eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor IX: Follow-up

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

Follow-up

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.

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 (see Images 25-27).
• 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.¹⁶

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.

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.

Deterrence/Prevention

• Routine immunizations with hepatitis A and B vaccines and other routine care, as for influenza and pneumonia, should be provided.

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 (see Images 8-24).
• Chronic severe joint deformities and arthritis occur. Excess bleeding is related to the use of NSAIDs.
• Risk of bleeding while taking protease inhibitors is higher in individuals with hemophilia who are positive for HIV.
• Risk of bleeding is higher in patients using St. John's Wort (over-the-counter herbal medicine).
• 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 PCCs or rFVIIa.
• 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. TTV and Parvovirus B 19 also can be transmitted by transfusions. Recently, TTV contamination of first-generation rFIX concentrate was reported¹⁷ ; 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. The difficulty of treating HCV infection has been addressed in a recent review.¹⁸
• Parvovirus B 19 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.¹⁹
• 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, especially in patients with inhibitors undergoing long-term factor replacement for ITI to occur.
• Anemia, leukopenia, or thrombocytopenia may occur. Gene therapy may be associated with an increased incidence of inhibitors.
• Potential transmission of prions causing Creutzfeldt-Jacob disease (CJD) or nvCJD is being monitored closely. Currently, no individual with hemophilia nor any other blood product recipient is known to have developed CJD.^20,19 A recent review suggests a serious concern for the possible transmission of CJD or its variant form (vCJD) in recipients of blood products. The US Food and Drug Administration's Transmissible Spongiform Encephalopathies Advisory Committee has proposed to limit the pool of potential donors and to exclude those who have resided in Europe for more than 5 years starting in 1980 or those who have lived in the United Kingdom for a total of more than 3 months. The availability in the near future of a test for vCJD should help screen blood supplies.²⁰
• Psychosocial impact, including addiction to narcotic analgesics and abuse of alcohol and other substances, 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 who are symptomatic for 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. Today, 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.
• Gene therapy to correct defects can be used when the best method of vector transfer has been determined or in clinical trials.

Patient Education

• Registration with the National Hemophilia Foundation, educational seminars, and one-on-one discussions with patient and family members are essential.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Hemophilia and Blood in the Urine.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis of the type of hemophilia
• Missing diagnosis of HIV, hepatitis, and inhibitors
• Death resulting from anaphylaxis during repeated antigen (clotting factor concentrates) exposure, particularly in children who are severely deficient and just beginning therapy

Special Concerns

• Prenatal testing: Hemophilia carriers can choose to undergo prenatal testing. Carriers whose children with hemophilia, siblings, or other family members had complications of therapy choose prenatal testing more often than carriers who have not witnessed such complications. A woman with a child who has hemophilia has fewer children than a woman who has undergone prenatal testing.
• Pregnancy, labor, and delivery: Management of the pregnancy is based on the level of FIX and bleeding.
• Pediatric patients: Severe allergic reaction following initial exposure to product requires prompt IV hydration, diphenhydramine, epinephrine, and corticosteroids. Patients may require desensitization; thus, initiating treatment in a hospital setting is preferable.
• Dogs: FIX deficiency occurs in dogs. Gene knockout animal models are highly informative about structure-activity relationships.
  • Several canine breeds (eg, Airedale terrier, beagle, bichon frise, chow, Doberman pinscher, German shepherd, German wirehaired pointer, golden retriever, Jack Russell terrier, Labrador retriever, Maltese, pit bull terrier, rottweiler, Saint Bernard, Scottish terrier, Sealyham terrier, shih tzu, weimaraner, wirehaired fox terrier) and unrelated mixed-breeds have been identified with familial or sporadic mild, moderate, or severe hemophilia B.
  • The incidence of hemophilia A in dogs is 3-4 times that of hemophilia B, similar to the ratio found in humans. The molecular defect within each family generally represents an independent mutation. More than a single molecular defect is the cause of hemophilia B in any single breed.
• Potential exists for future use of FIX-related products as antithrombotic agents.
  • Recent data indicate that there is a more rapid activation of FIX to FIXa by the FVII-TF complex of the extrinsic pathway than by FXIa of the intrinsic pathway, indicating the importance of FIX in in vivo thrombin generation. It is thought that with the presence of trace amounts of FVIIa in the circulation and the limited availability of TF normally, FIX is activated preferentially over FX. Later, a burst of thrombin generation results from the participation of the intrinsic pathway. The possible efficacy of a monoclonal murine antibody to FIX and FIXa as an antithrombotic agent is yet to be proven in humans.²¹
  • Inactivation of FIX or FIXa appears to have antithrombotic effects, with a reduced hemorrhagic risk when compared with standard anticoagulants.
  • Another approach has been the use of active site-blocked activated factor IX (FIXai), which inhibits TF initiated coagulation in a cell-based model, with inhibition of fibrin formation without much effect on preventing a platelet thrombus.²²
  • Active site-blocked activated factor X (FXai) has been used successfully for cardiopulmonary bypass without heparin in dogs.²³ It has been used to prevent thrombosis during synthetic vascular patch-repair procedures with reduced blood loss. FIXai is as capable as FXai of inhibiting thrombosis in an arteriovenous shunt model and blocks coronary thrombosis in a canine model but is less effective than FXai at inhibiting venous thrombi. Thus, both the monoclonal antibodies to FIX and FIXai appear to be useful in preventing arterial thrombosis.
  • Further evaluation of these agents is ongoing, but future use will depend on their efficacy and safety profile when compared with other thrombin inhibitors and other antithrombotic agents in development.

• Search for CME/CE on This Topic »

• Hemophilia A and B (Pediatrics: General Medicine)
• Hemophilia, Type B (Emergency Medicine)
• Alpha2-Plasmin Inhibitor Deficiency (Hematology)
• Hemophilia, Musculoskeletal Complications (Radiology)

• Hemophilia Overview
• Blood and Lymphatic System Center
• Hemophilia Treatment
• Hemophilia Causes
• Hemophilia Symptoms
• Kidneys and Urinary System Center
• Blood in Urine Overview

• Pelvic Surgery in A Child With Hemophilia C: A Rare Disease, A Real Challenge, A Simple Solution
• Management of Spontaneous and Iatrogenic Retroperitoneal Haemorrhage: Conservative Management, Endovascular Intervention or Open Surgery?
• Chronic Kidney Disease and Venous Thromboembolism: Epidemiology and Mechanisms