title: Factor XIII deficiency enhances thrombin generation due to impaired fibrin polymerization - An effect corrected by Factor XIII replacement.
abstract: BACKGROUND
  Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates.
  
  
  OBJECTIVE
  As the mechanisms protecting patients with low FXIII levels (<5IU/dL) from spontaneous bleeds remain unknown we assessed the interplay between thrombin generation (TG), fibrin formation and clot kinetics before and after FXIII administration in three patients with FXIII deficiency.
  
  
  METHODS
  Patients received initially rFXIII (35IU/kg, A-subunit) following with pdFXIII at 1250IU or 2500IU (12-30IU/kg) monthly. TG (CAT), thromboelastometry (ROTEM), prothrombin fragments F1+2, fibrinogen and FXIII activity (FXIII:C) were measured at baseline and one-hour recovery.
  
  
  RESULTS
  FXIII was at the target level of 20±6IU/dL at the 4-week trough. rFXIII corrected FXIII to 98±15 and high-dose pdFXIII to a level of 90±6, whereas low-dose/half dose pdFXIII reached 45±4IU/dL. Although fibrinogen (Clauss Method) was normal, coagulation in FIBTEM was impaired, which FXIII administration tended to correct. CAT implied 1.6- to 1.9-fold enhanced TG, which FXIII administration normalized. Inhibition of fibrin polymerization by Gly-Pro-Arg-Pro peptide mimicked FXIII deficiency in CAT by enhancing TG both in control and FXIII recovery plasma. Antithrombin, α2-macroblobulin-thrombin complex and prothrombin were normal, whereas F1+2 were elevated compatible with in vivo TG.
  
  
  CONCLUSIONS
  FXIII deficiency impairs fibrinogen function and fibrin formation simultaneously enhancing TG on the poorly polymerizing fibrin strands, when fibrin's antithrombin I -like function is absent. Our study suggests an inverse link between low FXIII levels and enhanced TG modifying structure-function relationship of fibrin to support hemostasis.
authors.affiliation: Helsinki University Hospital Research Institute, Helsinki, Finland; Helsinki University, Division of Anaesthesiology, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Hanna H
authors.initials: HH
authors.lastname: Pitkänen
authors.affiliation: Helsinki University Hospital Research Institute, Helsinki, Finland.
authors.forename: Annukka
authors.initials: A
authors.lastname: Jouppila
authors.affiliation: Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Center, and HUSLAB and Laboratory Services HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Lemponen
authors.affiliation: Helsinki University, Division of Anaesthesiology, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Ilmakunnas
authors.affiliation: Helsinki University, Division of Anaesthesiology, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Maternity Hospital, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Ahonen
authors.affiliation: Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Center, and HUSLAB and Laboratory Services HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: riitta.lassila@hus.fi.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
mesh_terms: D003029:Coagulants / Q000627:therapeutic use*; D005176:Factor XIII / Q000627:therapeutic use*; D005177:Factor XIII Deficiency / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000032:analysis / Q000378:metabolism*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use; D013917:Thrombin / Q000032:analysis / Q000378:metabolism*
chemical_list: D003029:Coagulants; D011994:Recombinant Proteins; D005337:Fibrin; D005176:Factor XIII; D013917:Thrombin
keywords: Congenital Factor XIII deficiency; FXIII concentrate; Fibrin polymerization; GPRP; Thrombin generation