Factor IX Deficiency (Hemophilia B) 

Updated: Mar 09, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP 

Overview

Practice Essentials

Factor IX (FIX) deficiency or dysfunction, or hemophilia B, is an X-linked inherited bleeding disorder, usually manifested in males and transmitted by females who carry the causative mutation on the X chromosome. Hemophilia B results from a variety of defects in the FIX gene. FIX deficiency is 4-6 times less prevalent than factor VIII (FVIII) deficiency (hemophilia A).

Hemophilia B may be classified as severe, moderate, or mild, based on the plasma levels of factor IX in affected individuals (< 1%, 2-5%, 6-30%, respectively).[1] Multiple underlying mutations have been identified and linked with different levels of clinical severity.[2, 3] For example, a study from Colombia found fourteen unique FIX gene variants: seven missense, three nonsense, one variant in the 3' UTR region, two large deletions > 50 bp, and one intronic substitution present in 7/20 patients (35%). In the variants previously described, genotype-phenotype association correlated with those reported in the literature.[4] Another molecular genetic analysis of FIX in hemophilia B showed that the patient was hemizygous for a novel missense mutation.[5]

Highly purified FIX concentrates are available for treatment of FIX deficiency. These include monoclonal antibody–purified plasma-derived FIX and recombinant FIX. See Treatment and Medication.

Background

The most significant breakthroughs in comprehending the mechanisms associated with coagulation first came from an understanding of the individual causes of the bleeding disorders. 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.

The existence of inherited bleeding disorders in males had long been recognized, however. The newspaper item below demonstrates what appears to be a late 19th-century record of hemophilia passed from mother to sons.

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

Pathophysiology

Structure, production, and half-life

FIX, a vitamin K–dependent single-chain glycoprotein, is synthesized first by the hepatocyte as a precursor protein (protein in vitamin K absence). It then undergoes extensive posttranslational modification to become the fully gamma-carboxylated mature zymogen that is secreted into the blood.

The precursor protein has the following parts, starting with (1) a signal peptide at the amino (NH2) terminal end (as marked in the diagram below), which directs the protein to the endoplasmic reticulum in the liver, and continuing with (2) the prepro leader sequence recognized by the gamma-glutamylcarboxylase, which is responsible for the posttranslational modification (carboxylation) of the glutamic acid residues (Gla) in the NH2 -terminal portion of the molecule. These 2 parts of the molecule are removed before the protein is secreted into the circulation.

Major components of the factor IX structure. Major components of the factor IX structure.

Single-chain plasma FIX has the Gla domain (12 gamma-carboxyglutamic acid residues) at its amino terminal end; this is a characteristic feature of all vitamin K–dependent factors. The Gla domain is responsible for Ca2+ binding, which is necessary for the binding of FIX to phospholipid membranes. The Gla region is followed by (1) two epidermal growth factor regions, (2) the activation peptide, which is removed when the single-chain zymogen FIX is converted to activated factor IX (FIXa), ie, the 2-chain active enzyme, and (3) the catalytic domain, which contains the enzymatic activity.

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 demonstrated 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. The process of gamma-carboxylation of the glutamic acid residues forms gamma-carboxyglutamyl (Gla) residues in the mature protein and requires reduced vitamin K, oxygen, and carbon dioxide to perform its functions.

Vitamin K–dependent carboxylation of precursor fac 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 resulting from a lack of available reduced vitamin K, hypocarboxylated and decarboxylated forms of the vitamin K–dependent factors are found in the circulation of patients ingesting 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.

FIX is present 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) compared to FIX concentrates.[6]

Extensive homology is found between FIX and the other vitamin K–dependent proteins (procoagulants factor VII [FVII], factor X [FX], factor II [FII] and anticoagulant proteins C and S), 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. 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).[7] The activation peptide for FIX is detectable in the plasma of control subjects.[8] The image below diagrams the activation of FIX.

Activation of factor IX and function of the intrin 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 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.

Antithrombin is the most important physiologic inhibitor of FIXa. Clinically, hemophilias A and B are indistinguishable. Variability in bleeding manifestations in patients with similar reductions in FVIII, FIX, or factor XI (FXI) is a well-known fact to clinicians. Modulation of the hemorrhagic disorder induced by deficiencies of intrinsic coagulation factors by co-inheritance of thrombophilic mutations is another well-recognized determinant of the extent of disruption of hemostasis in patients with a bleeding diathesis.

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.

These data, along with the known effects of epsilon-aminocaproic acid (EACA; Amicar) certainly raise the question of the efficacy of prolonged fibrinolytic inhibition in individuals with hemophilia as a possible mechanism with which not only to reduce the frequency of spontaneous bleeding but also to provide reduction in product usage in surgically induced bleeding in which fibrinolytic inhibitors currently are not used as adjuvant therapy. An expansion in the role of fibrinolytic inhibitors to control all types of bleeding in individuals with hemophilia could be explored in properly designed prospective clinical trials. Such trials could provide the first objective data on the true frequency of thromboembolic and other complications involved in the use of fibrinolytic inhibitors with replacement therapy.

Cell surface–directed hemostasis

The concept of coagulation as a waterfall or cascade, with a series of reactions each impacting the subsequent reaction, has been prevalent for a long time. 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 the reader to conceptually visualize 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 new concept of hemostasis.[9, 10]

Cell surfaced-directed hemostasis. Initially, a sm Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)

Epidemiology

Frequency

United States

Incidence of hemophilia B is approximately 1 case per 30,000 male births.

International

Frequency by ethnic background (countries) is currently not available. FIX deficiency has been found in many parts of the world. A prospective multicenter cohort project of inherited bleeding disorders in France identified 10,047 patients, 1300 (13.7%) of whom had  hemophilia B.[11]

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 only available, less pure, earlier products. Currently available concentrates and recombinant products have a better safety profile.[12]

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 (discussed later) contribute to morbidity and mortality. These include diffuse alveolar hemorrhage, which is rare but potentially life-threatening.[13]

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.

Highly purified FIX concentrates are not associated with thromboembolic complications and are associated with a reduced incidence of transmission of hepatitis and HIV. With currently available products, some individuals with hemophilia B can achieve a normal lifespan.

Death results from central nervous system (CNS) bleeding, progressive hepatitis with hepatic failure, anaphylaxis in children, development of inhibitors with severe bleeding, and AIDS.

Development of inhibitors (alloimmunization) in persons with hemophilia exposed to FIX-containing products or autoantibodies to FIX represents a serious complication, adding to morbidity and mortality.

Race

The disorder is found in all ethnic groups, and it does not have a specific ethnic or geographic distribution.

Ethnic differences in polymorphisms close to or in the FIX gene are important because they provide linkage data when identifying carriers, particularly when the mutation is unknown or for identification of de novo mutations.

A common G10430A mutation (Gly 60 Ser) in the factor IX gene was described in the moderate and mild hemophilia B in the majority of the Gujarati population.[14]

Sex

The disorder is X-linked, with the FIX gene located on the long arm of the X chromosome. Consequently, males with hemophilia B usually are symptomatic, while females usually are silent carriers (no bleeding disorder).As demonstrated in the diagram below, all female offspring of a male with hemophilia B are obligatory carriers, while no male offspring are carriers. Chances are 50/50 that each female offspring of a carrier female is a carrier and 50/50 that each male offspring of a carrier has hemophilia.

Possible genetic outcomes in individuals carrying Possible genetic outcomes in individuals carrying the hemophilic gene.

Carrier females usually are asymptomatic but can have bleeding (eg, easy bruising, menorrhagia, or excess bleeding after trauma) when they have significant reductions in FIX levels, which are caused by the greater (extreme) inactivation of the normal FIX gene, compared with the hemophilic FIX gene, during early embryogenesis. Other reasons a female may have clinical bleeding resulting from reduced levels of FIX include X-mosaicism, Turner syndrome, testicular feminization, or situations in which the father has hemophilia B and the mother is a carrier for the disorder. Carriers with basal levels of FIX of less than 30% can be expected to have a clinically evident bleeding disorder.

Age

Hemophilia B can be detected prenatally by measuring FIX activity in fetal blood samples obtained at 20 weeks of gestation by fetoscopy, but the presence of maternal FIX in amniotic fluid complicates the assessment. In addition, the procedure carries a high risk of complications, with a risk of fetal death of up to 6%. Detection of hemophilia B by linkage studies or gene mutation analysis (when the defect is known) can be performed by chorionic villous sampling at 12 weeks of gestation or by amniocentesis from 16-20 weeks, with complication rates of up to 2.0%.

Postnatal evaluation is triggered by a history of bleeding, which can start immediately after birth or, in mild hemophilia, can be delayed to a later age. Newborns without hemophilia have reduced levels of approximately 40%, with a gradual rise in the first year into the low-normal adult range. Prematurity is associated with lower levels due to the immaturity of the liver.

An age- and puberty-related (testosterone induced) rise in FIX levels, with an amelioration in bleeding symptoms, occurs in patients with FIX Leyden.

 

Presentation

History

The relationship between the basal level of FIX and bleeding is shown in Table 1. Severity of bleeding correlates with the level of basal FIX activity.

Table 1. Correlation Between Severity of Bleeding and the Level of Basal FIX Activity (Open Table in a new window)

Severity

Functional FIX Levels, %

Bleeding and Hemarthroses

Severe

≤ 1

Lifelong spontaneous hemorrhages and hemarthroses starting in infancy

Moderate

2-5

Hemorrhage secondary to minor trauma or surgery; occasional spontaneous hemarthrosis

Mild

6-25

Hemorrhage secondary to trauma, surgery, or precipitated by the use of drugs such as nonsteroidal anti-inflammatory drugs

 

See the list below:

  • Hematomas (seen below), hemarthroses, and mucocutaneous bleeding are spontaneous, secondary to trauma or surgery, or precipitated by the use of antiplatelet drugs.

    Extensive spontaneous abdominal wall hematoma and Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
    Extensive spontaneous abdominal wall hematoma and Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
  • Family history of bleeding is consistent with an X-linked recessive disorder; however, approximately one third of persons with hemophilia have no family history of bleeding.

  • In the immediate postnatal period, CNS bleeding can develop following labor and delivery, or excessive bleeding may develop after circumcision.

  • During infancy, easy bruising, frequent hematomas, and bleeding from the oral cavity and lips due to cuts and bites are more common in severe hemophilia. Muscle bleeds develop when the infant starts walking. Joint bleeds develop as physical activity increases.

  • Soft tissue hematomas that dissect through fascial planes can compromise vital organs and lead to major blood loss if they extend into the retroperitoneal space, femoral canal (causing nerve weakness and palsy), or thoracic cavity, or they bleed into the brain.

  • Delayed bleeding, which develops several hours to days after trauma, surgery, or dental extractions, is characteristic of the hemophilias.

  • Crippling arthropathy, examples of which appear below, develops after repeated hemarthroses because of repeated damage to joints and muscles. The most commonly affected joints in order of frequency are the knee, elbow, ankle, hip, shoulder, and wrist. Intraarticular cartilage and adjacent bones are destroyed by synovial proliferation and the release of proteolytic enzymes within the joint as a result of repeated bleeds.

    Older adult man with chronic fused extended knee f Older adult man with chronic fused extended knee following open drainage of right knee bleed many years previously.
    Severe bilateral hemophilic arthropathy and muscle Severe bilateral hemophilic arthropathy and muscle wasting. Three puncture sites demonstrate attempts to aspirate a recent bleed into the knee joint.
    Chronic severe arthritis, fusion, and loss of cart Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the knees. Findings are of advanced hemophilic arthropathy.
    Chronic severe arthritis, fusion, and loss of cart Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the elbow. Findings are of advanced hemophilic arthropathy.
    Hemophilic knee at surgery with synovial prolifera Hemophilic knee at surgery with synovial proliferation caused by repeated bleeding and requiring synovectomy.
    Large amount of vascular synovium removed during k Large amount of vascular synovium removed during knee surgery.
  • Hematuria often is mild but can lead to major blood loss. Renal colic due to a solid blood clot–induced ureteral obstruction can develop when the patient receives FIX concentrates along with fibrinolytic inhibitors to treat hematuria. An underlying structural defect in the genitourinary system should be excluded in patients presenting with hematuria.

  • Mucocutaneous bleeding, such as epistaxis or GI tract bleeding, is common and is accentuated by consuming alcohol or anti-inflammatory drugs and by cirrhosis with portal hypertension.

  • Pseudotumors (illustrated below) are cystic lesions that arise in subperiosteal bone or in soft tissue. Pseudotumors can expand after repeated bleeding and can compress vital organs. They develop gradually over time, can reach an enormous size, and should be treated early by complete surgical excision.

    Intravenous pyelogram showing extreme displacement Intravenous pyelogram showing extreme displacement of the left kidney and ureter by the pseudocyst.
    Dissection of a pseudocyst. Dissection of a pseudocyst.
    Transected pseudocyst with old chocolate brown–bla Transected pseudocyst with old chocolate brown–black blood.
    Large pseudocyst involving left proximal femur. Large pseudocyst involving left proximal femur.
    Transected pseudocyst (following disarticulation o Transected pseudocyst (following disarticulation of the lower left extremity because of vascular compromise, nerve damage, loss of bone, and nonfunctional lower left extremity) showing old black-brown blood, residual muscle, and bone.
  • Neurologic complications arise as a result of intracranial bleeding, bleeding into the spinal canal, and peripheral nerve compression resulting from expanding hematomas.

  • 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. Thus, chronic hepatitis, progressive cirrhosis, hepatic failure, and hepatocellular carcinoma are more common in individuals with hemophilia who received the less pure earlier products.

  • The seroprevalence of Parvovirus B 19 is approximately 80%. Adults with Parvovirus B 19 infection usually are asymptomatic, but the infection can cause aplastic anemia in immunocompromised hosts.

  • Patients with mild hemophilia may be diagnosed later in life when abnormal bleeding is precipitated by trauma, surgery, or drugs.

  • An increased frequency of bleeding compared with the past or failure to control bleeding with doses effective in the past suggests the development of an inhibitor (alloantibody) to FIX.

  • The frequency of acquired inhibitors to FIX is much less than the frequency of acquired FVIII inhibitors. The onset of a serious bleeding diathesis in a previously hemostatically competent individual (of either sex) and persistent bleeding postsurgery or after trauma are clues to the presence of an acquired inhibitor.

Physical

See the list below:

  • Severe pain in the target joint(s), bogginess around the involved joint(s) due to an inflamed synovium, presence of blood and fluid, fullness of joint space and/or surrounding bursa, and limitation of joint mobility

  • Deep muscle hematomas with pain, tenderness, and limitation of movement; delayed onset of bleeding from sites of trauma and/or surgery

  • Blood in the urine

  • Blood in the stool

  • Changes in neurologic function, headache, and other neurologic deficits

  • Jaundice, spider angiomas, hepatomegaly, tenderness, splenomegaly, and signs related to chronic hepatitis/cirrhosis

  • Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses including HIV and HCV infection

  • Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS

  • Anaphylaxis occurring early after the start of FIX infusions in children who are severely deficient

  • Of 298 pediatric patients evaluated for perceived bleeding disorders at a major American children's hospital, 8% had von Willebrand disease.[15] About one third had low von Willebrand factor, and 16% had a nonspecific platelet aggregation disorder. A single- and multiple-variable logistic regression analysis showed neither a personal nor family bleeding history at presentation, nor the presence of 2 or more bleeding symptoms being predictive of von Willebrand disease or low von Willebrand factor.

Causes

The gene for FIX is on the distal region of the long arm of the X chromosome, bands q27.1-q27.2. The gene is reported to be approximately 34 kilobases long with 8 exons and 7 introns and is located close to the fragile X site. The FIX gene has been studied extensively. Structural and functional defects in FIX are due to gene alterations, including large or small deletions, insertions or splice junction alterations, single base substitutions, or nonsense mutations. Similar to hemophilia A, approximately 30% of cases represent a de novo mutation. Extensive homologies exist between the gene and protein structures of all of the vitamin K–dependent factors. The introns occur in identical positions in FIX, FVII, FX, and protein C, suggesting evolution from a common ancestral gene.

Most patients deficient in FIX have point mutations; the nature of the mutation determines the level of FIX activity. More than one third of the mutations affect critical arginine residues (cytosine-guanine dinucleotide site mutations) resulting in a dysfunctional molecule.

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.

Many mutations in the FIX gene cause hemophilia B. The mutations provide an understanding of structure-activity relationships. Three groups of mutations are particularly instructive and have important clinical consequences.

The first group consists of gross FIX 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 in patients. 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 mutations in the FIX promoter region. The patients may have a spontaneous increase in basal FIX levels during and after puberty. Anabolic steroids also can raise the level of FIX in patients. In the FIX 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.

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 patients 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.

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.[16]

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 in patients with known hemophilia.

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.

 

DDx

Diagnostic Considerations

Other problems to be considered in the differential diagnosis of hemophilia B include the following:

  • Hemophilia A and von Willebrand disease

  • Other inherited coagulation disorders - Multiple vitamin K–dependent factor deficiencies and FXI deficiency

  • Acquired antibodies against FIX in persons with known hemophilia (for more information, see Medication)

  • Acquired antibodies against FIX in patients without hemophilia

  • Common coagulation disorders secondary to liver disease, warfarin sodium or heparin overdose, disseminated intravascular coagulation, dysproteinemias causing coagulopathies, and vitamin K deficiency

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • Preliminary identification of the coagulation disorder - aPTT, PT, platelet counts, and bleeding time testing

    • A prolonged aPTT with a normal PT indicate an abnormality in the early part of the intrinsic coagulation pathway. However, a normal aPTT does not exclude hemophilia B, since aPTT may not be sufficiently sensitive to detect slightly reduced levels of FIX in the 20-30% range, as occurs in mild hemophilia or in carriers.[17] If the clinical history warrants, a specific FIX level should be obtained.

    • Prolongation of PT alone, or both the PT and aPTT, is not consistent with hemophilia B alone. This kind of coagulopathy may result from superimposition of other causes, such as liver disease, overdose of heparin or warfarin sodium, or disseminated intravascular coagulation (DIC).

    • Thrombocytopenia and platelet dysfunction are not consistent with hemophilia B alone.

  • Assessment of nature and severity of bleeding – CBC, stools for blood, and urinalysis for hematuria

  • Confirmatory tests - Specific coagulation factor assays

    • A mixing test is performed in which the patient's plasma is mixed with normal pooled plasma, incubated at 37°C, and then tested for aPTT.

    • Correction of the aPTT in this test implies a deficiency, whereas persistence of an abnormally prolonged aPTT suggests the presence of an inhibitor.

  • Determination of the specific titer of an inhibitor to FIX - Ideally, a special method termed the Nijmegen modification of the Bethesda inhibitor assay (used to detect presence of an inhibitor if the mixing test is positive)

    • 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.

  • Identification of carriers

    • Using coagulation assays for the plasma level of FIX, only two thirds of carriers can be identified by a reduced FIX level.

    • Carriers can be detected by linkage studies using restriction fragment length polymorphism analysis. This test can be used only if the precise genetic defect is known.

  • Prenatal diagnosis

    • Use of several diagnostic procedures has been well established in the treatment of patients with FVIII and FIX deficiencies. Prior to the availability of molecular diagnostic techniques, cord blood sampling by fetoscopy at approximately 20 weeks of gestation was used to identify a male fetus with hemophilia with reduced in utero FIX levels.

    • Currently, many reports exist of antenatal diagnosis using molecular diagnostic techniques. Chorionic villous sampling at approximately 10-12 weeks of gestation or amniocentesis at 16-20 weeks of gestation can be performed to obtain fetal cells for DNA analysis when the mutation in the family is known or for linkage studies.

    • In general, these procedures carry a risk ranging from a low of approximately 0.5% for maternal-fetal complications to a high of approximately 1-6% for fetal death for fetoscopy. These procedures should be undertaken only after intense genetic and obstetric counseling of the parents.

  • Other laboratory tests

    • Other tests include liver function tests, kidney function testing, HIV type 1 and HIV type 2 antigen/antibody tests, and hepatitis A, B, C, D, and E antigen/antibody tests.

    • Assess alpha-fetoprotein levels for evidence of hepatocellular carcinoma in patients with chronic longstanding hepatitis.

Imaging Studies

See the list below:

  • MRI, CT scans, and ultrasound have been used to localize and size bleeds and to follow response to therapy.

Other Tests

See the list below:

  • An electrocardiogram (ECG), which is a general test for identifying cardiac abnormalities, is performed prior to procedures requiring anesthesia. Patients receiving factor replacement therapy are at risk for thrombotic complications, especially those receiving activated concentrates.

Procedures

See the list below:

  • Individuals with hemophilia require procedures for routine care, such as colonoscopy for GI tract bleeding or dental extractions. FIX must be replaced preprocedurally and postprocedurally until the biopsy or other surgical site heals well.

 

Treatment

Medical Care

Highly purified factor IX (FIX) concentrates are now available. These include monoclonal antibody–purified plasma-derived FIX (pdFIX; Immunine and Mononine) and recombinant FIX (rFIX).

A review of the global experience with pdFIX and rFIX products showed that the two types of products have comparable reliability, tolerability, and clinical efficacy. Serious adverse effects occur rarely with either product. The major difference was variable pharmacokinetics, with a similar half-life but an approximately 25-30% lower in vivo recovery after rFIX, particularly in younger children (in children < 16 y, according to Poon[18] ; in children < 15 y, according to Roth et al[19] ).

Data obtained from a survey of several French hemophilia centers and presented at the International Society of Thrombosis and Haemostasis meeting in July 2001 showed an average recovery of 61% for rFIX use versus 85% for pdFIX. Initial dosing of FIX for both inpatient and outpatient treatment is on the basis of standard guidelines (Indiana Hemophilia & Thrombosis Center).

Development of inhibitors is a serious matter affecting 1.5–3% of patients with hemophilia B. Thus, successful eradication of inhibitor may be challenging and require rituximab, with or without desensitization therapy.[20]  

Inhibitors in hemophilia B patients have been associated with the development of severe allergic or anaphylactic reaction.[21] Given the risk of potentially life-threatening reactions, close monitoring of infants and small children with severe hemophilia B for their first 20 or more infusions with any FIX-containing product has been recommended, with the infusions performed in a facility equipped to treat anaphylactic shock.[22]

Although many reports exist of the successful use of different continuous infusion regimens of FIX, ongoing data collection and studies will allow development of a standardized regimen in the future. Potential benefits include the ability to mimic the physiologic state and reduction in product usage, providing much-needed economic savings.

Although administration of clotting factor in prophylaxis has been shown to be beneficial for both hemophilia A and B, it is more commonly used with hemophilia A than hemophilia B. The reasons for this are unclear.[23]

In children who are starting therapy for the first time or in persons with hemophilia who are HIV negative, recombinant products are used whenever possible because of their presumed higher viral safety. Note that approximately 25% of the lots of human albumin containing first-generation recombinant factor VIII (rFVIII) concentrates have been found to be positive for transfusion-transmitted virus (TTV) from contaminated human serum albumin. All of the second-generation rFVIII preparations (free from human albumin) were negative for the virus.[24]

It is important to understand the pharmacokinetics of factor IX.[25] Factor IX in vivo recovery is also relatively short, possibly due to its reversible binding to endothelium and possibly to platelets. There is considerable pharmacokinetic variability of factor IX between products (particularly between plasma-derived factor IX and recombinant factor IX), and between individuals.

Factor replacement in patients with hemophilia B should be guided by an experienced hematologist who is familiar with treating patients with coagulation disorders.

The location and severity of bleeding determine the dose and duration of factor replacement therapy.

The first dose should be 20-80 IU/kg, depending on the FIX level necessary to treat the specific clinical condition. Approximately 50% of the first dose is administered approximately every 24 hours to maintain the initial level of FIX

If therapy is to last for more than 2 days or is occurring for the first time, FIX levels should be obtained immediately after the first dose, with a subsequent trough level taken to determine appropriate dose and frequency of replacement therapy based on in vivo response to a specific product. Children and surgical patients require closer monitoring of FIX levels because of known variable pharmacokinetics and a lack of a steady state, respectively.

Preservation of the hemostatic plug formed in the presence of adequate levels of FIX at the time of surgery (ie, dental extraction) can be achieved by inhibiting fibrinolysis with epsilon-aminocaproic acid (EACA) or tranexamic acid (Cyklokapron) administered orally or intravenously as needed. Inhibitors of fibrinolysis, such as EACA or tranexamic acid, can be used in combination with factor replacement to prevent bleeding from mucosal sites, including after dental extractions or sinus surgery.

Following a surgical procedure, fibrinolytic inhibitors are continued, then tapered as the wound heals. A single dose can be used to prevent bleeding from minor procedures. However, fibrinolytic inhibitors are not of value in the treatment of hemarthroses or deep-seated bleeding. The prolonged use of fibrinolytic inhibitors in joint and deep hematomas can lead to persistence (lack of absorption) of the clot with negative consequences.

Fibrinolytic inhibitors are used as follows:

  • A dose of EACA, 5 g orally or IV, is administered immediately before the surgical procedure along with a dose of FIX, followed by 1 g per hour postoperatively until the decision is made to taper the dose over the next 5 days.

  • Tranexamic acid can be administered in a dose of 1.5 g every 6-8 hours for 5 days; this drug is not available in the United States.

  • Administration of these fibrinolytic inhibitors is contraindicated in patients with hematuria who are receiving or have recently received an FIX product because of the risk of an acute persistent thrombus obstructing the ureters and causing acute hydronephrosis.

Nonnarcotic and narcotic analgesics are used to relieve pain. Narcotic analgesics are used to manage severe acute pain, such as occurs with joint bleeding or perioperatively. Chronic persistent pain of chronic joint disease can be difficult to manage.

Ideally, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with a bleeding disorder because the addition of platelet dysfunction caused by the drugs can potentiate bleeding. However, because of the persistent demand by individuals with hemophilia, cyclooxygenase 2 (COX-2) inhibitors may be tried with caution because of a lack of efficacy of nonnarcotic pain relievers in severe arthritis. Use of NSAIDs by individuals with hemophilia has increased in an attempt to relieve the severe joint pain of chronic arthritis.

Peripartum care

A review of written guidelines and practices of obstetricians, hematologists, and neonatologists in the United States for the treatment of pregnant carriers and newborns with hemophilia and intracranial hemorrhage showed that more than 94% of the major facilities reviewed had no written guidelines. Survey findings led to the following recommendations[26, 27] :

  • Vacuum devices and fetal scalp monitors should not be used during vaginal delivery of known carriers of hemophilia.
  • All infants with intracranial hemorrhage should be evaluated for a bleeding disorder.
  • Women with postpartum hemorrhage should have a coagulation workup.
  • A national registry should be created.
  • National guidelines should be developed, which should improve care for pregnant women with bleeding disorders.

Gene therapy

Several approaches to gene therapy have been undertaken in treating patients with severe hemophilia B.[28] Considerable success has been reported with systemic administration of an adeno-associated virus (AAV) encoding an optimized factor IX construct, although efforts to maintain long-term FIX expression continue.[29] Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.

Nathwani et al reported long-term efficacy and safety of gene therapy in 10 patients with severe hemophilia B using an AAV serotype 8 (AAV8) vector, scAAV2/8-LP1-hFIXco, that contains a codon-optimized modified FIX transgene. After a single intravenous infusion of the vector, circulating FIX levels increased to 1% to 6% of normal in all 10 patients over a median of 3.2 years. Four of the seven patients previously on factor replacement were able to discontinue it, and the others were able to decrease the dose.[30]

The most significant toxicity was mild elevation of the alanine amino-transferase level that occurred 7 to 10 weeks after infusion. The increase resolved over a median of 5 days with prednisolone treatment. This contrasts with results of earlier studies that used intrahepatic administration of AAV2 vector, which did not result in long-term expression of FIX and was associated with appreciable hepatic toxicity.[30]

Nevertheless, FIX levels achieved with gene therapy, although above the current usual target trough levels achieved with FIX prophylaxis, fall well short of the level that longer-acting FIX preparations can produce. In addition, the high peak levels provided by FIX infusions permit patients to maintain an active lifestyle.

Widespread adoption of gene therapy also faces the barriers of high cost and a high seroprevalence of antibodies to AAV vectors in the general population. Other new technologies that do not require viral vectors (eg, stem cell therapy) may obviate that difficulty.

Surgical Care

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.

Small studies have established the efficacy of using lower than usually recommended doses of FIX concentrate, administered as an intermittent bolus infusion after major surgical procedures. Preoperatively, FIX was used in a dose of 77 U/kg to achieve a presurgical level of 107% (range 50-104%). Between days 1 and 3 after surgery, an average of 23 U/kg/d was used with an average trough value of FIX of 34% (range 11-52%). After day 4, an average of 18 U/kg/d of FIX was used until wound healing occurred. This resulted in a significant reduction in overall factor used without hemostatic inadequacy. Such data underscore the importance of defining the least amount of factor replacement necessary to obtain and maintain adequate hemostasis.

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, pseudotumors, 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.

In total, the measures result in improved quality of life in patients with hemophilia, while achieving a reduction in medical care costs. Bovine thrombin used in these preparations may result in development of inhibitors to several factors, including thrombin and FV, as it has in other postoperative states.

Warn patients to avoid any antiplatelet drug starting 1 week prior to surgery and in the immediate postoperative period to minimize the risk of bleeding.

The use of ice packs at surgical sites may be beneficial to reduce the size of the surgical site hematoma.

Consultations

See the list below:

  • Hematologist, including general medical evaluation
  • Orthopedist
  • Physical therapist
  • Dentist
  • Surgeon
  • Social worker
  • Psychiatrist, particularly in the management of HIV-related issues [31]
  • Geneticist for genetic testing and counseling for family members

Activity

Activity recommendations depend on such factors as joint disease and resolution of bleed into joints and muscles. Appropriate use of physical therapy is advised.

Complications

Despite safe and effective replacement therapy, patients still experience breakthrough bleeding, progressive joint disease. and  high rates of inhibitor development.[32]

 

Medication

Medication Summary

Currently, highly purified preparations—recombinant factor IX (rFIX) or purified monoclonal antibody and solvent-detergent–treated FIX products—are used for the treatment of hemophilia B. rFIX products are free of the usual viral contaminants and are the only products free of parvovirus B19. These products have significantly reduced risks of viral transmission; however, a report exists of contamination of first-generation recombinant products with TT virus due to the use of human serum albumin.[24]  

The development of alloantibodies against infused FIX also remains a concern. This has prompted research into a new class of therapeutic agents that enhance coagulation, such as emicizumab, or that inhibit anticoagulant pathways, such as fitusiran and concizumab. These agents have reached an advanced stage of clinical investigation.[33]

Recombinant products result in 20-30% less factor recovery, possibly because of the presence of nonneutralizing antibodies. These products can cause severe allergic reactions, especially in patients who are severely deficient in FIX. These potentially life-threatening reactions are associated with development of inhibitors. Young children can experience such reactions, especially at the start of treatment.

Serious allergic reactions to FIX preclude further use of FIX or prothrombin-complex concentrates (PCCs) or activated prothrombin-complex concentrates (aPCCs); desensitization may be attempted. PCCs/aPCCs are crude plasma preparations containing concentrates of vitamin K–dependent factors, some in an activated form. Liver disease diminishes clearance of activated coagulation factors and synthesis of physiologic inhibitors. Rapid infusion increases risk of thromboembolic complications, especially disseminated intravascular coagulation (DIC), in patients with liver disease. The addition of very small amounts of heparin (1 U of heparin for every 100 U of FIX activity) has been used to minimize the effect of activators present in the aPCCs.

Most data suggest an approximate 50% drop in FIX level within approximately 24 hours. However, the actual in vivo FIX level that is achieved varies. Peak and trough levels following bolus dosing dictate the amount and timing of subsequent doses. Generally, an appropriate second dose is approximately one half of the initial dose, which is administered every 24 hours for moderate or minor bleeds and more often for severe or life-threatening bleeds. Ideally, FIX levels should be monitored in any serious situation to assess adequacy of dose and response.

Home care on-demand factor replacement therapy doses depend on the individual's response to the product and on the type of bleed. The goal of prophylactic therapy is to maintain the basal FIX level in an approximate 5% range, which reduces frequency and risk of spontaneous bleeding. Attempts are underway to determine the lowest level of FIX necessary for adequate hemostasis and to reduce dose requirements by using continuous infusion of FIX concentrates.

Dosing guidelines relate to the in vivo level of FIX needed. Different products have different in vivo recovery. Dosing guidelines require verification for each patient. Educating patients regarding their response to specific products is important so that the information does not have to be generated repeatedly, and patients can advise an emergency department physician regarding personal dose response to a specific product.

Current products are safer in regards to viral and HIV infection. However, contamination with previously unknown pathogens may occur. Currently, blood from donors who have new variant Creutzfeldt-Jacob disease (nvCJD) has been withdrawn from the manufacturing process. Potential risk of nvCJD or transmissible spongiform encephalopathies remains a concern when plasma-derived products are used. Patients should be vaccinated for hepatitis A and B.

DIC and thromboembolism are complications that have occurred using PCCs and aPCCs. Fibrinolytic inhibitors should not be used concomitantly with these products because of the risk of accelerating thrombosis.

FIX inhibitors develop in 3-5% of patients with hemophilia B who are receiving concentrates. An inhibitor should be suspected if FIX levels do not rise to predicted (expected) levels following treatment with concentrates, a hemorrhage does not respond to previously adequate doses, or severe allergic reactions occur soon after starting a patient on a replacement product. Laboratory confirmation of the presence of an inhibitor is essential.

Treatment of patients with FIX inhibitors is complex, requiring the services of a competent hematologist. Patients with low titers of inhibitors of 10 Bethesda units can be treated using PCCs, starting with a dose of 75 U/kg q6-12h, or recombinant activated factor VIIa (rFVIIa) can be used to treat patients with FIX inhibitors; doses vary from 30-90 mcg/kg IV q2-3h, with 1 additional dose after hemostasis is achieved.

Availability of rFVIIa resulted in another leap forward in the ability to treat patients with inhibitors to FIX or factor VIII coagulant activity (FVIII-C), allowing them to undergo previously impossible major surgical procedures, such as joint replacements or pseudocyst excisions, which require extensive procedures. As a result of its cost, rFVIIa previously was used as backup therapy when other products failed, but as experience with this product grows, it is being used more often as first-line therapy. The starting dose can vary from 30-90 mcg/kg IV every 2-3 hours.

Excellent or effective response may be seen in patients with inhibitors within 12 hours of starting therapy. Data from compassionate-use experience shows that hemostasis was obtained in approximately 92% of patients with inhibitors within 2-3 doses using 90 mcg/kg, suggesting an up-front use of the larger dose.

A decline of inhibitor titer to approximately one third of the original level was seen in patients who had received repeated doses of rFVIIa for treatment of bleeding. A continuous infusion regimen, rather than administration of an intermittent bolus, has been used successfully in patients with inhibitors. Since FVIIa in concert with TF, phospholipids, and calcium activates FX to FXa, thereby leading to thrombin generation, fibrinogen levels were monitored in treated patients and found to be similar to baseline values in the majority.

Additionally, follow-up samples obtained in patients treated with rFVIIa did not detect any antibody levels above the cutoff value, and no new antibodies were found to baby hamster kidney cells or to murine IgG. Despite these data, further studies are needed to refine dosing for the treatment of different types of bleeding in patients with inhibitors. Duration of therapy depends on adequacy of control of bleeding as balanced against possible adverse effects. Thromboembolic complications are infrequent, based on currently available information.

Advantages of rFVIIa are that it is a recombinant protein with no risk of transmission of the usual viruses, hemostasis is localized to the site(s) of injury, anaphylactic reactions have not occurred in patients with FIX deficiency, and rFVIIa does not induce an anamnestic rise in FIX antibody titer. rFVIIa can be used at home, postoperatively. Disadvantages are its expense, the need for good venous access, frequent repetitive administration, and activation of coagulation with possible DIC and rare thromboembolic events.

Immune tolerance induction (ITI) using prolonged gradually increasing doses of IV FIX concentrate, IV IgG, Cytoxan, other immunosuppressives, and inhibitor-antibody column has been used to treat patients with FIX inhibitors. ITI can be associated with development of nephrotic syndrome, which usually is steroid resistant and requires withdrawal of the antigenic protein. Disadvantages of ITI are that it is time intensive (6-24 mo), requires a high degree of patient compliance and daily venous access, is expensive, and has a significant failure rate.

The use of PCC/aPCC products in patients with inhibitors has several disadvantages. They have a poorly defined mode of action and an unpredictable hemostatic response. Since they are derived from pooled plasma, they carry a greater potential for transmission of viral and other illnesses. In addition, response is variable, frequent administration is required (at least q12h), and they are associated with significant failure rate, induce an anamnestic response with increase in antibody titer, and are not for use in patients who have developed anaphylaxis to FIX products.

To reduce factor usage and cost, the potential use of FIX variants with enhanced specific clotting activity has been investigated.[34] One of seven tested appeared to be a possible candidate for protein replacement therapy as well as gene-based therapeutic strategies.

In practice, administration of concentrates must be individualized by the evaluation of the extent, site, and cause of bleeding, response to therapy, current laboratory data, and the patient's history.

Using a decision analytic model, Lin et al calculated the total adult lifetime cost for a patient with severe or moderately severe hemophilia in the United States, as follows[35] :

  • Standard half-life FIX prophylaxis: $21,086,607
  • Extended half-life FIX prophylaxis: $22,987,483
  • On-demand FIX treatment with FIX prophylaxis: $20,971,826

The cost of FIX treatment accounted for more than 90% of the total hemophilia B treatment costs.

Table 2. Rough Guidelines for Treatment Using Factor IX Concentrates (Open Table in a new window)

Type of Hemorrhage

Desired FIX Activity, % of Normal

Duration of Therapy, Days

Minor -

Uncomplicated

hemarthroses

superficial large

hematomas

20-30

1-2

Moderate -

Hematoma with dissection

Oral/mucosal hemorrhages and epistaxis hematuria*

25-50

3-7

(2-5 in oral hemorrhages)

Dental extraction(s)*

50-100

2-5

Major -

Pharyngeal/retropharyngeal,

retroperitoneal,

GI tract bleeding,

CNS bleeding surgery

~100 until bleeding is controlled; then taper to minimum required to prevent rebleed

7-10

(5-10 in

oral hemorrhages)

*Concomitant administration of EACA or tranexamic acid (both fibrinolytic inhibitors) can help reduce the dose of clotting factor replacement required to treat such bleeds.

 

Coagulation Factors

Class Summary

For use in patients with FIX deficiency.

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

Recombinant factor IX (rFIX) is indicated for control and treatment of spontaneous or surgery-related bleeding or prevention of bleeding in patients proven to be deficient in FIX. It is used as first-line therapy, particularly in previously untreated patients, owing to its safety regarding common virally transmitted illnesses associated with nonrecombinant products.

In vivo recovery of rFIX is lower than that obtained with plasma-derived products.

Factor IX (AlphaNine SD, Mononine)

Factor IX prevents and treats spontaneous or surgery-associated bleeding in patients with proven FIX deficiency. As with any factor replacement therapy, documenting actual recovery for a given dose and product is essential in every patient.

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

Factor IX complex is standardized in terms of factor IX content, and each vial is labeled for the factor IX content. One IU of factor IX corresponds to the activity of factor IX in 1 mL of fresh normal human plasma. It also contains factor II, factor X, and low (nontherapeutic) levels of factor VII.

Factor VIIa, recombinant (NovoSeven RT, Sevenfact)

Factor VIIa is indicated for treatment of bleeding episodes in hemophilia A or B with inhibitors. FVIIa activates conversion of Factor X to Factor Xa, which initiates the common pathway of the coagulation cascade; prothrombin is activated to thrombin, which then converts fibrinogen to fibrin to form a hemostatic plug, thereby achieving clot formation at the site of hemorrhage (hemostasis) Dosage of brands differ.  

Antifibrinolytics

Class Summary

Use together with single-dose factor replacement for minor surgical procedures, such as dental extractions or sinus surgery, so that the procedures can be accomplished on an outpatient basis with the use of a single dose of product.

Aminocaproic acid (Amicar)

Hemostatic agent that diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. Can be used PO or IV.

Tranexamic acid (Cyklokapron, Lysteda)

Fibrinolytic inhibitor used with FIX replacement to reduce need for hospitalization and more than 1 dose of FIX concentrate in patients with hemophilia B requiring dental or sinus procedures. Can be used similarly in patients with hemophilia A. Also used to inhibit fibrinolysis in other conditions.

 

Follow-up

Further Outpatient Care

Home care programs with self-infusion of FIX concentrate at the earliest sign of bleeding have medical and psychological benefits to the patient. Home care allows prompt care for bleeding, minimizes delays, and reduces complications. Home care must be undertaken with caution and combined with intensive education, supervision, and support, with selection of appropriate patients for home care. The images below demonstrate tourniquet application prior to self-infusion.

Application of Velcro tourniquet followed by self- Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
Application of Velcro tourniquet followed by self- Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.

Complete annual physical examinations are performed, with laboratory testing for inhibitors, hepatitis, HIV, and other tests as needed. In addition, routine care as given to other patients, ie, mammography, rectal examination, prostate-specific antigen level, colonoscopy, and dental care should be undertaken.

Prophylactic care includes vaccination for hepatitis A and B, routine dental care, orthopedic care, physical therapy, and psychosocial and economic support. Although hepatitis A is transmitted infrequently by transfusion, superimposition of hepatitis A in a patient with chronic hepatitis increases the risk of acute hepatic failure.[36]

Further Inpatient Care

Patients are hospitalized only for serious complications requiring complex interdisciplinary care. Constant close clinical evaluation and serial laboratory monitoring are necessary to properly treat these patients, requiring the daily services of a trained hematologist.

Inpatient & Outpatient Medications

The availability of a continuous supply of products containing FIX to treat severe hemophilia as part of home therapy is essential for early and prompt self-treatment of bleeds. This minimizes the need for expensive hospitalization, reduces joint damage, and improves the quality of life for the patient.

Instruct patients to avoid use of acetylsalicylic acid, NSAIDs, and other over-the-counter and herbal medications that can precipitate or accentuate bleeding. Routine immunizations with hepatitis A and B vaccines and other routine care, as for influenza and pneumonia, should be provided.

Transfer

With the availability of qualified hematologists, surgeons, and laboratory support, many patients can be cared for at local community hospitals, many of which have access to sophisticated laboratory tests and thus allow local and convenient care. However, additional services are available at local hemophilia centers through state and federal programs to assist these patients in coping with the many consequences of a burdensome illness. Thus, it may not always be necessary to transfer such patients to university centers, where the cost of care may be higher.

Complications

Potential complications include severe arthropathy, with limitation of joint motion, pseudocysts, hepatitis, HIV-related illnesses, nephrotic syndrome, severe allergic reactions, development of inhibitors, CNS bleeding, infections, and death. Along with these, patients experience severe economic and social consequences.

Increased bleeding risk occurs with use of the following:

  • NSAIDs
  • Protease inhibitors, in HIV-infected individuals
  • St. John's wort ( Hypericum perforatum), an over-the-counter herbal medicine used for depression

Contribution of products of intermediate purity to immunosuppression is greater than with products of high purity.

Development of FIX inhibitors is a serious complication. Overall incidence of inhibitors in hemophilia B (3-5%) is less than in hemophilia A, but it rises to 12% in patients with severe hemophilia B. Hemophilia B is more likely to develop in patients with severe FIX deficiency because of large deletions or major abnormalities of the FIX gene. In these patients, development of severe allergic/anaphylactic reactions to FIX infusions is associated with the appearance of an inhibitor.

Data from children who developed inhibitors showed that the median number of infusion days of product prior to development of an inhibitor was 11; 50% of inhibitors develop before patients reach age 9 years. The frequency of anaphylaxis is higher on exposure to products containing FIX in patients with hemophilia B who subsequently develop inhibitors. Such anaphylaxis is rare in patients with hemophilia A.

An anamnestic rise in antibody titers in patients who already have an inhibitor can occur following transfusion of products containing FIX. Antibody development leads to failure of therapy usually effective for controlling bleeding, increases morbidity and mortality, and makes the performance of even minor surgery difficult.

Allergic reactions to older less pure coagulation factor concentrates can occur due to sensitization to foreign proteins. They include skin rash, fever, headache and, sometimes, anaphylaxis.

Acute decompensated DIC, myocardial infarction, or stroke can occur with the use of prothrombin complex concentrates (PCCs) or recombinant factor VIIa.

Hepatitis resulting from virus types A-E, hepatitis virus G, the SEN family of viruses A-H, with SEN d and SEN H transmitted parenterally and causing posttransfusion hepatitis; progression to cirrhosis; hepatic failure; and hepatocellular carcinoma are all problems that develop in individuals with hemophilia who were transfused with older less pure products.

Parvovirus B19 can be transmitted, depending on the product transfused, and it can cause aplastic anemia in immunocompromised hosts as well as a variety of illnesses. Human herpesvirus 8, HIV type 2, and HIV group O are other emerging pathogens.[37] Transfusion-transmitted virus (TTV) contamination of first-generation rFIX concentrate has been reported[38] ; second-generation recombinant products that do not use human serum albumin were free of TTV contamination.

HCV infection remains a serious problem, with progression to chronic hepatitis and hepatic failure in most patients, and it has been used as an indication for liver transplantation.

Other unidentified viruses (eg, those possibly present in Chinese hamster ovary cells, which are used to produce rFIX concentrates), can present potential health threats. HIV infection is possible. Transmission of other viruses currently is unknown.

Nephrotic syndrome is a concern, especially in patients with inhibitors undergoing long-term factor replacement. Anemia, leukopenia, or thrombocytopenia may occur. Gene therapy may be associated with an increased incidence of inhibitors.

Potential transmission of prions causing Creutzfeldt-Jakob disease (CJD) or its variant form (vCJD) in recipients of blood products was a serious concern early in this century. However, no individual with hemophilia nor any other blood product recipient in the United States is known to have developed CJD. A United Kingdom study found that as of May 2015, no new cases of transfusion-associated vCJD had occurred since 2007 and there was no evidence of transfusion transmission of sporadic CJD.[39] A sensitive and specific blood test for vCJD has been developed and has entered clinical use; it could be used to screen blood supplies.[40]

Hemophilia can also have a significant psychosocial impact, including addiction to narcotic analgesics and abuse of alcohol and other substances, which leads to unstable relationships. Lack of availability of appropriate jobs; inability to maintain a job due to recurrent illnesses; need for repeated job absences; and the need for repeated expensive medical care all lead to the likelihood of an inability of individuals with hemophilia to adequately support themselves.

Prognosis

Prognosis depends on the types of complications that develop, as well as the type of product replacement available when the patient started undergoing care. Currently, younger patients with hemophilia who receive recombinant products do much better than patients who received the older products. Gene therapy for these disorders is currently under evaluation.

Early and complete genetic testing of all persons newly diagnosed with hemophilia is key to anticipating and preventing serious complications.

Preventing or suppressing the anamnestic rise of FIX inhibitors in patients with severe FIX deficiencies may be feasible with the use of monoclonal antibodies, which target T-cell response to antigenic stimulation. The blockade of CTLA4 and CD28-B7 interactions with T cells is shown to have implications for successfully preventing destructive T-cell responses in autoimmune disease.

Patient Education

Registration with the National Hemophilia Foundation, educational seminars, and one-on-one discussions with patient and family members are essential. For patient education information, see Hemophilia.

 

Questions & Answers

Overview

What is factor IX deficiency (FIX) (hemophilia B)?

When was factor IX deficiency (FIX) (hemophilia B) first differentiated from hemophilia A?

What is the structure, production, and half-life of factor IX (FIX)?

What is the role of activation in the pathophysiology of factor IX deficiency (hemophilia B)?

What are is the role of thrombin activatable fibrinolytic inhibitor in the pathophysiology of factor IX (FIX) deficiency (hemophilia B)?

What is the role of cell surface–directed hemostasis in the pathophysiology of factor IX (FIX) deficiency (hemophilia B)?

What is the prevalence of factor IX deficiency (FIX) (hemophilia B) in the US?

What is the global prevalence of factor IX deficiency (FIX) (hemophilia B)?

What is the mortality and morbidity associated with factor IX deficiency (FIX) (hemophilia B)?

What are the racial predilections of factor IX deficiency (FIX) (hemophilia B)?

What are the sexual predilections of factor IX deficiency (FIX) (hemophilia B)?

At what age is factor IX deficiency (FIX) (hemophilia B) typically diagnosed?

What are the treatment recommendations for pregnant carriers and newborns with factor IX deficiency (FIX) (hemophilia B)?

Presentation

How does the basal level of factor IX (FIX) correlate with the severity of bleeding in factor IX deficiency (FIX) (hemophilia B)?

Which clinical history findings are characteristic of factor IX deficiency (FIX) (hemophilia B)?

Which physical findings are characteristic of factor IX deficiency (FIX) (hemophilia B)?

What causes factor IX deficiency (FIX) (hemophilia B)?

What is the role of factor IX inhibitors in the etiology of factor IX deficiency (FIX) (hemophilia B)?

What is the role of combined congenital deficiencies in the etiology of factor IX deficiency (FIX) (hemophilia B)?

DDX

Which conditions are included in the differential diagnoses of factor IX deficiency (FIX) (hemophilia B)?

What are the differential diagnoses for Factor IX Deficiency (Hemophilia B)?

Workup

What is the role of lab tests in the workup of factor IX deficiency (FIX) (hemophilia B)?

What is the role of imaging studies in the workup of factor IX deficiency (FIX) (hemophilia B)?

What is the role of ECG in the workup of factor IX deficiency (FIX) (hemophilia B)?

When is FIX replacement required for patients with factor IX deficiency (FIX) (hemophilia B) undergoing routine procedures?

Treatment

How is factor IX deficiency (FIX) (hemophilia B) treated?

What is the role of fibrinolytic inhibitors in the treatment of factor IX deficiency (FIX) (hemophilia B)?

What is the role of analgesics in the treatment of factor IX deficiency (FIX) (hemophilia B)?

What is the role of gene therapy in the treatment of factor IX deficiency (FIX) (hemophilia B)?

What is included in the care of patients with factor IX deficiency (FIX) (hemophilia B) undergoing surgical procedures?

Which consultations are beneficial to patients with factor IX deficiency (FIX) (hemophilia B)?

Which activity modifications are used in the treatment of factor IX deficiency (FIX) (hemophilia B)?

Medications

What is the role of medication in the treatment of factor IX deficiency (FIX) (hemophilia B)?

Which medications in the drug class Antifibrinolytics are used in the treatment of Factor IX Deficiency (Hemophilia B)?

Which medications in the drug class Coagulation Factors are used in the treatment of Factor IX Deficiency (Hemophilia B)?

Follow-up

What is included in the long-term monitoring of factor IX deficiency (FIX) (hemophilia B)?

When is inpatient care indicated for factor IX deficiency (FIX) (hemophilia B)?

What are the benefits of home therapy for the treatment of factor IX deficiency (FIX) (hemophilia B)?

Which medications are contraindicated in patients with factor IX deficiency (FIX) (hemophilia B)?

When is patient transfer considered for the treatment of factor IX deficiency (FIX) (hemophilia B)?

What are the potential complications of factor IX deficiency (FIX) (hemophilia B)?

What is the prognosis of factor IX deficiency (FIX) (hemophilia B)?

What is included in patient education about factor IX deficiency (FIX) (hemophilia B)?