Hanna H Pitkänen1, Annukka Jouppila2, Marja Lemponen3, Minna Ilmakunnas4, Jouni Ahonen5, Riitta Lassila6. 1. 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. 2. Helsinki University Hospital Research Institute, Helsinki, Finland. 3. Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Center, and HUSLAB and Laboratory Services HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 4. Helsinki University, Division of Anaesthesiology, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 5. 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. 6. 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.
Abstract
INTRODUCTION: Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates. AIM: 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. DISCUSSION: 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.
INTRODUCTION: Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates. AIM: 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. DISCUSSION: 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: Joline L Saes; Saskia E M Schols; Kathleen F Betbadal; Mark van Geffen; Kitty Verbeek-Knobbe; Sweta Gupta; Brandon M Hardesty; Amy D Shapiro; Waander L van Heerde Journal: Haemophilia Date: 2019-08-30 Impact factor: 4.287
Authors: Johanna Aronniemi; Satu Långström; Katariina A Mattila; Anne Mäkipernaa; Päivi Salminen; Anne Pitkäranta; Johanna Pekkola; Riitta Lassila Journal: Children (Basel) Date: 2021-04-20
Authors: Mayank Saraswat; Beata Przybyla; Sakari Joenvaara; Tiialotta Tohmola; Tomas Strandin; Maija Puhka; Annukka Jouppila; Riitta Lassila; Risto Renkonen Journal: Front Cell Dev Biol Date: 2022-09-07