The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937, when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF).

Hemophilia B was differentiated from hemophilia A in 1952, when it was found that mixing plasma from patients with the two conditions corrected the clotting time. The hemophilia B patient in that study had the surname Christmas, and hence the disorder became known as Christmas disease.[3]

In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

In the 1980s, the risk of transmitting viral contaminants in commercial FVIII concentrates became increasingly recognized. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). New viricidal techniques have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The present standard of using recombinant products, especially those without exposure to animal proteins, in the treatment of hemophilia virtually eliminates the risk of viral exposure.

Severity classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or plasma procoagulant levels; the latter 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 factor IX 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. A minority of patients have coexisting thrombophilic states such as factor V Leiden mutation, protein C or protein S deficiency, or prothrombin G20210A mutations, which counterbalance bleeding tendencies and therefore lessen or delay symptoms.

Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, central nervous system (CNS), GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system. 

Factor IX structure, production, and half-life

FIX, a vitamin K–dependent single-chain glycoprotein, is synthesized first by the hepatocyte as a precursor protein. Before secretion from the hepatocyte, the FIX protein undergoes extensive posttranslational modifications, which include gamma-carboxylation, beta-hydroxylation, and removal of the signal peptide and propeptides, addition of carbohydrates, sulfation, and phosphorylation.

Gamma-carboxylation, as shown in the diagram below, is a vitamin K–dependent process in which the enzyme gamma-glutamylcarboxylase binds to specific sites on the propeptide region of the precursor protein in the liver. Gamma-carboxylation of the glutamic acid residues forms gamma-carboxyglutamyl (Gla) residues in the mature protein.

Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.

These Gla regions are the high-affinity Ca2+ binding sites necessary for binding FIXa to lipid membranes so FIXa can express its full procoagulant activity. All of the vitamin K–dependent procoagulants and anticoagulants are biologically inactive unless the glutamic acid residues at the amino terminal end are carboxylated; the exact number of Gla regions varies with each protein.

Warfarin prevents the reduction and recycling of oxidized vitamin K (vitamin K epoxide) that is generated during this carboxylation reaction. As a result of the indirect inhibition of the carboxylation reaction due to a lack of available reduced vitamin K, hypocarboxylated and decarboxylated forms of the vitamin K–dependent factors are found in the circulation of patients taking warfarin. These abnormal forms have reduced or absent biological activity. Following these modifications, the carboxyterminal (C-terminal) region is recognized by the hepatic secretion process. Mutations that increase the charge of this region result in decreased hepatic secretion of all vitamin K–dependent proteins, including FIX, and lead to deficiencies of multiple vitamin K–dependent factors (procoagulants factor VII [FVII], factor X [FX], factor II [FII] and anticoagulant proteins C and S).

FIX is present in plasma in a concentration of 4-5 µg/mL with a half-life of approximately 18-24 hours. A 3-fold variation in the activity of FIX in plasma is normal. Since FIX is smaller than albumin, it distributes in both the extravascular and intravascular compartments.

Following intravenous (IV) administration, recovery of FIX concentrates varies significantly, which has been ascribed to the development of nonneutralizing antibodies. In vivo binding of FIX to collagen IV has been proposed as another reason for reduced recovery of FIX following infusion of FIX concentrates in hemophilia B patients. FIX concentrates generally are replaced every 18-24 hours under steady state conditions. Lower recoveries are seen with recombinant factor IX (rFIX) than with FIX concentrates.[4]

FIX shares extensive homology with the other vitamin K–dependent proteins, especially in the prepro sequence and the Gla regions. Despite numerous similarities, each vitamin K–dependent protein performs a different function in the hemostatic pathway, which is diagrammed in the following image.

The hemostatic pathway: role of factor IX.

Activation

The gamma-carboxylated region of FIX is essential for calcium binding and is the site at which vitamin K–dependent coagulation proteins bind to cell surface phospholipids and efficient coagulation reactions take place. Ca2+ binding to the Gla region results in a conformational change leading to exposure of previously buried hydrophobic residues in the FIX molecule, which then can be inserted into the lipid bilayer.

Tissue factor (TF) is a glycosylated membrane protein present in cells surrounding blood vessels and in many organs. On the other hand, endothelial cells, tissue macrophages, and smooth muscle cells express TF only when stimulated by serine proteases, such as thrombin, and by inflammatory cytokines. In vivo, under physiologic conditions, only a trace amount of FVII is present in the activated form (activated factor VII [FVIIa] of approximately 1%). When TF becomes available, it complexes with FVII or FVIIa, and current concepts support the view that activation of FIX to FIXa is more rapid with the TF-FVII complex than with activated factor XI (FXIa).[5]  The activation peptide for FIX is detectable in the plasma of control subjects.[6]  The image below diagrams the activation of FIX.

Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.

Following activation, the single-chain FIX becomes a 2-chain molecule, in which the 2 chains are linked by a disulfide bond attaching the enzyme to the Gla domain. Activated factor VIII (FVIIIa) is the specific cofactor for the full expression of FIXa activity. Platelets not only provide the lipid surface on which solid-phase reactions occur, but they also possess a binding site for FIXa that promotes complex formation with FVIIIa and Ca2+. The complex of FIXa, FVIIIa, Ca2+, and activated platelet (phospholipid surface) reaches its maximum potential to activate FX to activated factor X (FXa). This activator complex, which contains FIXa, is termed the intrinsic tenase complex in contradistinction to the FVIIa-TF (extrinsic tenase) or FXa, activated factor V (FVa), Ca2+, and phospholipid (prothrombinase) complexes; all ultimately lead to thrombin generation.

In vivo, the active FVIIa-TF complex is responsible for the initial activation of FX to FXa, leading first to the generation of small amounts of thrombin. When the FIXa generated by the FVIIa-TF complex is part of the intrinsic tenase complex, it activates additional FX to FXa and leads to the second and explosive burst of thrombin generation with subsequent clot formation.

Many feedback loops exist in the coagulation pathway, and some evidence suggests that FIXa can activate FVII and FVIII in addition to FX. Support for the important role of FIX in producing FVIIa, essential for normal hemostasis in vivo, was provided by a study using a sensitive, highly specific FVIIa assay, which showed that healthy individuals had basal FVIIa levels of 4.34 ng/mL. Patients with severe FIX deficiency were found to have markedly reduced FVIIa levels of 0.33 ng/mL, whereas individuals with severe FVIII deficiency had FVIIa levels of 2.69 ng/mL, values higher than those seen in patients with severe hemophilia B.[7]

Possible interactions between deficiencies of FIX and thrombin activatable fibrinolytic inhibitor

The demonstration that thrombi generated in plasmas obtained from patients with hemophilia A or B underwent premature lysis generated the hypothesis that bleeding in patients with hemophilia may be due not only to failure of adequate thrombin generation and clot formation, but also to a failure of adequate suppression of fibrinolysis leading to accelerated clot removal.

Proof of the concept of the latter has been provided for decades in patients with hemophilia, long before the role of thrombin activatable fibrinolytic inhibitor (TAFI) was even suspected, by the amply proven hemostatic adequacy of a single dose of replacement factor when combined with prolonged inhibition of fibrinolysis in patients with severe hemophilia undergoing dental or other mucocutaneous procedures. The demonstration in vitro of rapid clot lysis in hemophilic plasmas was followed by a demonstration of rapid clot lysis in plasmas deficient in FXI or factor XII (FXII), with prolongation of clot lysis by restitution of the missing factor.

A large amount of information has accrued regarding the pathophysiologic role of TAFI in thrombohemorrhagic disorders. TAFI, a single-chain carboxypeptidase B–like zymogen, is activated by thrombin to generate activated TAFI (TAFIa). Thrombin, plasmin, and trypsin all can activate TAFI, but thrombin bound to thrombomodulin has an approximate 1250-fold greater catalytic rate than thrombin alone; however, thrombin alone is sufficient to achieve significant TAFI activation.

The importance of TAFIa in influencing fibrinolysis is emphasized by the fact that conversion of only 1% of the zymogen to TAFIa is sufficient to suppress normal fibrinolysis by approximately 60%. TAFIa suppresses fibrinolysis by removing C-terminal lysine and arginine residues in a fibrin clot that has been partially degraded by plasmin. Removal of C-terminal lysine residues reduces the rate of plasminogen activation by a number of mechanisms, attenuating fibrinolysis. This effect is counterbalanced in normal plasma by the activation of protein C, which has profibrinolytic properties due to its ability to suppress thrombin generation by its major effect in degrading FVa and, to a lesser extent, FVIIIa.

In normal plasma, a balance exists between the effects of activated protein C on the one hand (profibrinolytic) and TAFIa on the other (antifibrinolytic). Thrombin secures survival of the thrombus created by its action on fibrinogen by activating TAFI, thereby inhibiting fibrinolysis. In this context, note that cross-linking of fibrin induced by activated factor XIII (FXIIIa, activated by thrombin) also renders the clot insoluble (for more information, see Factor XIII). Thus, thrombin uses multiple prongs to assure survival of its creation, fibrin, and affects the normal delicate balance between thrombus formation and thrombus resolution.

A reduction in the level of FIX via reduction of thrombin generation reduces TAFI activation and increases fibrinolysis, whereas persistence of FVa (as is the case with co-inheritance of factor V [FV] Leiden) leads to increased (persistent) thrombin production and TAFI activation, thereby inhibiting fibrinolysis.

Cell surface–directed hemostasis

The concept of coagulation as a waterfall or cascade, with a series of reactions each impacting the subsequent reaction, dates back to the 1960s.[8]  The fact that fluid-phase reactions are inefficient and that platelets and other cell surfaces provide the anionic phospholipids needed for complex formation so that reactions can proceed efficiently also has been recognized. This model allowed  conceptual visualization of the activated partial thromboplastin time (aPTT) and prothrombin time (PT) tests as the intrinsic and extrinsic pathways. One review proposed that coagulation is essentially a cell surface–based event in overlapping phases, suggesting the need for a paradigm shift from the old concept in which coagulation reactions were controlled by coagulation proteins to a new concept in which the process is controlled by cellular elements.

In this model, diagrammed below, 3 phases are proposed including (1) initiation of coagulation on the surface of a TF-bearing cell, with formation of FXa, FIXa, and thrombin, (2) amplification of this reaction next on the platelet surface as platelets are activated, adhere, and accumulate factors/cofactors on their surfaces, and (3) the propagation phase, in which the large second burst of thrombin occurs on the platelet surface resulting from the interaction of proteases with their cofactors, resulting in fibrin polymerization. Platelets are an early and essential feature of hemostasis, making them an ideal cell to regulate this process, and these authors provide a series of cogent reasons for switching to this concept of hemostasis.[9, 10]

Clinical manifestations

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children and the ankles, knees, and elbows in adults and adolescents), resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Prolonged increase in intra-articular pressure may eventually lead to osteonecrosis, especially in the femoral head.

Human synovial cells synthesize high levels of TF pathway inhibitor, resulting in a higher degree of factor Xa inhibition, which predisposes hemophilic joints to bleed. Joint bleeds result in progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage, with eventual subchondral bone-cyst formation.

Inhibitors

Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize FIX. These inhibitors are usually immunoglobulin G antibodies and appear after the first infusions of FIX concentrate.

Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) and an absence or paucity of endogenous factor IX (severe disease) are associated with a higher incidence of inhibitor development. Inhibitors are more likely to develop in Black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development.

Hemophilia B is an X-linked recessive disease caused by a mutation in the factor IX gene or by an acquired factor IX inhibitor. Similar to hemophilia A, approximately 30% of cases represent a de novo mutation. The gene for factor IX, ​F9, is located on the long arm of the X chromosome in band q27. Factor IX contains 415 amino acids and has a molecular weight of 57,000 d. The gene that encodes this protein is 33 kb and contains 8 exons and 7 introns.

More than 1000 mutations with different amino acid substitutes have been described in hemophilia B.[1] These mutations include partial and total deletions, missense mutations, and others that result in the decreased or absent production of factor IX or the production of an abnormal protein. Most patients deficient in FIX have point mutations.

Variability in clinical bleeding manifestations is due to heterogeneity of the molecular defects found in this disorder, with each mutation resulting in a specific pattern of alteration of FIX activity. Baseline levels of FIX and the severity of bleeding tend to be similar in members of a family, who have inherited the same specific defect.

Three groups of mutations are particularly instructive and have important clinical consequences. The first group consists of gross F9 gene deletions and gene rearrangements causing severe deficiency of FIX, which results in a severe bleeding diathesis. These patients are prone to developing severe anaphylactic reactions when factor replacement therapy is started. Allergic/anaphylactic reactions are associated with development of a specific FIX inhibitor.

New patients with severe FIX deficiency should be screened for such large gene defects, which can alert the clinician prior to development of life-threatening anaphylaxis. Patients with large gene defects should be selected to receive initial FIX product infusions under well-supervised conditions that will allow prompt attention to serious complications.

The second group consists of the FIX Leyden phenotype, which is caused by several different point mutations in the FIX promoter region.[1]  In the Leyden phenotype, baseline FIX levels are in the 1-13% range, and FIX levels can rise to approximately 30% in childhood (age 4-5 y) and to approximately 70% with the onset of puberty and testosterone production.[11]  Patients may become clotting factor independent by early adulthood.[12] Anabolic steroids also can raise the level of FIX in these patients.

The third group involves missense mutations in the propeptide sequence of FIX, resulting in a markedly decreased affinity of abnormal FIX for vitamin K–dependent carboxylase. Patients have normal baseline levels of FIX, but because of increased sensitivity to vitamin K antagonists, they develop unexpected and severe reductions in FIX following administration of oral anticoagulants, which then predisposes them to an increased risk of bleeding.

Identification of mutations in families is feasible because of the small size of the gene, and it is useful for carrier detection. The different types of intragenic polymorphisms vary with the ethnic group. These are useful in counseling families with unknown mutations. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

Factor IX inhibitors

FIX gene deletions are present in 50% of patients with FIX inhibitors. In contrast, the risk of inhibitor development is 20% in patients with mutations resulting in loss of coding information.

A study of eight alloantibodies to FIX that developed after repeated infusions of FIX in patients with hemophilia B showed that the antibodies were immunoglobulin G (IgG), predominantly IgG subclass 1 and IgG subclass 4. They were directed against the Gla and protease domains and inhibited binding of FIX to phospholipids and binding of the light chain of FVIIIa to FIXa. They also inhibited the FVIIIa-dependent activation of FX.[13]

Combined disorders

Combined congenital deficiencies of vitamin K–dependent factors include reductions in FIX. A mutation in the carboxylase enzyme can lead to a reduction in all Gla-containing proteins, including FIX. Bleeding manifestations depend on the basal level of factors. Patients have a heterogeneous response to oral/parenteral vitamin K administration, varying between a slight response to no response.

Hemophilia B may be associated with other hemostatic defects due to co-inheritance of von Willebrand disease, platelet defects, or other defects, which then compromise hemostasis at multiple sites, thus further accentuating bleeding manifestations.

Co-inheritance of thrombophilic mutations can ameliorate bleeding in patients with FIX deficiency and can predispose patients to thrombosis when FIX levels are normal and patients are subject to a thrombogenic stimulus.

Hemophilia has a worldwide distribution. The incidence of hemophilia B is estimated to be approximately 1 case per 25,000-30,000 male births. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.

Hemophilia B is much less common than hemophilia A. Of all hemophilia cases, 80-85% are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities.

Racial, sexual, and age-related differences in incidence

Hemophilia B occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, Blacks, and Hispanic males in the United States are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, carriers may have mild hemophilia. In one study, 5 of 55 patients with mild hemophilia (factor IX levels 5-50%) were girls.[14]  Females may have clinical bleeding due to hemophilia if one of the following conditions is present:

• Extreme lyonization (ie, inactivation of the normal factor IX allele in one of the X chromosomes
• Homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent mutations, or some combination of inheritance and new mutations)
• Turner syndrome (XO) associated with the affected hemophilia gene.

Significant deficiency in factor IX may become evident in the neonatal period and continue through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia. Excessive bleeding after normal trauma encountered during ambulation at the toddler stage may be the first indication of hemophilia. Mild hemophilia may remain undetected until relatively late in life, when a traumatic challenge reveals impaired hemostasis.

Mortality/Morbidity

The consequences of the repeated bleeding experienced by individuals with hemophilia are serious and result from the repeated need for FIX replacement to control bleeding. Availability of replacement products has changed the lives of patients with FIX deficiency, although serious problems were incurred by the use of the less pure earlier products. Currently available concentrates and recombinant products have a better safety profile.[15]

Persons with severe hemophilia have recurrent joint and muscle bleeds, which are spontaneous or follow minor trauma and cause severe acute pain and limitation of movement. The presence of blood in the joint leads to synovial hypertrophy, with a tendency to rebleed, which results in chronic synovitis, with destruction of synovium, cartilage, and bone leading to chronic pain, stiffness of the joints, and limitation of movement because of progressive severe joint damage.

Intramuscular hemorrhage, the second most common bleeding event, also produces acute pain, swelling, and limitation of movement. Other sites of bleeding and many other complications contribute to morbidity and mortality. These include diffuse alveolar hemorrhage, which is rare but potentially life-threatening.[16]

Current treatment methods have succeeded in reducing not only the morbidity but also the death rate, and for the first time, persons with hemophilia have been able to pursue economically viable careers. However, several problems remain.

Spontaneous or trauma-related hemarthroses and bleeding are controlled better using home care programs, which allow on-demand and prompt treatment of bleeds by the use of prophylactic and/or therapeutic infusions of FIX concentrates. This has led to a marked improvement in the quality of life for persons with hemophilia and allows them to participate in activities previously denied to them. With currently available products, some individuals with hemophilia B can achieve a normal lifespan.

Death results from central nervous system (CNS) bleeding, anaphylaxis in children, development of inhibitors with severe bleeding. In patients who received replacement therapy before the advent of highly purified and recombinant FIX concentrates, causes of death also included hepatitis-induced liver failure and AIDS.

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with factor concentrate that is safe from viral contamination have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia age 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.[17]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. Currently, the mortality rate in people with hemophilia is approaching that of the general population.[18]  

However, viral infection from contaminated factor concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, B, or C viruses.

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 HIV seroconversion were more than 75% for those with severe disease, 46% for those with moderate disease, and 25% for those with mild disease.

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. After the year 2000, however, the percentage of deaths attributable to HIV in persons with hemophilia dropped to 13.9%. The proportion of deaths due to hemorrhage remained unchanged, at 26%[18]

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications are now mostly of historical importance. However, even with these methods, some viruses (eg, parvovirus B19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include those that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. 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. 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%.

Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

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).

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation.

Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing 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-life–impairing 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.

For patient education information, see Hemophilia.

Hemophilia is suggested by a history of hemorrhage disproportionate to trauma or of spontaneous hemorrhage, or a family history of bleeding problems. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases, hematologic malignancies (in acquired hemophilia), and allergic drug reactions.

For individuals with documented hemophilia, inquire regarding the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status.

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area or at sites of blood draws or immunizations.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.

As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

With mild disease, hemorrhage is most likely to occur with trauma or surgery. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is suspected.

Signs of hemorrhage include the following:

• General - Weakness and orthostasis

• Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)

• CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes

• GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain

• Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

• Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions

Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia. Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Chronic hepatitis, progressive cirrhosis, liver failure, and hepatocellular carcinoma are more common in older individuals with hemophilia B who received the less pure earlier products. Before the introduction of hepatitis B vaccine, as many as 90% of persons with hemophilia had antibodies to hepatitis B surface antigen, and as many as 15% became long-term carriers. Hepatitis C virus (HCV) seropositivity is common in patients who started treatment before 1985. 

The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The muscles 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.

In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.

Systemic signs of hemorrhage include the following:

• Tachycardia
• Tachypnea
• Hypotension
• Orthostasis

Organ system–specific signs of hemorrhage include the following:

• Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, swelling, effusion, and warmth
• Central nervous system - Abnormal neurologic exam findings, altered mental status, and meningismus
• Gastrointestinal - Can be painless; hepatic/splenic tenderness and peritoneal signs
• Genitourinary - Bladder spasm/distension/pain, costovertebral angle pain
• Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Direct the examination to identify signs related to bleeding in the joints, muscles, and other soft tissues that has occurred spontaneously or after minimal challenge. 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.

Especially in older patients, look for manifestations of chronic infectious disease, such as the following: include the following:

• Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C virus infection
• Jaundice, spider angiomas, hepatomegaly, abdominal tenderness, splenomegaly, and other signs related to chronic hepatitis/cirrhosis
• Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS

Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.

Table 1. Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)

Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX (FIX) assay. Never delay indicated coagulation correction pending diagnostic testing. The United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) recommends that in the emergency setting, clinical assessment should be performed no more than 15 minutes after the patient arrives, and if treatment is required it should be initiated no longer than 30 minutes after arrival.[19]

On the hemoglobin/hematocrit, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are typically normal.

Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test, especially with factor levels greater than 15%.[20] The aPTT is significantly prolonged in severe hemophilia.

For FIX assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FIX U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

• Mild - Greater than 5% to 40%
• Moderate - 1-5%
• Severe - Less than 1%

Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.

Usually, von Willebrand factor (vWF) levels are also measured. The combination of low FVIII and low vWF may indicate vWF deficiency as the primary diagnosis.

Because FIX is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of coagulation factors in the cord blood. However, early diagnosis of FIX deficiency is complicated by the physiologic reduction of vitamin K–dependent factors in young infants. In term and healthy premature neonates, FIX values are low (20-50% of the normal level), due to hepatic immaturity. Levels rise to normal after 6 months of age. FVIII levels are normal during that period of life.

In patients with an established diagnosis of hemophilia B, laboratory evaluations include periodic screening for the presence of FIX inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV. Screening for infectious disease may be less important in patients who have received only recombinant product.

Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and anatomic location of involvement.

Head computed tomography (CT) scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. Magnetic resonance imaging (MRI) is also useful in the evaluation of the cartilage, synovium, and joint space.

Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.

Laboratory confirmation of a FIX inhibitor is clinically important when infusion of adequate amounts of factor concentrate fails to control a bleeding episode. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Nijmegen modification of the Bethesda inhibitor assay. Specific antibodies to FIX usually are IgG subclass 4 or a mixture of IgG subclasses 1 and 4. An experienced laboratory must perform these tests.

By convention, more than 0.6 Bethesda units (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. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of factor concentrate.

Plasma FIX levels are normal in approximately a third of FIX carriers. If the specific FIX gene mutation is known, direct genetic testing provides accurate results. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FIX mutations.

For fetal testing, if the mutation is known, then RFLP can be performed on chorionic villus or amniocentesis samples. If the mutation is not known, gene sequencing can be performed.

Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation. 

Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[4]  See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia

Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.

The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilic synovitis.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers 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 a factor IX (FIX) activity level of 30% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or for 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; and hemorrhage related to head injury, surgery, or dental work.

Patients may 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.[21, 22] According to a review of six randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, thus decreasing overall joint deterioration and improving patients' quality of life.[23]

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.[24]  In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has been established to prevent worsening of the joint) is instituted for a defined period.[25, 26]

Dosing is designed to maintain trough levels greater than 2%. With the development of FIX preparations that have extended half-lives, dosing for routine prophylaxis may be as infrequent as every 10 days.

In the future, oral administration of FIX for prophylaxis may become possible, through the use of hydrogel carriers that protect FIX from destruction in the stomach and release it in the intestines.[16] Gene therapy offers the potential for a definitive cure, and has now entered clinical practice, with US Food and Drug Administration (FDA) approval of the first product in November 2022.[27]

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Prehospital providers should address the emergency ABCs (airway, breathing, circulation) while rapidly transporting the patient to a definitive care facility. In the prehospital setting, 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

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

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.

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

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, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.

Various FIX concentrates are available to treat hemophilia B. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload. Cryoprecipitate contains no FIX and is not appropriate for hemophilia ​B therapy.

Various purification techniques are used in plasma-based FIX 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.

Recombinant FIX products (eg, BeneFIX, Rixubis, Alprolix, Ixinity) are commercially available and have a lower risk of viral contamination. All the products are approved by the FDA for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis, Ixinity, and Alprolix are also approved for routine prophylaxis in adults and children.

Idelvion, a long-acting recombinant FIX albumin fusion protein (rIX-FP, albutrepenonacog alfa) was approved in 2016 for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes. Approval was based on open-label trials in children and adults (n=90) with FIX activity < 2%. Mean trough levels of FIX activity were 20 IU/dL on prophylaxis with rIX-FP 40 IU/kg weekly and 12 IU/dL FIX on prophylaxis with 75 IU/kg every 2 weeks. The switch from on-demand treatment to prophylaxis with rIX-FP resulted in a 100% reduction in the median annualized spontaneous bleeding rate and 100% resolution of target joints (P < 0.0001).[28]

Rixubis approval for adults was based on a study demonstrating that twice-weekly prophylactic treatment for 6 months achieved a median annualized bleed rate of 2.0 with 43% of patients experiencing no bleeds.[29, 30]

Rebinyn (nonacog beta pegol) is a recombinant glycopegylated FIX with an extended half-life. Pegylation slows removal of FIX from the blood circulation. Rebinyn was approved by the FDA in 2017 for control and prevention of bleeding episodes and for perioperative management in adults and children.[31]

Doses of FIX concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.

Target levels by hemorrhage severity are as follows:

• Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a FIX level of 30%

• Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain a FIX level of 50%

• Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain a FIX level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days

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

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 assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.

Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply.

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 FIX.

Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.

Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.

Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[32]

Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.

Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.

Gastrointestinal bleeding

GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Depending on their location, they may be confused with acute abdomen or appendicitis. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FIX.

Intracranial bleeding

Intracranial hemorrhage is often trauma induced; in the pediatric population, spontaneous intracranial hemorrhages are more common than those related to trauma. 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. Late-onset bleeding has been reported at up to 4 weeks.

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 family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Inhibitors are antibodies that neutralize FIX and can render replacement therapy ineffective. FIX inhibitors are less common than FVIII inhibitors; they occur found in only 1-3% of patients with severe hemophilia B. These inhibitors typically appear after the first infusions of FIX concentrate. Patients with FIX inhibitors can have anaphylactic reactions to FIX infusions, and may develop steroid-resistant nephrotic syndrome due to immune complex formation; this typically occurs in individuals with complete gene deletions.

The relatively low frequency of FIX inhibitors has lead to a dearth of experience in its treatment. Early hematology consultation for these patients is essential.

Low-titer inhibitors and, occasionally, high-titer inhibitors can be overcome with high doses of FIX concentrate. Recombinant human coagulation factor VIIa (rFVIIa) is indicated for the treatment of patients with bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with inhibitors to FIX.[33]

Activated prothrombin complex concentrate (PCC) has shown promise, although it may trigger disseminated intravascular coagulopathy (DIC) at doses greater than 200 IU/kg/d. Desensitization and immune-tolerance strategies in those with identified inhibitors have been successful as well.

Recombinant activated FVIIa

Recombinant activated FVIIa (rFVIIa) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[34] It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has also been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.

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 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 FIX inhibitors. In addition, when recombinant activated FVIIa 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.[35]

Desensitization

Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FIX 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, such as vigorous plasmapheresis in conjunction with immunosuppression and infusion of FIX with or without antifibrinolytic therapy.

Immune tolerance induction

In immune tolerance induction (ITI), patients are rendered tolerant to FIX by means of daily exposure to FIX over several months to years.[36] The overall likelihood of success with ITI is 70% ± 10%. In patients with high-titer FIX inhibitors, ITI is less successful than it is in patients with FVIII inhibitors.

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FIX and with or without immunosuppressive therapy. This technique is well established in acquired hemophilia but not in congenital hemophilia.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in patients with hemophilia B and high titer inhibitors.[37] Reports describe durable complete responses with 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.[38] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[39, 40]

In several small trials, a 4-week course of weekly rituximab has resulted in durable and complete responses. The addition of prednisone with or without cyclophosphamide has increased response rates.

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.

Concizumab

Concizumab is a subcutaneously administered monoclonal IgG4 antibody that promotes thrombin generation by binding to tissue factor pathway inhibitor (TFPI); TFPI is the primary inhibitor of the initiation of coagulation. In phase II trials, concizumab has demonstrated benefit for prophylaxis in patients with hemophilia B with inhibitors.[41, 42] Phase III trials of concizumab were paused after the occurrence of thromboembolic events in 3 patients, but the trials have since been restarted with risk mitigation in place.[42] The European Commission has granted orphan drug designation to concizumab for the treatment of hemophilia B.[43] The US Food and Drug Administration granted concizumab Breakthrough Therapy designation for treatment of patients with hemophilia B with inhibitors.[44]

Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic 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. Hemophilic arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about one third of children with hemophilia B receiving this treatment modality in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability, repeated venipunctures, cost, and others.

Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects.

The long-acting recombinant FIX albumin fusion protein (Idelvion) was approved in 2016 for prophylaxis to reduce the frequency of bleeding episodes. Adults who respond to once-weekly prophylaxis may be switched to a slightly higher dose administered every 2 weeks. Clinical trial results demonstrated a 100% reduction in the median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < 0.0001).[28]

In 2013, the FDA approved the first recombinant coagulation factor IX (Rixubis) specifically indicated for the routine prevention of bleeding in patients with hemophilia B in children and adults.[45, 46] In addition to routine prophylaxis (prevention or reduction in frequency of bleeding episodes), Rixubis is indicated for the control of bleeding episodes and perioperative management in these patients. This purified protein is supplied in single-use vials of freeze-dried powder, and it is injected intravenously after reconstitution with sterile water. For routine prophylaxis, Rixubis is administered twice a week.[45, 46]

Approval of Rixubis was based on a multicenter study of 73 males (age range, 12-65 years) who received the drug for routine prophylaxis or as needed for hemostasis. Patients taking this agent prophylactically had a 75% lower annual rate of bleeding relative to those who had received on-demand therapy.[45, 46] The most common side effects associated with Rixubis in clinical studies included distorted taste, pain in an extremity, and atypical blood test results. Life-threatening anaphylaxis occurred less commonly.[45, 46]

In 2014, Rixubis was approved for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in children with hemophilia B. Approval was based on the results of a clinical trial in 23 previously-treated male patients aged < 12 years with severe or moderately severe hemophilia B. The tiral used a twice-weekly prophylaxis regimen (mean dose 56 IU/kg; mean treatment duration 6 months, mean of 54 exposure days). The median annualized bleeding rate was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients in the study (39.1%) experienced no bleeds and 23 bleeding episodes (88.5%) were treated with 1-2 infusions. There were no reports of inhibitor development, no severe allergic reactions, and no thrombotic or treatment-related adverse events among the study participants.[30]

The long-acting recombinant Fc fusion factor IX (rFIXFc), Alprolix, was approved by the FDA in 2014 for patients with hemophilia B. It is the first treatment designed to require less frequent injections for routine prophylaxis. The safety and efficacy were evaluated in a multicenter clinical trial that compared each of 2 prophylactic treatment regimens with on-demand treatment. A total of 123 individuals with severe hemophilia B, aged 12-71 years, were followed for up to 18 months. The studies demonstrated effectiveness in preventing and treating bleeding episodes and during perioperative management of patients undergoing surgical procedures.[47, 48]

Another long-acting recombinant, Ixinity, gained approval for routine prophylaxis for patients aged 12 years and older in 2020, in addition to its previous indications for on-demand usage and perioperative management. 

In 2013, the FDA expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. The approval was based on data from a pivotal Phase III study in which treatment with a prophylactic regimen showed a 72% reduction in median annual bleed rate (ABR) compared to treatment with an on-demand regimen.[49] An earlier study showed a 62% reduction in all bleeding episodes with anti-inhibitor coagulant complex prophylaxis compared with an on-demand regimen.[50]

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).[51]

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 associated with pain. Narcotic agents have been used, but frequent use of these drugs may result in addiction. Nonsteroidal anti-inflammatory drugs may be used instead because their effects on platelet function are reversible and because these drugs can be effective in managing acute and chronic arthritic pain. 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.

Appropriate preoperative evaluation includes an activated partial thromboplastin time (aPTT) mixing test after incubation for 1-2 hours at 37°C with pooled normal plasma to exclude an inhibitor, followed by administration of an appropriate preoperative dose of concentrate, followed by appropriate postoperative treatment.

A review by Hazendonk et al of perioperative management in hemophilia B recommends the following perioperative target ranges for FIX[52] :

• Day 1  (0-24 hours) -  0.80-1.00 IU/mL ⁻¹
• Days 2-5 (24-120 hours) - 0.50-0.80 IU/mL ⁻¹
• Days ≥6 (> 120 hours) - 0.30-0.50 IU/mL ⁻¹

These authors note that targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. In their review of 255 surgical procedures in 118 patients with hemophilia B, 60% of FIX levels within 24 hours of surgery were below target, while > 6 days after surgery, 59% of FIX levels were above target. However, clinically relevant bleeding complications occurred in only 7 procedures (2.7%). During the first 24 hours postoperatively, only bolus infusion was predictive of lower FIX levels, compared with continuous infusion.[52]

Long-acting FIX products have proved effective for surgical hemostasis, with nearly all patients requiring only a single preoperative dose and infrequent postoperative doses.[53, 54] In patients with FIX inhibitors, recombinant FVIIa has consistently demonstrated effectiveness, and with only rare thrombotic events.[55]

The use of fibrin sealants (ie, fibrin glue, fibrin adhesive), which consist of fibrinogen and thrombin with variable incorporation of factor XIII (FXIII) and fibrinolytic inhibitors, has helped improve surgical hemostasis markedly, thereby permitting necessary high-risk surgery (eg, pseudocyst removal, surgery in patients with hemophilia with inhibitors). This technology reduces or eliminates the need for prolonged replacement using expensive clotting factor concentrates and may eliminate or reduce the need for hospitalization.

HIV-associated immune thrombocytopenia is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to more than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces 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.

Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FIX 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 route (rather than deep intramuscular route) 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 FIX infusions. Prophylactic replacement is used to maintain a measurable FIX level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[56] 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 age 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. 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.

Phenotypic and genotypic (ie, restriction fragment–length 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.[57, 58, 59] 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.

With the cloning of FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived. Preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding disorders, and in some cases a permanent cure. However, the induction of neutralizing antibodies often precluded stable phenotypic correction.

In addition, the relatively high prevalence of antibodies against adeno-associated virus serotype 8 (AAV8), which has been used as a vector for the normal FIX gene, has limited enrollment of clinical trial subjects.[60] Nevertheless, Nathwani and colleagues reported sustained long-term expression of therapeutic levels of FIX in 10 men with severe hemophilia B after a single intravenous infusion of an AAV8 vector expressing a codon-optimized FIX transgene.[61]

Other AAV serotypes have also proved effective as vectors. In November 2022, the FDA approved etranacogene dezaparvovec, an AAV5-based gene therapy, for the treatment of adults with hemophilia B who currently use FIX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.[27]  

The approval was supported by the single-arm, open-label HOPE-B trial in 54 men who relied on FIX replacement therapy. Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = 0.0002), and FIX-treated bleeds fell 77% (P < 0.0001). Additionally, 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued FIX prophylaxis. Durability remains uncertain, but mean FIX activity was 39 IU/dL at 6 months (39% of normal) and 36.9 IU/dL at 18 months (approximately 37% of normal). To date, no patient has developed inhibitors against the infusion.[62]

In a phase 1-2 trial of AAVS3 gene therapy with FLT180a (verbrinacogene setparvovec), 9 of 10 men with severe or moderately severe hemophilia B (FIX level, ≤2% of normal) maintained FIX activity at a median follow-up of 27.2 months and no longer required FIX injections. In the patients who responded, FIX levels ranged from 23-260%, depending on their gene therapy dose. This protocol requires immunosuppression (with glucocorticoids, with or without tacrolimus) to decrease the risk of vector-related immune responses; of reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression.[63]

Other gene therapies for hemophilia B include lentiviral and CRISPR (clustered regulatory interspaced short palindromic repeats)/Cas-9 gene therapy approaches.[64] A proof-of-principle study by Morishige et al demonstrated that gene repair in hemophilia B can be accomplished with CRISPR  technology. Using CRISPR/Cas9 on patient-derived induced pluripotent stem cells, these researchers repaired an in-frame deletion in exon 2 of the factor IX gene.[65] Chen et al reported long-term correction of hemophilia B in a rat model, using CRISPR/Cas9-induced homology-independent targeted integration.[66]

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning.

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.

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 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 provided in coordination with a comprehensive hemophilia care center.

United Kingdom Haemophilia Centre Doctors’ Organisation guidelines

Guidelines for the management of acute joint bleeds and chronic synovitis in hemophilia from the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) include recommendations for patients with and without inhibitors.[67]

Hemostatic management of patients with inhibitors to factor IX includes the following:

• Patients with inhibitors should be encouraged to be on a home treatment program, and bleeds should be treated as early as possible.
• Activated prothrombin complex (aPCC) 50–100 μg kg ⁻¹ or recombinant factor VIIa (rFVIIa) 270 μg kg ⁻¹ as a single dose (or 90 μg kg ⁻¹ 2–3 hourly) are equally acceptable treatments for joint or soft tissue bleeds, with repeated doses as necessary. The frequency of infusion and duration of treatment should be determined by the clinical response.
• The total daily dose of aPCC should not exceed 200 IU kg ⁻¹.
• Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa.
• Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening bleeds.

Hemostatic management of patients without inhibitors includes the following:

• All patients with severe hemophilia A and B and other patients at risk of joint bleeding should be offered home treatment.
• The initial treatment of early and moderate bleeds should aim for a peak factor IX (FIX) level of 50 to 60 IU dL ⁻¹. This is equivalent to 40 to 60 IU kg ⁻¹ for severe hemophilia B, with extended half-life FIX being dosed at the lower end of the recommended range. Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may require up to 2 infusions.
• Children may require more frequent or higher doses, as they have a shorter factor half-life than adults.
• For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak factor IX level to 60 to 80 IU dL ⁻¹. Doses should be administered every 24 hr until complete resolution of pain. For severe bleeds, more frequent administration may be required in the initial 48 hr with standard FIX.

International consensus recommendations

Consensus recommendations on the management of hemophilia B by an international group of hematology experts cover the following topics[68] :

• Factor treatment choice
• Therapeutic agent laboratory monitoring
• Pharmacokinetics considerations
• Inhibitor management
• Preparing for gene therapy

Factor treatment choice:

• Consider FIX prophylaxis in all people with severe hemophilia B, including those who have non-severe disease according to their basal FIX levels but with a severe bleeding phenotype); initiate prophylaxis as early as possible (ie, before the onset of joint bleeding) and donot interrupt it.
• Both standard half-life FIX and extended half-life recombinant FIX (EHL rFIX) are effective treatment options for prophylaxis, and can be used to offer adequate hemostatic cover for bleeds, surgery, and invasive procedures; however, when using EHLs, consider product-specific laboratory requirements for monitoring.
• Adapt the dose and frequency of FIX prophylaxis treatment to the clinical phenotype (eg, bleed rates) and lifestyle considerations, and not   plasma trough levels exclusively.

Pharmacokinetics considerations

To determine whether pharmacokinetic analysis may guide individualized prophylaxis dosing, clinicians should review product-specific characteristics, as well as patient phenotype and joint status. Clinicians should consider population pharmacokinetics (ie, analysis of pharmacokinetics using a predictive algorithm derived from a large data repository for a given FIX product).

Laboratory monitoring

Recommendations for clinicians include the following:

• Chromogenic substrate assays (CSAs) provide higher levels of precision and accuracy in the assessment of FIX activity, whereas there may be variability with different one-stage assays (OSAs); however, CSAs may not be suitable for routine monitoring of recombinant FIX–albumin fusion protein (albutrepenonacog alfa).

• Insufficient evidence exists for thrombin generation assay or other global assays to guide routine clinical management.

• Current FIX gene therapy demonstrates consistently lower FIX activity when measured by CSA than by OSA; it is unclear which assay should be used to aid clinical decision making in gene therapy recipients.

Inhibitor management

Recommendations for patients with severe hemophilia B include the following:

• Determine the causative FIX genetic defect as soon as possible after the diagnosis, to identify the patients at increased risk of inhibitor development and/or severe allergic reaction.
• Perform inhibitor screening routinely, and intensify scrutiny in patients who develop allergic reactions to FIX and/or who have an inadequate response to FIX replacement therapy.
• During the first 20 exposure days, provide FIX infusion and close clinical observation for allergic reaction in the hospital setting.
• Recombinant activated factor VII should be the first choice for bleeding control and/or surgical cover in patientsand high-responding inhibitors, as well as in those who have developed allergic reactions; aPCC is an option, but the content of FIX and associated risk of anamnesis and/or worsening of allergic reaction(s) needs to be considered.
• Consider immune tolerance induction (ITI) to eradicate persistent inhibitors; however, the relative benefits and risks need to be taken into account; ITI should be initiated only in a hemophilia treatment center with an experienced team.
• Monitor patients closely during ITI for the development of nephrotic syndrome and/or severe allergic reactions.
• For those patients who have an allergic reaction, consider desensitization; importantly, further serious allergic reaction(s) should be anticipated in these patients, and subsequent infusions should occur in the hospital setting with appropriate resuscitation expertise and equipment.
• For FIX inhibitor eradication, first-line treatment consists of ITI protocols with a combination of FIX and immunosuppressive agents.

Preparing for gene therapy:

• Based on current AAV hemophilia B trial data, gene therapy should be considered as a future treatment option in adults with severe hemophilia B.
• As part of the informed consent process, patients should be made aware of the unpredictability of achieved FIX level and duration of expression.
• With liver-directed AAV gene therapy, patients should be aware that pre-existing liver pathology may be an exclusion criterion, and patients proceeding to gene therapy should be counselled about other potential sources of hepatotoxicity that may interfere with FIX expression (eg, medication use, alcohol)
• Clinicians should be aware that a rise in transaminase levels during the acute phase of gene therapy may indicate an immune response that can potentially threaten the expression of FIX; close monitoring of transaminase levels is needed to ensure that timely immunosuppression can be implemented.
• Clinicians should consider that the specific geographic pattern of AAV seropositivity may help direct which gene therapy is chosen.

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal, genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).

One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is approximately 100 mL/kg. To find the number of units of factor IX needed to correct the factor IX activity level, use the following:

Units factor IX = (weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)

The difference between the desired factor IX activity level and the patient's native factor IX activity level is expressed as a fraction. For example, if 100% activity is desired and the patient’s native activity is 5%, the calculation is as follows:

100% - 5% = 95% or 0.95

As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the emergency department with a serious upper GI bleed. The desired factor IX activity level is 100%. The dose of factor IX to administer to the patient would be calculated as follows:

Units factor IX = (80 kg)(100 mL/kg)(1 U factor IX/mL)(.99) = 7920

The next dose should be administered 24 hours after the first and is one half of the initial calculated dose.

Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for major hemorrhage.

Class Summary

These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Factor IX, recombinant (BeneFIX, Rixubis, Alprolix, Ixinity, Rebinyn)

Recombinant factor IX (rFIX) uses no human products for stabilization. Each of the brands is FDA-approved for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis, Ixinity, and Alprolix are also approved for routine prophylaxis in adults and children. Alprolix is a long-acting product, it may be administered for routine prophylaxis once weekly or every 10 days. Rebinyn is a glycopegylated long-acting rFIX. Pegylation slows removal of FIX from the blood circulation.

Factor IX, recombinant/albumin fusion protein (Idelvion)

Recombinant protein that temporarily replaces missing coagulation Factor IX needed for effective hemostasis. Comprised of genetically fused recombinant coagulation Factor IX and recombinant albumin, which extends the half-life of Factor IX. It is indicated for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes.

Factor IX (Mononine, AlphaNine SD)

Human blood-derived Factor IX indicated for control and prevention of bleeding episodes, and for perioperative management in adults and children.

Factor IX Complex (Bebulin, Bebulin VH, Profilnine SD)

Human plasma-derived prothrombin complex concentrates. These pooled plasma products (high purity) replace deficient FIX and other coagulation factors.

Class Summary

These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.

Factor VIIa, recombinant (NovoSeven RT, Sevenfact)

This agent is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.

Class Summary

These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. These agents are used in prophylaxis for oral surgery and in the treatment of excessive bleeding in the oral mucosa that results from local fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).

Epsilon aminocaproic acid (Amicar)

This is a lysine analog that binds to natively produced plasmin, reducing its fibrinolytic activity.

This agent inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.

This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.

Tranexamic acid (Cyklokapron)

Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.

Class Summary

These agents are used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.

These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.

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.[69]

These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.

Desmopressin (DDAVP, Stimate)

The main effect of desmopressin is enhancement of water reabsorption in the kidney and smooth muscle constriction. It causes a dose-dependent increase in plasma FVIII and plasminogen activator.

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

Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)

This agent is a freeze-dried sterile human plasma fraction with factor VIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and factor VII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors. Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.

Human antihemophilic factor (Hemofil M, Koate-DVI)

FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.

Recombinant human antihemophilic factor (Recombinate, Kogenate, Helixate, Advate)

FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.

Plasma-derived prothrombin complex concentrates/Factor IX complex concentrates (Bebulin, Profilnine SD)

This agent replaces deficient FIX and other factors in the complex.

Plasma-derived coagulation factor IX concentrate (Alpha Nine SD, Mononine, BeneFIX)

This agent replaces deficient FIX and other factors in the complex. AlphaNine SD and Mononine contain only FIX. BeneFIX is a recombinant product.

Class Summary

These agents are monoclonal antibodies directed against the CD20 antigen on B cells. They are recommended as second-line therapy in the treatment of factor IX inhibitors, especially in cases with high inhibitor titers.

Rituximab (Rituxan)

Rituximab binds to, and mediates destruction of, B-cells, thereby decreasing production of inhibitors and autoimmunization.

Class Summary

The first adeno-associated virus-5 (AAV5)-based gene therapy designed to deliver a copy of a gene encoding the Padua variant of human coagulation factor IX (hFIX598 Padua) was approved by the FDA. A single IV infusion results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

Etranacogene dezaparvovec (Hemgenix)

Indicated for adults with hemophilia B (congenital factor IX deficiency) who currently use factor IX prophylaxis, have current or historical life-threatening hemorrhage, or repeated serious spontaneous bleeding episodes.