Clinical Use of Factor XIII Concentrates

 

 Buy Article Permissions and Reprints

Abstract

Factor (F) XIII deficiency is a congenital rare bleeding disorder (RBD), with an estimated prevalence of 1 in 1 to 2 million individuals, and more than 1,200 patients have been diagnosed to date. In newborns, umbilical cord bleeding is typical, and later in life during trauma, surgery and even spontaneously prolonged bleeds, reproduction, and delivery complications occur frequently without appropriate replacement therapy. Also, an acquired form of FXIII deficiency may occur via massive bleeds or neutralizing antibodies. In the inherited form of FXIII deficiency, prophylaxis with FXIII concentrate is administered to prevent the very high risk of intracranial bleeds, the incidence being close to 30%. Laboratory diagnosis of FXIII deficiency is based on measuring plasma FXIII antigen and activity, and it is claimed that FXIII activity of around 5 IU/dL would suffice to protect from bleeds. However, at the low levels of detection, most FXIII methods are inaccurate, and quality controls and collaboration with reference laboratories are important to improve the accuracy of low-level FXIII measurements. The trough target for prophylaxis should be set to 10 to 20 IU/dL, which is achievable by administration of 25 to 35 IU/kg every 4 to 6 weeks. However, general risk factors influencing hemostasis should be carefully evaluated, including anemia and hypertension. Fibrin cross-linking by FXIII is of major importance and red cells bind to fibrin partially via platelets and FXIII to promote clot strength. Physiologically, platelets and macrophages contain FXIII providing cellular support; thus, the patients may benefit from platelet transfusion during problematic bleeds. Plasma-derived and recently a recombinant FXIII concentrate are available; however, the latter has mainly anecdotal data regarding management of bleeds and surgery, and its access is limited due to the high cost. The international registry RBD database, (RBDD) continues to gain cumulative knowledge, and registration of all FXIII deficient patients, both inherited and acquired, is highly recommended.

• References

• 1 Bolton-Maggs PH, Perry DJ, Chalmers EA , et al. The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia 2004; 10 (5) 593-628
  CrossrefPubMedGoogle Scholar
• 2 Di Paola J, Nugent D, Young G. Current therapy for rare factor deficiencies. Haemophilia 2001; 7 (Suppl. 01) 16-22
  PubMedGoogle Scholar
• 3 Peyvandi F, Palla R, Menegatti M , et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (4) 615-621
  CrossrefPubMedGoogle Scholar
• 4 Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII deficiency. Semin Thromb Hemost 2009; 35 (4) 426-438
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Kurniawan NA, Grimbergen J, Koopman J, Koenderink GH. Factor XIII stiffens fibrin clots by causing fiber compaction. J Thromb Haemost 2014; 12 (10) 1687-1696
  CrossrefPubMedGoogle Scholar
• 6 Naderi M, Dorgalaleh A, Alizadeh S , et al. Polymorphism of thrombin-activatable fibrinolysis inhibitor and risk of intracranial haemorrhage in factor XIII deficiency. Haemophilia 2014; 20 (1) e89-e92
  CrossrefPubMedGoogle Scholar
• 7 Schroeder V, Kohler HP. Factor XIII deficiency: an update. Semin Thromb Hemost 2013; 39 (6) 632-641
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Peyvandi F, Di Michele D, Bolton-Maggs PH, Lee CA, Tripodi A, Srivastava A ; Project on Consensus Definitions in Rare Bleeding Disorders of the Factor VIII/Factor IX Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost 2012; 10 (9) 1938-1943
  CrossrefPubMedGoogle Scholar
• 9 Egbring R, Kröniger A, Seitz R. Factor XIII deficiency: pathogenic mechanisms and clinical significance. Semin Thromb Hemost 1996; 22 (5) 419-425
  Article in Thieme ConnectPubMedGoogle Scholar
• 10 van Dijk K, Fischer K, van der Bom JG, Grobbee DE, van den Berg HM. Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed. Haemophilia 2005; 11 (5) 438-443
  CrossrefPubMedGoogle Scholar
• 11 Sharief LA, Kadir RA. Congenital factor XIII deficiency in women: a systematic review of literature. Haemophilia 2013; 19 (6) e349-e357
  CrossrefPubMedGoogle Scholar
• 12 Ahonen J, Stefanovic V, Lassila R. Management of post-partum haemorrhage. Acta Anaesthesiol Scand 2010; 54 (10) 1164-1178
  CrossrefPubMedGoogle Scholar
• 13 Karkouti K, von Heymann C, Jespersen CM , et al. Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial. J Thorac Cardiovasc Surg 2013; 146 (4) 927-939
  CrossrefPubMedGoogle Scholar
• 14 Soendergaard C, Kvist PH, Seidelin JB, Nielsen OH. Tissue-regenerating functions of coagulation factor XIII. J Thromb Haemost 2013; 11 (5) 806-816
  CrossrefPubMedGoogle Scholar
• 15 Boehlen F, Casini A, Chizzolini C , et al. Acquired factor XIII deficiency: a therapeutic challenge. Thromb Haemost 2013; 109 (3) 479-487
  Article in Thieme ConnectPubMedGoogle Scholar
• 16 Szántó T, Salmela B, Mäkipernaa A, Armstrong E, Lassila R. Management of acute myocardial infarction in a patient with factor XIII deficiency using prophylactic factor replacement therapy. Haemophilia 2008; 14 (1) 163-165
  PubMedGoogle Scholar
• 17 Vagge E, Dornes C, Abu Samra M , et al. Factor XIII deficiency in patients with acute leukemia: one out of three is presenting with deficiency [abstract]. Blood 2014; 124: 1528
  PubMedGoogle Scholar
• 18 Macrae FL, Evans HL, Bridge KI, Johnson A, Scott DJ, Ariëns RA. Common FXIII and fibrinogen polymorphisms in abdominal aortic aneurysms. PLoS ONE 2014; 9 (11) e112407
  CrossrefPubMedGoogle Scholar
• 19 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14 (6) 1190-1200
  CrossrefPubMedGoogle Scholar
• 20 Ivaskevicius V, Biswas A, Bevans C , et al. Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function. Haematologica 2010; 95 (6) 956-962
  CrossrefPubMedGoogle Scholar
• 21 Jennings I, Kitchen S, Woods TA, Preston FE ; UK NEQAS. Problems relating to the laboratory diagnosis of factor XIII deficiency: a UK NEQAS study. J Thromb Haemost 2003; 1 (12) 2603-2608
  CrossrefPubMedGoogle Scholar
• 22 Kappel A, Stephan S, Duwe C , et al. Fully automated immunoassay for quantitative determination of FXIII. Hamostaseologie 2011; 31 (2) 105-109
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Hsu P, Zantek ND, Meijer P , et al. Factor XIII Assays and associated problems for laboratory diagnosis of factor XIII deficiency: an analysis of International Proficiency testing results. Semin Thromb Hemost 2014; 40 (2) 232-238
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 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; 119 (22) 5111-5117
  CrossrefPubMedGoogle Scholar
• 25 Pitkänen H, Jouppila A, Mowinckel M-C , et al. Enhanced thrombin generation and reduced tissue factor pathway inhibitor and intact protein S in processed solvent detergent plasma. Thromb Res 2015; 135: 167-174
  CrossrefPubMedGoogle Scholar
• 26 Carcao M, Inbal A, Kerlin B, Brand-Staufer B, Garly M-L. Efficacy, safety and pharmacokinetics of recombinant FXIII at steady-state in patients with congenital FXIII-A subunit deficiency [abstract]. Haemophilia 2014; 20: 104
  CrossrefPubMedGoogle Scholar
• 27 Ashley C, Chang E, Davis J, Mangione A, Frame V, Nugent DJ. Efficacy and safety of prophylactic treatment with plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency. Haemophilia 2015; 21 (1) 102-108
  CrossrefPubMedGoogle Scholar
• 28 Nugent DJ, Ashley C, García-Talavera J, Lo LC, Mehdi AS, Mangione A. Pharmacokinetics and safety of plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency. Haemophilia 2015; 21 (1) 95-101
  PubMedGoogle Scholar
• 29 Kerlin B, Brand B, Inbal A , et al. Pharmacokinetics of recombinant factor XIII at steady state in patients with congenital factor XIII A-subunit deficiency. J Thromb Haemost 2014; 12 (12) 2038-2043
  CrossrefPubMedGoogle Scholar
• 30 Janbain M, Nugent DJ, Powell JS, St-Louis J, Frame VB, Leissinger CA. Use of Factor XIII (FXIII) concentrate in patients with congenital FXIII deficiency undergoing surgical procedures. Transfusion 2015; 55 (1) 45-50
  CrossrefPubMedGoogle Scholar
• 31 Sharief LT, Lawrie AS, Mackie IJ, Smith C, Peyvandi F, Kadir RA. Changes in factor XIII level during pregnancy. Haemophilia 2014; 20 (2) e144-e148
  CrossrefPubMedGoogle Scholar
• 32 Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv 2007; 62 (4) 255-260
  CrossrefPubMedGoogle Scholar
• 33 Mitchell JL, Lionikiene AS, Fraser SR, Whyte CS, Booth NA, Mutch NJ. Functional factor XIII-A is exposed on the stimulated platelet surface. Blood 2014; 124 (26) 3982-3990
  CrossrefPubMedGoogle Scholar
• 34 Pénzes K, Vezina C, Bereczky Z , et al. Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody. Haemophilia 2015; 12786 : 10.1111/hae
  PubMedGoogle Scholar
• 35 Hur WS, Mazinani N, Lu XJ , et al. Coagulation factor XIIIa is inactivated by plasmin. Blood 2015; 126 (20) 2329-2337
  CrossrefPubMedGoogle Scholar