eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor IX

Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Elzbieta Klujszo, MD, Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce; Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Contributor Information and Disclosures

Updated: Aug 30, 2007

Introduction

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. The recognition in 1952 that hemophilia B was due to a deficiency of a coagulation factor followed the discovery that hemophilia A was caused by the deficiency of another clotting factor. Also termed Christmas disease, hemophilia B is an X-linked inherited bleeding disorder, usually manifested in males and transmitted by females when they carry the abnormality on the X chromosome. Hemophilia B is caused by a deficiency or dysfunction of factor IX (FIX) resulting from a variety of defects in the FIX gene. FIX deficiency is 4-6 times less prevalent than factor VIII (FVIII) deficiency (see Image 1).

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); then, it 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, which directs the protein to the endoplasmic reticulum in the liver (see Image 2), 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.

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 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 (see Image 3).

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.

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 (see Image 4).

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 (see Image 5). 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). The activation peptide for FIX is detectable in the plasma of control subjects.¹

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.

Recently, 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. A recent review proposes 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" (see Image 6).

In this model, 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.^2,3

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.

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 (see Images 8-24).

• 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.
• 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 describes in the moderate and mild hemophilia B in the majority of the Gujarati population.⁴

Sex

• Males with hemophilia B usually are symptomatic, while females usually are silent carriers (no bleeding disorder).
• The disorder is X-linked, with the FIX gene located on the long arm of the X chromosome (see Image 7). 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.
• Carrier females usually are asymptomatic but can have bleeding (eg, are easily bruised or have 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.
• 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 (ICH) showed that more than 94% of the major facilities reviewed had no written guidelines. As a result of data obtained in the survey, it has been suggested that (1) vacuum devices and fetal scalp monitors not be used during vaginal delivery of known carriers of hemophilia, (2) all infants with ICH be evaluated for a bleeding disorder, (3) women with postpartum hemorrhage should have a bleeding workup, (4) a national registry be created, and (5) national guidelines be developed, which should improve care for pregnant women with bleeding disorders.^5,6

Clinical

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 new window

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

• 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

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 a specific defect.
• Many mutations in the FIX gene cause hemophilia B. The mutations provide an understanding of structure-activity relationships. The following, less common 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.
• 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 recent study of 8 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.⁷
• 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.
• FIX gene knockout mice develop normally during pregnancy but may have spontaneous hemorrhages in some tissues. Clipping the tail vein after birth leads to fatal hemorrhage.
• 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.

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