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:
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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 thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
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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.
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In the immediate postnatal period, CNS bleeding can develop following labor and delivery, or excessive bleeding may develop after circumcision.
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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.
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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.
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Delayed bleeding, which develops several hours to days after trauma, surgery, or dental extractions, is characteristic of the hemophilias.
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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 following open drainage of right knee bleed many years previously.
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 cartilage and joint space with deformities in the knees. Findings are of advanced hemophilic arthropathy.
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 proliferation caused by repeated bleeding and requiring synovectomy.
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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.
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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.
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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 of the left kidney and ureter by the pseudocyst.
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.
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Neurologic complications arise as a result of intracranial bleeding, bleeding into the spinal canal, and peripheral nerve compression resulting from expanding hematomas.
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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.
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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.
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Patients with mild hemophilia may be diagnosed later in life when abnormal bleeding is precipitated by trauma, surgery, or drugs.
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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.
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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:
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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
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Deep muscle hematomas with pain, tenderness, and limitation of movement; delayed onset of bleeding from sites of trauma and/or surgery
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Blood in the urine
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Blood in the stool
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Changes in neurologic function, headache, and other neurologic deficits
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Jaundice, spider angiomas, hepatomegaly, tenderness, splenomegaly, and signs related to chronic hepatitis/cirrhosis
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Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses including HIV and HCV infection
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Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS
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Anaphylaxis occurring early after the start of FIX infusions in children who are severely deficient
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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.
Over 1000 mutations in the FIX gene may cause hemophilia B. [16] 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. [17]
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.
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Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
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Major components of the factor IX structure.
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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.
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The hemostatic pathway: role of factor IX.
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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.
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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.)
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Possible genetic outcomes in individuals carrying the hemophilic gene.
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Teenage boy with bleeding into right thigh, both knees, and ankles.
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Older adult man with chronic fused extended knee following open drainage of right knee bleed many years previously.
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Severe bilateral hemophilic arthropathy and muscle wasting. Three puncture sites demonstrate attempts to aspirate a recent bleed into the knee joint.
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Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the knees. Findings are of advanced hemophilic arthropathy.
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Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the elbow. Findings are of advanced hemophilic arthropathy.
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Hemophilic knee at surgery with synovial proliferation caused by repeated bleeding and requiring synovectomy.
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Large amount of vascular synovium removed during knee surgery.
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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, would show diffuse deposits. Iron-laden macrophages are present.
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Male patient presenting with a slowly expanding abdominal and flank mass with increasing pain, inability to eat, weight loss, and weakness of the lower extremity.
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Plain radiograph of the pelvis showing a large lytic area.
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Intravenous pyelogram showing extreme displacement of the left kidney and ureter by the pseudocyst.
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Dissection of a pseudocyst.
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Transected pseudocyst with old chocolate brown–black blood.
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Large pseudocyst involving left proximal femur.
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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.
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Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
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Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
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Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
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Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
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Quality of life at summer camp.
Tables
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 |
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. |
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