What is the role of medications in the treatment of factor XIII (FXIII) deficiency?

Updated: Apr 02, 2018
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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Factor XIII (FXIII) replacement therapy can be accomplished with FXIII concentrate; with fresh frozen plasma (FFP) or solvent/detergent-treated pooled plasma (Octaplas); or with cryoprecipitate. FXIII concentrate, human (Corifact) is commercially available in the United States. In December 2013, a recombinant FXIII A-subunit product (Tretten) was approved for preventing bleeding episodes in patients with congenital FXIII-a subunit deficiency. [71]

Dosing of cryoprecipitate is empiric, since no standardized amount of FXIII exists for cryoprecipitate. Repeat dosing should be guided by the adequacy of a prior dose as determined by FXIII assays.

Traditionally, FFP has been the source of factors for the treatment of coagulation factor deficiencies for which no concentrates are available, as was once the case with FXIII deficiency. An FFP dose of 2-3 mL/kg every 4 weeks has been used for replacement therapy under steady-state conditions. Higher risks of virally transmitted illnesses remain among patients who are recipients of multiple units of FFP. The greater degree of viral safety assured by this treatment has led to the exclusive use of solvent/detergent-treated pooled plasma instead of FFP in some countries (Norway and Belgium).

Solvent/detergent-treated pooled plasma is ABO blood type specific and offers more protection to patients than is found in standard FFP. As a result of treatment with 1% tri(n- butyl)phosphate (or TNBP as the solvent) and 1% Triton X-100 (as the detergent), lipid-enveloped viruses (eg, HIV, hepatitis B and C viruses, Hantavirus, Marburg virus, Ebola virus) are disrupted and killed in significant numbers. The resulting fragments are inactive and cannot replicate or cause disease. Patients with FXIII deficiency have been specifically treated successfully with this product. [118]

Adverse reactions include minor allergic reactions, which respond to antihistamines, and volume overload. Rarely, citrate toxicity, hypothermia, and other metabolic problems arise if large volumes are used rapidly. Noncardiogenic pulmonary edema can occur. Antibody-induced positive results to the direct antiglobulin test and hemolysis also may occur rarely. This product is contraindicated in patients with known IgA deficiency.

Careful screening of blood donors and viral testing of donated blood (HBV surface antigen, antibody to HBV core antigen, HCV, antibody to HIV-1 and HIV-2, HIV p24 antigen, antibodies to human T-cell leukemia virus [HTLV] types I and II, and screening for elevated levels of alanine aminotransferase [ALT]) have improved safety of blood products, but risks remain for a variety of reasons including failure to detect infections during the "window" or incubation period before currently available test results become positive.

Other types of infections in which screening currently is not performed, tests are not available, or the presence of infection is unknown continue to cause concerns. Some of the emerging pathogens previously referred to include HIV-2, HIV type O, hepatitis G, TTV, human herpesvirus 8, the SEN family of viruses, and prions causing Creutzfeldt Jacob disease [CJD] and nvCJD. [119, 120, 121]

Newer emerging technologies, such as those using nucleic acid chemistry, are being used to inactivate viruses, bacteria, and parasites and to attempt to remove prions, thus making blood and blood components safer than they are currently. These newer technologies attempt to preserve clinically useful components of blood while improving its safety. Potentially, these methodologies could be used to improve the safety of a wide variety of products.

Adjunctive role of inhibitors of fibrinolysis: Recognition of the importance of the lysine-binding sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogs such as epsilon aminocaproic acid (EACA) and tranexamic acid (AMCA). These synthetic lysine analogs induce a conformational change in plasminogen when they bind to its lysine-binding site; plasminogen has the shape of a prolate ellipsoid after EACA binds to it. The bound plasminogen-EACA elongates into a long structure in which the interaction between the parts of plasminogen, as they existed, are lost. In vivo, the structures probably prevent plasminogen activation and, in large doses, bind plasmin, thereby preventing it from binding to its substrate fibrin. In the plasminogen-EACA binding sites, the tightest binding is to kringle 1 followed by kringles 4 and 5. The interaction with kringle 2 is weak, and kringle 3 does not interact at all.

A model of the structure of kringle 4 shows that the shallow trough formed by the hydrophobic amino acids is surrounded by positively and negatively charged amino acids at a distance ideal for EACA interaction. For further details regarding these interactions, please see Bachmann, 2001. [122] EACA is the most widely used antifibrinolytic drug in the United States. The minimal dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed well orally, and 50% is excreted in the urine within 24 hours.

Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit fibrinolysis until excess bleeding is controlled. Then, the maintenance dose is tapered gradually until it can be discontinued. Rarely, myopathy and muscle necrosis can develop. Lower doses are adequate when bleeding involves the urinary tract, since drug concentrations are 75- to 100-fold higher in urine than in plasma.

AMCA also is excreted rapidly in the urine, with more than 90% excreted within 24 hours. However, its antifibrinolytic effect lasts longer than EACA. AMCA inhibits fibrinolysis at lower plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, AMCA can be administered less frequently and at lower doses. EACA and AMCA doses must be reduced when renal failure is present.

Aprotinin (Trasylol), a third antifibrinolytic drug obtained from bovine lung, is a nonhuman protein inhibitor of several serine proteases, including plasmin. It is approved by the FDA for use in patients undergoing open heart surgery to reduce operative blood loss. Aprotinin administration also has reduced blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation or in patients undergoing elective resection of a solitary liver metastasis originating from colon cancer. Aprotinin is the most expensive of the 3 drugs discussed here. Aprotinin is now only available via a limited-access protocol. Fergusson et al reported an increased risk for death compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery. [123]

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