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Factor IX Deficiency Follow-up

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

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.[27]

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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.

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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.

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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.

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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.[28] Transfusion-transmitted virus (TTV) contamination of first-generation rFIX concentrate has been reported[29] ; 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.[30] A sensitive and specific blood test for vCJD has been developed and has entered clinical use; it could be used to screen blood supplies.[31]

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.

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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.

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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.

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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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