What are the potential complications of factor IX deficiency (FIX) (hemophilia B)?

Updated: Mar 09, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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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. [37] Transfusion-transmitted virus (TTV) contamination of first-generation rFIX concentrate has been reported [38] ; 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. [39] A sensitive and specific blood test for vCJD has been developed and has entered clinical use; it could be used to screen blood supplies. [40]

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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