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Factor IX Deficiency Treatment & Management

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
 
Updated: Jun 17, 2016
 

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[14] ; in children <15 y, according to Roth et al[15] ).

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).

Worldwide, only 25 patients with allergic reactions have been reported to the manufacturer of rFIX, with mild-to-moderate skin and respiratory reactions in most of the patients. Of 5 patients with anaphylaxis, some developed an inhibitor, and no fatalities were reported. Three thrombotic events were reported: two were catheter related and the third was a transient ischemic event in a 14-year-old patient who did well when continued on rFIX. Seventeen of 4500 patients had red cell agglutination when blood was withdrawn into the catheter or syringe containing rFIX; this practice must be avoided.

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.[16]

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.[17]

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.[18]

It is important to understand the pharmacokinetics of factor IX.[19] 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.

Gene therapy

Several approaches to gene therapy have been undertaken in treating patients with hemophilia B or A with severe deficiency. Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.

The most successful and least toxic method of introducing the gene remains to be determined. The use of an attenuated adenoviral vector, although associated with high short-term expression in a canine model of hemophilia, led to liver toxicity, thrombocytopenia, and an antibody to the factor due to an immunologic response to the vector. An additional question is the appropriate in vivo–vector dose to be administered; evidence is emerging for the need for a minimum threshold dose. Features of gene therapy research have included the following:

  • Short-term correction resulting from high gene expression in the neonatal period following in utero injection of an adenoviral murine vector has been accomplished with FVIII.
  • Use of a parvovirus, use of transduced endothelial cells, or the possibility of cutaneous gene therapy are being explored in animal models and in humans.
  • Development of antibodies to replaced proteins is a major problem, and the possibility of using CTLA4-Ig to block T-cell function to prevent antibody response has been explored in murine models of hemophilia A.
  • Possible approaches to gene therapy include ex vivo gene therapy, in which the cells to be injected are modified to secrete FIX or FVIII and then are reimplanted into the recipient, and in vivo gene therapy, in which cells modified to secrete the missing factor are packaged in immunoprotected devices and implanted in recipients.

Gene therapy with a variety of vectors has been tested in humans, with the most successful method still to be determined. Gene therapy studies were halted following the death of a patient treated for a metabolic disorder. Reevaluation of the type of vector, dose, route, and toxicity of the different approaches to gene therapy was undertaken. Oligonucleotides possibly can be used in vivo to correct point mutations. Advantages and disadvantages of several approaches to gene therapy in individuals with hemophilia and other patients have been updated in two recent publications.[20, 21]

Gene therapy with viral-based vectors has had efficacy limited by immune responses against the viral components.[22]

Gene therapy remains promising.[7, 23, 22]  Sadly, however, current techniques produce factor levels well short of those achieved by prophylaxis with longer-acting products, and gene therapy is unlikely ever to be an inexpensive treatment option.[24]

In humans, one hemophilia B patient achieved 10% of normal activity after liver-directed gene therapy with a single-stranded adeno-associated virus vector expressing human factor IX, but expression fell at 1 month. Thus, gene therapy may be viewed as successful in a patient with hemophilia B, but expression was unstable, probably due to an immune response. Abrogating immune responses may be the next important hurdle for achieving long-lasting gene therapy.

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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.

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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 [25]
  • Geneticist for genetic testing and counseling for family members
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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.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

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

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Additional Contributors

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, AMDA - The Society for Post-Acute and Long-Term Care Medicine, American Society of Hematology, Infectious Diseases Society of America, Phi Beta Kappa

Disclosure: Nothing to disclose.

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Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
Major components of the factor IX structure.
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.
The hemostatic pathway: role of factor IX.
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.
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.)
Possible genetic outcomes in individuals carrying the hemophilic gene.
Teenage boy with bleeding into right thigh, both knees, and ankles.
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.
Large amount of vascular synovium removed during knee surgery.
Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, would show diffuse deposits. Iron-laden macrophages are present.
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.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by the pseudocyst.
Dissection of a pseudocyst.
Transected pseudocyst with old chocolate brown–black blood.
Large pseudocyst involving left proximal femur.
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.
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.
Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
Quality of life at summer camp.
Table 1. Correlation Between Severity of Bleeding and the Level of Basal FIX Activity
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
Table 2. Rough Guidelines for Treatment Using Factor IX Concentrates
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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