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Factor XIII Deficiency Medication

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
 
Updated: Jun 17, 2016
 

Medication Summary

For FXIII replacement therapy, 2 intermediate-purity FXIII concentrates are being tested or are commercially available for use. FFP and cryoprecipitate also are used. An FFP dose of 2-3 mL/kg every 4 weeks has been used for replacement therapy under steady-state conditions. 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. 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.[116]

PLAS+SD is ABO blood type specific. 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, HBV, HCV, Hantavirus, Marburg virus, Ebola virus) are disrupted and killed in significant numbers. The resulting fragments are inactive and cannot replicate or cause disease. PLAS+SD has proven efficacy in treating coagulation factor deficiencies when factor concentrate is unavailable. SD-treated plasma offers more protection to patients than is found in standard FFP. Patients with FXIII deficiency have been specifically treated successfully with PLAS+SD. Information regarding PLAS+SD can be found in the manufacturer's product circular.[117]

Traditionally, FFP has been the source of factors for the treatment of coagulation factor deficiencies for which no concentrates are available; FXIII deficiency falls into this category.

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 PLAS+SD instead of FFP in some countries (Norway and Belgium).

PLAS+SD delivers consistent and reproducible levels of coagulation factors. In contrast to the extreme variability in FFP, PLAS+SD contains no leukocytes, and physiologic inhibitor levels are mostly within reference range, with the exception of a moderate reduction in the levels of a2 PI (approximately 0.48 IU/mL) and protein S (approximately 0.52 IU/mL). In addition, coagulation zymogens are not activated, reference range levels of other plasma proteins and immunoglobulins are present, and all lots have anti-HAV antibody levels greater than 0.8 IU/mL, providing passive administration of antibody that may neutralize HAV. PLAS+SD also lacks the largest vWF multimers and has proven efficacy in the treatment of a variety of bleeding disorders.

Disadvantages of PLAS+SD use include minor allergic reactions as observed with other blood products but that respond to antihistamines. PLAS+SD is contraindicated in patients with known IgA deficiency.

FXIII levels and efficacy of PLAS+SD: FXIII levels in 3 representative lots of pooled plasma (starting material prior to SD and other treatments) were 1.18 ± 0.05 U/mL (average ± standard deviation), with levels of 1.23 ± 0.06 U/mL in the final SD-treated, ultrafiltered, and sterile-filtered product.

Four patients with an inherited FXIII deficiency received successful prophylaxis with 1-2 U of PLAS+SD administered every 21-40 days on a total of 39 occasions over 42 months (range in each patient, 2-15 mo). PLAS+SD was proven to be equivalent to FFP in preventing hemorrhages in patients with known FXIII deficiency. A fifth patient with FXIII deficiency was treated successfully for soft tissue hemorrhages on an on-demand basis.[118]

When PLAS+SD was stored at -18°C, FXIII activity was 1.14 ± 0.09 U/mL at the start and 1.33 ± 0.05 U/mL after 18 months of storage. Currently, based on additional data submitted, PLAS+SD has a US Food and Drug Administration (FDA)-approved 2-year shelf life according to F. Darr, MD, of the American Red Cross (Fred Darr, MD, e-mail, February 2002). Therefore, evidence exists that FXIII activity remains stable during long-term storage.

All PLAS+SD units that are administered should be ABO compatible with each patient's red cells. Adverse reactions include minor allergic reactions 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.[118]

See the drug tables below for further details on the use of PLAS+SD instead of FFP.

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 EACA and 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]

A novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency was evaluated as safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency.[116]

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Clotting factors

Class Summary

FXIII is the terminal enzyme in the blood coagulation cascade; when activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot. FXIII is a proenzyme that is activated, in the presence of calcium ion, by thrombin cleavage of the A-subunit to become activated FXIII (FXIIIa). It promotes cross-linking of fibrin during coagulation and is essential to the physiological protection of the clot against fibrinolysis.

Factor XIII A-subunit, recombinant (Tretten)

 

FXIII A-subunit recombinant is a human factor XIII-A2 homodimer composed of 2 FXIII A-subunits. It is indicated for routine prevention of bleeding in patients with congenital Factor XIII A-subunit deficiency.

Factor XIII concentrate, human (Corifact)

 

Temporarily replaces missing clotting factor XIII which corrects and/or prevents bleeding. It is indicated for routine prophylactic treatment of congenital factor XIII (FXIII) deficiency.

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Blood Products

Class Summary

Use antifibrinolytic agents with fresh frozen plasma (FFP) replacement for minor surgical procedures (eg, dental extractions or sinus surgery) so that the surgery can be accomplished on an outpatient basis with the use of a single dose of product.

Concern remains regarding the possible relationship to acute thrombotic events, although a causal relationship is being questioned because the underlying disease state determines the site and extent of thrombosis.

Fresh frozen plasma (FFP, Octaplas)

 

Plasma is the fluid compartment of blood containing the soluble clotting factors. Octaplas is a solvent detergent treated, pooled FFP.

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Antifibrinolytic agents

Class Summary

These agents are used as an ancillary measure and to diminish bleeding.

Aminocaproic acid (Amicar)

 

EACA diminishes bleeding by inhibiting lysis of hemostatic plugs. Can be used PO or IV.

Tranexamic acid injection (Cyklokapron)

 

Diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. A PO form is also available.

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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)

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.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Investigation, Association of American Physicians, American Society for Biochemistry and Molecular Biology, American Heart Association, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Acknowledgements

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, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

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Coagulation reactions leading to thrombin generation and activation of factor XIII.
Final steps in clot formation (from article: Factor XIII).
Activation of factor XIII and generation of insoluble cross-linked fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.
Postulated interaction between factor XIII and thrombin-activatable fibrinolytic inhibitor.
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 (from article: Factor XIII). Adapted from Hoffman and Monroe. Thromb Haemost. 2001;85(6):958-65.
Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Table. Some Features of the A and B Chains of Factor XIII
Properties A Chain B Chain
Plasma FXIII Has 2 A chains Has 2 B chains
Plasma level Approximately 15 mg/mL Approximately 21 mg/mL
Chains are free in plasma No. All bound to B chain and present as an A2 B2 tetramer Yes. Excess B chain present in plasma as a B2 dimer
Chain contains the catalytic site Yes No
Chain is the carrier protein No Yes
Chain acts as a brake on FXIII activation No Yes
Cellular FXIII Has 2 A chains (A2 dimer) Has no B chains
Mutations can lead to decreased FXIII activity Yes Yes
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