Factor XIII Deficiency Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD more...
FXIII replacement is used to treat bleeding, to prevent perioperative bleeding during elective surgical procedures or, prophylactically, to prevent recurrent bleeding, as in CNS or joint hemorrhages. Serial monitoring of achieved FXIII levels is essential to document the adequacy of any therapy.
Prompt and adequate therapy for acute bleeding is essential along with immobilization of the affected sites and pain relief. Most patients receive FFP or cryoprecipitate to treat bleeding. Information regarding the amount of FXIII present in either of these products usually is not available; therefore, monitoring the adequacy of FXIII levels is essential.
Virus-inactivated FXIII concentrates made from human plasma or placenta are an improvement over traditional products. Human factor XIII concentrate (Corifact) is approved for prophylaxis in congenital FXIII deficiency by the US Food and Drug Administration (FDA). It is marketed under the brand name Fibrogammin P in Europe, South America, South Africa, and Japan. A second FXIII concentrate (Bio Products Laboratory, Elstree, Hertfordshire, UK) is available on a per-patient request.
Factor XIII A-subunit, recombinant (Tretten) was approved by the FDA in December 2013. Approval was based on results from a clinical study that demonstrated the safety and efficacy of rFXIII A-subunit. The phase 3 trial included 41 patients and showed that when compared to an historic control group of individuals who did not receive routine FXIII infusions preventive treatment with monthly 35 IU/kg rFXIII A-subunit injections significantly decreased the number of treatment-requiring bleeding episodes.
The long half-life of FXIII of 6-19 days and the hemostatic efficacy of even small amounts of FXIII of approximately 5% allow replacement therapy to be administered every 4-6 weeks. An FFP dose of 2-3 mL/kg may be effective for up to 4 weeks.[102, 103] The dose of concentrate in adults with deficiency is 35 U/kg every 4 weeks.[104, 105, 106]
A paucity of data exists concerning the pediatric population. Hemostatic evaluation following a head trauma-induced large subcutaneous hematoma associated with recurrent postsurgical bleeding led to a diagnosis of severe FXIII deficiency in a 22-month-old boy. Following initial therapy, subsequent replacement with an FXIII concentrate dose of 50 U/kg every 5 weeks was sufficient to prevent rebleeding and allow healing. Serial monitoring of actual levels achieved is important in children to determine adequacy of any therapy.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure, ice, and use of antifibrinolytic drugs. Avoidance of trauma and nonsteroidal anti-inflammatory drugs (NSAIDs) is helpful in reducing bleeding events.
Several reports exist of the use of FXIII in unusual circumstances. Note the following:
Effectiveness of normalizing FXIII levels in the treatment of a cerebrospinal fluid leak, which started 2 weeks after removal of a meningioma, was reported in a Japanese patient. 
The potential use of transglutaminases to mechanically stabilize and allow cultured epithelial autografts to take when used to repair extensive skin wounds supports a possible role of FXIII in the formation of de novo dermoepidermal junctions, thereby facilitating permanent skin replacement. 
Improved stability of surgical wounds has been reported following infusion of FXIII concentrates.
Although a few reports exist concerning the use of FXIII replacement in patients with scleroderma, Henoch-Schönlein purpura, and malignancies, the value of such replacement therapy remains to be established by proper clinical trials. [10, 109, 110, 111]
Patients with acquired inhibitors to FXIII should be treated using well-established principles of therapy. Note the following:
FXIII dose depends on the characteristics of the inhibitor. One patient was treated preoperatively using a 10-fold dose of FXIII concentrate (350 U/kg) followed by a similar postoperative dose resulting in adequate hemostasis after coronary bypass graft surgery. 
In addition to administering an FXIII concentrate whenever available, treat the underlying disorder and, when appropriate, use immunosuppressive agents, including the newer B-cell-directed monoclonal antibodies.
Note that spontaneous disappearance of acquired inhibitors is part of their natural history, and the use of milder less toxic immunomodulators, such as steroids, may suffice.
The proper choice of agent is dictated by clinical circumstances. Simple immediate ancillary measures of ice, pressure, ace wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.
The complexity of required treatment is exemplified by a patient with an INH-induced inhibitor in whom INH was discontinued, cryoprecipitate and FXIII concentrate were administered, the patient underwent plasma exchanges and treatment with an immunoadsorption column to reduce the inhibitor's titer, and immunosuppressives were administered before hemostatic success was achieved. [89, 87, 91]
To date, prophylactic factor replacement has been undertaken mainly in patients with intracranial bleeding or recurrent miscarriages caused by severe FXIII deficiency. Successful prevention of recurrent joint bleeds also has been accomplished using periodic transfusions of FFP and cryoprecipitate. FFP can be administered in a dose of 2-3 mL/kg every 4 weeks.
A literature review of bleeding risks and reproduction among patients with severe FXIII deficiency suggests that patients with clinically significant bleeding should start receiving factor replacement therapy in childhood to reduce early mortality from hemorrhages and to allow patients to reach adulthood. During pregnancy, monthly replacement was found to be effective in preventing miscarriages. However, both short-term benefits and potential long-term adverse consequences of prophylactic use of these products must be discussed, with full patient participation in all decision making.
Advances in the types of available products improve care. Addition of Tween 20 makes a reduction of the generation of soluble and insoluble aggregates of rFXIII possible when rFXIII is subjected to freezing and thawing or agitation. Another advance in the technology relates to solving problems faced during freeze-drying and storing the dry solid. Improvement in storage stability of therapeutic proteins has obvious advantages for both storage and transport.
Pooled plasma treated with solvent-detergent (PLAS+SD) is available to treat any condition in which FFP typically is used and for which no factor concentrate is available. Viral inactivation using the solvent-detergent (SD) process has been used in preparation of coagulation factor concentrates in the past. In vitro treatment of donor plasma with 1% of the solvent tri(n- butyl) phosphate (TNBP) and 1% of the detergent Triton X-100 leads to significant inactivation of a broad spectrum of lipid-enveloped viruses. Note the following:
Studies of viral inactivation using the SD process show significant inactivation of the human pathogenic viruses hepatitis B and C and HIV. Other lipid-enveloped viruses (eg, Sindbis virus, bovine viral diarrhea virus) also have been used to monitor inactivation.
PLAS+SD is ABO blood type specific, and SD-treated plasma should be ABO compatible with the recipient's red cells.
The frozen product is supplied in 200-mL bags. Each 200-mL bag has been demonstrated to raise factor levels by approximately 2-3%, with 4-6 bags raising the factor level of a 70-kg person by approximately 8-18%.
Monitoring of specific factor levels before and after product infusion is important to ensure that hemostatically adequate levels are achieved and maintained to provide adequate hemostasis.
Antifibrinolytic agents are not used commonly to treat patients with FXIII deficiency but may be used as ancillary therapy. Note the following:
The hemostatic plug formed in the presence of adequate levels of FXIII at the time of surgical trauma (as with dental procedures or with mucosal bleeding) can be preserved by inhibiting fibrinolysis with ε-aminocaproic acid (EACA; Amicar) or trans- p- aminomethyl-cyclohexane carboxylic acid (AMCA; also termed tranexamic acid; Cyklokapron) administered orally or, if needed, intravenously. EACA has been administered in a dose of 5 g orally or intravenously slowly prior to the surgical procedure, along with a dose of the appropriate FXIII replacement. This is followed by a maintenance dose of 1 g/h postoperatively until it is appropriate to start tapering the dose over the next several days.
AMCA is administered in a dose of 1.5 g intravenously every 6-8 hours and tapered, as needed; however, it is not available in the United States.
Antifibrinolytic agents also can be used as a mouthwash for oral bleeding and have been used to stop local intracavitary oozing.
Antifibrinolytic agents are contraindicated in patients with hematuria because of the possible risk of development of a firm occluding clot in the ureters when administered simultaneously with factor replacement. The drugs are not useful in the treatment of joint bleeding (see Factor VIII for more information).
In recent years, the use of NSAIDs to relieve pain has increased in patients with bleeding disorders. Although they provide relief from inflammatory pain, patients experience increased GI tract or other bleeding because of the impact of the drugs on primary hemostasis, and they require additional FXIII replacement to control bleeding. The problem is magnified by the availability of over-the-counter NSAID pain relievers. Non-NSAIDs, such as acetaminophen and codeine-type analgesics, are much less effective, and some are addictive.
Routine dental care is of the utmost importance in maintaining dental hygiene.
Other routine care, such as mammography in women older than 50 years or colonoscopy for patients older than 50 years, must be provided as in nonbleeding patients.
All elective procedures require proper perioperative management. Note the following:
Patients with severe FXIII deficiency require FXIII replacement both preoperatively and postoperatively. Levels of as little as 3-5% may be sufficient to provide adequate hemostasis, and a single dose is sufficient to last several weeks unless excessive blood loss occurs. Serial factor levels must be performed to ensure adequacy of FXIII levels.
Procedures such as endoscopies, although considered routine for unaffected individuals, require preprocedural product replacement so that patients do not bleed during or following a needed biopsy. Postbiopsy replacement must continue until the biopsy site has healed.
Dental extractions or mucosal procedures can be handled using a single preprocedure dose of FXIII along with Amicar or AMCA. A standardized approach to dental extractions, as has been proposed for patients with hemophilia, may be used in patients with FXIII deficiency. Continuing antifibrinolytics on an outpatient basis for several days after a dental extraction is routine practice, with gradual tapering of dosage.
Avoidance of NSAIDs and other platelet-inhibiting drugs perioperatively is essential to minimize bleeding risk. Ice packs and pressure are always useful when feasible.
Application of fibrin glue as an ancillary measure is useful in helping control bleeding at surgical sites. Fibrin glue consists of a mixture of fibrinogen, thrombin, and FXIII used to cross-link freshly formed fibrin. Cryoprecipitate also has been used as a source of fibrinogen and FXIII, with the use of bovine thrombin to clot fibrinogen. Some preparations also incorporate antifibrinolytic agents to prevent clot lysis. In particular, fibrin glue has been useful in orthopedic surgery and with surgical procedures in patients with FXIII inhibitors. Bovine thrombin may elicit antibodies.
Bleeding from suture holes is a complication in a variety of invasive vascular procedures (surgery, radiologic procedure, coronary angiography). In an experimental porcine vascular graft model, fibrin sealant containing FXIII effectively reduced blood loss and reduced the time to achieve adequate hemostasis more than fibrin alone or thrombin-coated gelatin sponges. 
A hematologist, orthopedist, physical therapist, dentist, social worker, psychologist, infectious disease specialist, gastroenterologist/hepatologist, geneticist, and an appropriately equipped special laboratory all play important roles in providing optimal care for patients with FXIII deficiency and their families.
The efforts of the National Hemophilia Foundation and its regional chapters must be recognized in helping to educate patients, assist service providers, foster dialog regarding problems and solutions among patients with bleeding disorders, and improve conditions for the entire community through support of legislation.
A healthy and nutritional diet should be encouraged.
Appropriate physical activity and physical therapy must be encouraged to maintain and preserve muscle function.
Shanbhag S, Ghosh K, Shetty S. Genetic basis of severe factor XIII deficiency in a large cohort of Indian patients: Identification of fourteen novel mutations. Blood Cells Mol Dis. 2016 Mar. 57:81-4. [Medline].
Thakker S, McGehee W, Quismorio FP Jr. Arthropathy associated with factor XIII deficiency. Arthritis Rheum. 1986 Jun. 29(6):808-11. [Medline].
McKenna R. Abnormal coagulation in the postoperative period contributing to excessive bleeding. Med Clin North Am. 2001 Sep. 85(5):1277-310, viii. [Medline].
Wilmer M, Rudin K, Kolde H, et al. Evaluation of a sensitive colorimetric FXIII incorporation assay. Effects of FXIII Val34Leu, plasma fibrinogen concentration and congenital FXIII deficiency. Thromb Res. 2001 Apr 1. 102(1):81-91. [Medline].
Laki K, Lóránd L. On the Solubility of Fibrin Clots. Science. 1948 Sep 10. 108(2802):280. [Medline].
Duckert F, Jung E, Sherling DH. An undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh. 1960. 5:179.
Duckert F. Documentation of the plasma factor XIII deficiency in man. Ann N Y Acad Sci. 1972 Dec 8. 202:190-9. [Medline].
Laki K. Our ancient heritage in blood clotting and some of its consequences. Ann N Y Acad Sci. 1972 Dec 8. 202:297-307. [Medline].
Reitsma PH. Genetic principles underlying disorders of procoagulant and anticoagulant proteins. Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 59-87.
Loewy AG, McDonagh J, Mikkola H, et al. Structure and function of F XIII. Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 233-48.
Cushman M, O'Meara ES, Folsom AR, Heckbert SR. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood. 2009 Oct 1. 114(14):2878-83. [Medline]. [Full Text].
Hoppe B, Tolou F, Dörner T, Kiesewetter H, Salama A. Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population. Thromb Haemost. 2006 Oct. 96(4):465-70. [Medline].
Wells PS, Anderson JL, Rodger MA, Carson N, Grimwood RL, Doucette SP. The factor XIII Val34Leu polymorphism: is it protective against idiopathic venous thromboembolism?. Blood Coagul Fibrinolysis. 2006 Oct. 17(7):533-8. [Medline].
Shafey M, Anderson JL, Scarvelis D, Doucette SP, Gagnon F, Wells PS. Factor XIII Val34Leu variant and the risk of myocardial infarction: a meta-analysis. Thromb Haemost. 2007 Apr. 97(4):635-41. [Medline].
Shin JI, Lee JS. Severe gastrointestinal vasculitis in Henoch-Schoenlein purpura: pathophysiologic mechanisms, the diagnostic value of factor XIII, and therapeutic options. Eur J Pediatr. 2007 Nov. 166(11):1199-200; author reply 1201. [Medline].
Shin JI, Lee JS. Could measurement of factor XIII level detect the vasculitic process of Henoch-Schönlein purpura without skin rash?. Acta Paediatr. 2008 Apr. 97(4):395. [Medline].
Kuroda K, Tajima S. Proliferation of HSP47-positive skin fibroblasts in dermatofibroma. J Cutan Pathol. 2008 Jan. 35(1):21-6. [Medline].
Ivaskevicius V, Biswas A, Loreth R, et al. Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency. Haemophilia. 2010 Mar 10. [Medline].
Ichinose A. Factor XIII is a key molecule at the intersection of coagulation and fibrinolysis as well as inflammation and infection control. Int J Hematol. 2012 Apr. 95(4):362-70. [Medline].
Schroeder V, Kohler HP. Factor XIII Deficiency: An Update. Semin Thromb Hemost. 2013 Sep. 39(6):632-41. [Medline].
Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann N Y Acad Sci. 2001. 936:291-311. [Medline].
Siebenlist KR, Meh DA, Mosesson MW. Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains. Biochemistry. 1996 Aug 13. 35(32):10448-53. [Medline].
Greenberg CS, Shuman MA. The zymogen forms of blood coagulation factor XIII bind specifically to fibrinogen. J Biol Chem. 1982 Jun 10. 257(11):6096-101. [Medline].
Mosesson M. Hereditary abnormalities of fibrinogen. Beutler E, Lichtman M, Coller BS, et al, eds. Williams Hematology. New York, NY: McGraw-Hill; 2001. 1659-71.
Jenner L, Husted L, Thirup S, Sottrup-Jensen L, Nyborg J. Crystal structure of the receptor-binding domain of alpha 2-macroglobulin. Structure. 1998 May 15. 6(5):595-604. [Medline].
Nagy B Jr, Simon Z, Bagoly Z, Muszbek L, Kappelmayer J. Binding of plasma factor XIII to thrombin-receptor activated human platelets. Thromb Haemost. 2009 Jul. 102(1):83-9. [Medline].
Monteiro MR, Murphy EE, Galaria NA, Whitaker-Menezes D, Murphy GF. Cytological alterations in dermal dendrocytes in vitro: evidence for transformation to a non-dendritic phenotype. Br J Dermatol. 2000 Jul. 143(1):84-90. [Medline].
Lorand L. Sol Sherry Lecture in Thrombosis : research on clot stabilization provides clues for improving thrombolytic therapies. Arterioscler Thromb Vasc Biol. 2000 Jan. 20(1):2-9. [Medline].
Noguchi K, Ishikawa K, Yokoyama Ki, Ohtsuka T, Nio N, Suzuki E. Crystal structure of red sea bream transglutaminase. J Biol Chem. 2001 Apr 13. 276(15):12055-9. [Medline].
Andersen MD, Kjalke M, Bang S, et al. Coagulation factor XIII variants with altered thrombin activation rates. Biol Chem. 2009 Dec. 390(12):1279-83. [Medline].
Fox BA, Yee VC, Pedersen LC, et al. Identification of the calcium binding site and a novel ytterbium site in blood coagulation factor XIII by x-ray crystallography. J Biol Chem. 1999 Feb 19. 274(8):4917-23. [Medline].
Casadio R, Polverini E, Mariani P, et al. The structural basis for the regulation of tissue transglutaminase by calcium ions. Eur J Biochem. 1999 Jun. 262(3):672-9. [Medline].
Hevessy Z, Haramura G, Boda Z, Udvardy M, Muszbek L. Promotion of the crosslinking of fibrin and alpha 2-antiplasmin by platelets. Thromb Haemost. 1996 Jan. 75(1):161-7. [Medline].
Moaddel M, Falls LA, Farrell DH. The role of gamma A/gamma ' fibrinogen in plasma factor XIII activation. J Biol Chem. 2000 Oct 13. 275(41):32135-40. [Medline].
Weiss MS, Metzner HJ, Hilgenfeld R. Two non-proline cis peptide bonds may be important for factor XIII function. FEBS Lett. 1998 Feb 27. 423(3):291-6. [Medline].
Jámbor C, Reul V, Schnider TW, Degiacomi P, Metzner H, Korte WC. In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood. Anesth Analg. 2009 Oct. 109(4):1023-8. [Medline].
Anwar R, Gallivan L, Edmonds SD, Markham AF. Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood. 1999 Feb 1. 93(3):897-905. [Medline].
Kangsadalampai S, Board PG. The Val34Leu polymorphism in the A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood. 1998 Oct 15. 92(8):2766-70. [Medline].
Saha N, Aston CE, Low PS, Kamboh MI. Racial and genetic determinants of plasma factor XIII activity. Genet Epidemiol. 2000 Dec. 19(4):440-55. [Medline].
van Wersch JW, Vooijs ME, Ubachs JM. Coagulation factor XIII in pregnant smokers and non-smokers. Int J Clin Lab Res. 1997. 27(1):68-71. [Medline].
Asahina T, Kobayashi T, Okada Y, et al. Studies on the role of adhesive proteins in maintaining pregnancy. Horm Res. 1998. 50 Suppl 2:37-45. [Medline].
Asahina T, Kobayashi T, Okada Y, Goto J, Terao T. Maternal blood coagulation factor XIII is associated with the development of cytotrophoblastic shell. Placenta. 2000 May. 21(4):388-93. [Medline].
Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol. 1999 Dec. 107(3):468-84. [Medline].
Cario E, Goebell H, Dignass AU. Factor XIII modulates intestinal epithelial wound healing in vitro. Scand J Gastroenterol. 1999 May. 34(5):485-90. [Medline].
Naito M, Nomura H, Iguchi A, Thompson WD, Smith EB. Effect of crosslinking by factor XIIIa on the migration of vascular smooth muscle cells into fibrin gels. Thromb Res. 1998 May 1. 90(3):111-6. [Medline].
Wozniak G, Noll T, Brunner U, Hehrlein FW. Topical treatment of venous ulcer with fibrin stabilizing factor: experimental investigation of effects on vascular permeability. Vasa. 1999 Aug. 28(3):160-3. [Medline].
Catani MV, Bernassola F, Rossi A, Melino G. Inhibition of clotting factor XIII activity by nitric oxide. Biochem Biophys Res Commun. 1998 Aug 10. 249(1):275-8. [Medline].
Bernassola F, Rossi A, Melino G. Regulation of transglutaminases by nitric oxide. Ann N Y Acad Sci. 1999. 887:83-91. [Medline].
Huang QQ, Teng MK, Niu LW. Purification and characterization of two fibrinogen-clotting enzymes from five-pace snake (Agkistrodon acutus) venom. Toxicon. 1999 Jul. 37(7):999-1013. [Medline].
Arocha-Pinango CL, Marval E, Guerrero B. Lonomia genus caterpillar toxins: biochemical aspects. Biochimie. 2000 Sep-Oct. 82(9-10):937-42. [Medline].
Zavalova L, Lukyanov S, Baskova I, et al. Genes from the medicinal leech (Hirudo medicinalis) coding for unusual enzymes that specifically cleave endo-epsilon (gamma-Glu)-Lys isopeptide bonds and help to dissolve blood clots. Mol Gen Genet. 1996 Nov 27. 253(1-2):20-5. [Medline].
Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation. 2001 May 8. 103(18):2248-53. [Medline].
Finney S, Seale L, Sawyer RT, Wallis RB. Tridegin, a new peptidic inhibitor of factor XIIIa, from the blood- sucking leech Haementeria ghilianii. Biochem J. 1997 Jun 15. 324 ( Pt 3):797-805. [Medline].
Lee SY, Chang SK, Lee IH, Kim YM, Chung SI. Depletion of plasma factor XIII prevents disseminated intravascular coagulation-induced organ damage. Thromb Haemost. 2001 Mar. 85(3):464-9. [Medline].
Sidelmann JJ, Gram J, Jespersen J, Kluft C. Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost. 2000. 26(6):605-18. [Medline].
Takahashi H, Isobe T, Horibe S, et al. Tissue transglutaminase, coagulation factor XIII, and the pro-polypeptide of von Willebrand factor are all ligands for the integrins alpha 9beta 1 and alpha 4beta 1. J Biol Chem. 2000 Aug 4. 275(31):23589-95. [Medline].
Salge U, Daubner E, Heiden M, Sietz R. Factor XIII does not stimulate growth of human cultured tumor cells. Blood Coagul Fibrinolysis. 2000 Mar. 11(2):217-8. [Medline].
Molnar P, Nemes Z. Hemangiopericytoma of the cerebello-pontine angle. Diagnostic pitfalls and the diagnostic value of the subunit A of factor XIII as a tumor marker. Clin Neuropathol. 1995 Jan-Feb. 14(1):19-24. [Medline].
Adany R, Bardos H, Antal M, et al. Factor XIII of blood coagulation as a nuclear crosslinking enzyme. Thromb Haemost. 2001 May. 85(5):845-51. [Medline].
Kallberg Y, Gustafsson M, Persson B, Thyberg J, Johansson J. Prediction of amyloid fibril-forming proteins. J Biol Chem. 2001 Apr 20. 276(16):12945-50. [Medline].
Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1995 Jun 16. 270(24):14477-84. [Medline].
Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. 1995 Nov. 96(5):2534-8. [Medline].
Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. 1996 Sep 15. 88(6):2093-100. [Medline].
Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001 Jun. 85(6):958-65. [Medline].
HGMD. Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. Available at: http://www.uwcm.ac.uk//uwcm/mg/hgmd0.html. Accessed April 9, 2002. [Full Text].
Attié-Castro FA, Zago MA, Lavinha J, et al. Ethnic heterogeneity of the factor XIII Val34Leu polymorphism. Thromb Haemost. 2000 Oct. 84(4):601-3. [Medline].
Sharief LA, Kadir RA. Congenital factor XIII deficiency in women: a systematic review of literature. Haemophilia. 2013 Aug 28. [Medline].
Mikkola H, Muszbek L, Laiho E, et al. Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA. Blood. 1997 Feb 15. 89(4):1279-87. [Medline].
Greenberg DL, Davie EW. Blood coagulation factors: their complementary DNAs, genes, and expression. Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 21-57.
Kangsadalampai S, Yenchitsomanus P, Chelvanayagam G, Sawasdee N, Laosombat V, Board P. Identification of a new mutation (Gly420Ser), distal to the active site, that leads to factor XIII deficiency. Eur J Haematol. 2000 Oct. 65(4):279-84. [Medline].
Koseki S, Souri M, Koga S, et al. Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation. Blood. 2001 May 1. 97(9):2667-72. [Medline].
Gomez Garcia EB, Poort SR, Stibbe J. Two novel and one recurrent missense mutation in the factor XIII A gene in two Dutch patients with factor XIII deficiency. Br J Haematol. 2001 Feb. 112(2):513-8. [Medline].
Anwar R, Gallivan L, Trinh C, Hill F, Markham A. Identification of a new Leu354Pro mutation responsible for factor XIII deficiency. Eur J Haematol. 2001 Feb. 66(2):133-6. [Medline].
Warner D, Mansfield MW, Grant PJ. Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography. Thromb Haemost. 2001 Mar. 85(3):408-11. [Medline].
Canavy I, Henry M, Morange PE, et al. Genetic polymorphisms and coronary artery disease in the south of France. Thromb Haemost. 2000 Feb. 83(2):212-6. [Medline].
Franco RF, Middeldorp S, Meinardi JR, van Pampus EC, Reitsma PH. Factor XIII Val34Leu and the risk of venous thromboembolism in factor V Leiden carriers. Br J Haematol. 2000 Oct. 111(1):118-21. [Medline].
Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood. 1999 Feb 1. 93(3):906-8. [Medline].
Kohler HP. Role of blood coagulation factor XIII in vascular diseases. Swiss Med Wkly. 2001 Jan 27. 131(3-4):31-4. [Medline].
Prata MJ, Miranda C, Rocha J, Amorim A. Allelic affinities between the F13A common gene products inferred by the analysis of an (AAAG)n STR polymorphism within the 5' untranslated region. Hum Hered. 2000 May-Jun. 50(3):189-93. [Medline].
Hedner U, Ginsburg D, Lusher JM, High KA. Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. Hematology Am Soc Hematol Educ Program. 2000. 241-265. [Medline].
Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Williston Park). 2001 Sep. 15(9):1197-204, 1207; discussion 1207-8. [Medline].
Chandler WL, Patel MA, Gravelle L, et al. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinolysis. 2001 Mar. 12(2):101-8. [Medline].
Holst FG, Hemmer CJ, Foth C, Seitz R, Egbring R, Dietrich M. Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity. Am J Trop Med Hyg. 1999 Jan. 60(1):99-104. [Medline].
Matayoshi T, Omi T, Sakai N, Kawana S. Clinical Significance of Blood Coagulation Factor XIII Activity in Adult Henoch-Schönlein Purpura. J Nippon Med Sch. 2013. 80(4):268-78. [Medline].
Lorand L, Velasco PT, Murthy SN, Lefebvre P, Green D. Autoimmune antibody in a hemorrhagic patient interacts with thrombin-activated factor XIII in a unique manner. Blood. 1999 Feb 1. 93(3):909-17. [Medline].
Feinstein DI. Immune coagulation disorders. Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 1003-20.
Ahmad F, Solymoss S, Poon MC, Berube C, Sullivan AK. Characterization of an acquired IgG inhibitor of coagulation factor XIII in a patient with systemic lupus erythematosus. Br J Haematol. 1996 Jun. 93(3):700-3. [Medline].
Tosetto A, Rodeghiero F, Gatto E, Manotti C, Poli T. An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide. Am J Hematol. 1995 Jan. 48(1):34-9. [Medline].
Krumdieck R, Shaw DR, Huang ST, Poon MC, Rustagi PK. Hemorrhagic disorder due to an isoniazid-associated acquired factor XIII inhibitor in a patient with Waldenstrom's macroglobulinemia. Am J Med. 1991 May. 90(5):639-45. [Medline].
Heinle K, Adam O, Rauh G. Factor XIII insufficiency in a patient with severe psoriasis vulgaris, arthritis, and infirmity. Clin Rheumatol. 1998. 17(4):346-8. [Medline].
Lorand L. Acquired inhibitors of fibrin stabilization: a class of hemorrhagic disorders of diverse origins. Anticoagulants: Physiologic, Pathologic and Pharmacologic. CRC Press; 1994. 169-91.
Dorgalaleh A, Kazemi A, Zaker F, Shamsizadeh M, Rashidpanah J, Mollaei M. Laboratory Diagnosis of Factor XIII Deficiency, Routine Coagulation Tests with Quantitative and Qualitative Methods. Clin Lab. 2016. 62 (4):491-8. [Medline].
Glidden PF, Malaska C, Herring SW. Thromboelastograph assay for measuring the mechanical strength of fibrin sealant clots. Clin Appl Thromb Hemost. 2000 Oct. 6(4):226-33. [Medline].
Karpati L, Penke B, Katona E, Balogh I, Vamosi G, Muszbek L. A modified, optimized kinetic photometric assay for the determination of blood coagulation factor XIII activity in plasma. Clin Chem. 2000 Dec. 46(12):1946-55. [Medline].
Katona E, Haramura G, Karpati L, Fachet J, Muszbek L. A simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2). Thromb Haemost. 2000 Feb. 83(2):268-73. [Medline].
Orosz ZZ, Katona E, Facsko A, Berta A, Muszbek L. A highly sensitive chemiluminescence immunoassay for the measurement of coagulation factor XIII subunits and their complex in tears. J Immunol Methods. 2010 Feb 28. 353(1-2):87-92. [Medline].
Brooks M. FDA Clears Tretten for Coagulation Factor XIII Deficiency. Available at http://www.medscape.com/viewarticle/818264. Accessed: January 6, 2014.
Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood. 2012 May 31. 119(22):5111-7. [Medline].
Gootenberg JE. Factor concentrates for the treatment of factor XIII deficiency. Curr Opin Hematol. 1998 Nov. 5(6):372-5. [Medline].
Green D. Spontaneous inhibitors to coagulation factors. Clin Lab Haematol. 2000 Oct. 22 Suppl 1:21-5; discussion 30-2. [Medline].
Lorand L, Losowsky MS, Miloszewski KJM. Human factor XIII: fibrin stabilizing factor. Spaet T, ed. Progress in Hemostasis and Thrombosis. New York, NY: Grune & Stratton; 1980. Vol 5: 245-90.
Abbondanzo SL, Gootenberg JE, Lofts RS, McPherson RA. Intracranial hemorrhage in congenital deficiency of factor XIII. Am J Pediatr Hematol Oncol. 1988 Spring. 10(1):65-8. [Medline].
Green D, Sanders J, Wong C, et al. Coronary revascularization in the presence of an inhibitory antibody to factor XIII. Bull Intensive Crit Care. 1996. 3(3):14-6.
Wiel E, Marciniak B, Wibaut B. [Recurrent hematomas and normal standard hemostasis tests]. Ann Fr Anesth Reanim. 1998. 17(1):61-4. [Medline].
Kawamura A, Tamaki N, Yonezawa K, Nakamura M, Asada M. [Effect of factor XIII on intractable CSF leakage after a transpetrosal-approach operation: a case report]. No Shinkei Geka. 1997 Jan. 25(1):53-6. [Medline].
Chamouard P, Grunebaum L, Wiesel ML, et al. Significance of diminished factor XIII in Crohn's disease. Am J Gastroenterol. 1998 Apr. 93(4):610-4. [Medline].
Linskens RK, van Bodegraven AA, Schoorl M, Tuynman HA, Bartels P. Predictive value of inflammatory and coagulation parameters in the course of severe ulcerative colitis. Dig Dis Sci. 2001 Mar. 46(3):644-8. [Medline].
Helio T, Wartiovaara U, Halme L, et al. Arg506Gln factor V mutation and Val34Leu factor XIII polymorphism in Finnish patients with inflammatory bowel disease. Scand J Gastroenterol. 1999 Feb. 34(2):170-4. [Medline].
Burrows RF, Ray JG, Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstet Gynecol Surv. 2000 Feb. 55(2):103-8. [Medline].
Kreilgaard L, Jones LS, Randolph TW, et al. Effect of Tween 20 on freeze-thawing- and agitation-induced aggregation of recombinant human factor XIII. J Pharm Sci. 1998 Dec. 87(12):1597-603. [Medline].
Kreilgaard L, Frokjaer S, Flink JM, Randolph TW, Carpenter JF. Effects of additives on the stability of recombinant human factor XIII during freeze-drying and storage in the dried solid. Arch Biochem Biophys. 1998 Dec 1. 360(1):121-34. [Medline].
Dickneite G, Metzner H, Nicolay U. Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII. J Surg Res. 2000 Oct. 93(2):201-5. [Medline].
Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood. 2012 May 31. 119(22):5111-7. [Medline].
ARC. FDA-approved product circular for Pooled Plasma, Solvent-Detergent-Treated (PLAS+SD) manufactured by the American Red Cross and V.I. Technologies, Inc. 2000.
ARC. PLAS+SD (pooled plasma, solvent-detergent treated). Monograph by the American Red Cross and V. I. Technologies, Inc. 1999. VIT-001A9/99:
MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Paper presented at: 53rd Annual Meeting of the National Hemophilia Foundation. November 16, 2001: Nashville, Tennessee.
Rigas B, Hasan I, Rehman R, Donahue P, Wittkowski KM, Lebovics E. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. 2001 Dec 8. 358(9297):1961-2. [Medline].
Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. 2001 Oct 15. 98(8):2571-3. [Medline].
Bachmann F. Plasminogen-plasmin enzyme system. Colman RW, Hirsh J, George JN, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Lippincott Williams & Wilkins; 2001. 275-320.
Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29. 358(22):2319-31. [Medline].
Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. 2001 Dec 8. 358(9297):1925-6. [Medline].
Treisman GJ, Angelino AF, Hutton HE. Psychiatric issues in the management of patients with HIV infection. JAMA. 2001 Dec 12. 286(22):2857-64. [Medline].
Urwin PJ, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang. 2016 May. 110 (4):310-6. [Medline].
Jackson GS, Burk-Rafel J, Edgeworth JA, Sicilia A, Abdilahi S, Korteweg J, et al. Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study. JAMA Neurol. 2014 Apr. 71 (4):421-8. [Medline].
|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|