PMID- 27094709
OWN - NLM
STAT- MEDLINE
DCOM- 20180103
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 14
IP  - 8
DP  - 2016 Aug
TI  - Reduced fibrinolytic resistance in patients with factor XI deficiency. Evidence 
      of a thrombin-independent impairment of the thrombin-activatable fibrinolysis 
      inhibitor pathway.
PG  - 1603-14
LID - 10.1111/jth.13342 [doi]
AB  - Essentials Plasma of factor XI-deficient patients (FXI-dp) displays enhanced 
      fibrinolysis. We investigated the role of thrombin activatable fibrinolysis 
      inhibitor (TAFI) in 18 FXI-dp. FXI-dp generated less activated TAFI (TAFIa) on 
      clotting challenge and were resistant to TAFIa. TAFI activation and TAFIa 
      resistance correlated with bleeding score and bleeding phenotype. SUMMARY: 
      Background Factor XI (FXI) deficiency, a rare disorder with unpredictable 
      bleeding, has been associated with reduced fibrinolytic resistance as a result of 
      abnormal fibrin density. Objective We investigated the involvement of 
      thrombin-activatable fibrinolysis inhibitor (TAFI) in the increased lysability of 
      FXI-deficient (FXI-def) clots and the role of thrombin. Patients/Methods Eighteen 
      patients with FXI deficiency (1-58%) and 17 matched controls were investigated 
      for fibrinolytic resistance to t-PA, thrombin generation, TAFI activation and 
      response to TAFIa. Results When clotting was induced by 0.5 pm tissue factor 
      (TF), FXI-def plasmas displayed less thrombin and TAFIa generation and shorter 
      lysis time than controls. A 100-fold higher TF concentration (to bypass FXI) 
      abolished the difference in thrombin generation but not in lysis time between 
      patients and controls. Normalization of FXI levels by a FXI concentrate increased 
      thrombin generation but had no effect on the lysis time of FXI-def plasma. 
      Moreover, when clots were induced by purified thrombin and high concentrations of 
      FXa inhibitor, FXI-def plasma still generated less TAFIa and displayed a shorter 
      lysis time than controls. Finally, upon TAFIa addition, the lysis time of FXI-def 
      plasma was prolonged significantly less than that of control plasma, suggesting a 
      TAFIa resistance. TAFIa generation and TAFIa resistance were correlated with the 
      bleeding score, displaying a considerable capacity to discriminate between 
      patients with and without bleeding. Conclusions TAFI pathway impairment, largely 
      caused by a hitherto unknown TAFIa resistance, appears to be one main cause of 
      decreased fibrinolytic resistance in FXI deficiency and might be clinically 
      useful for assessing the bleeding risk of FXI-def patients.
CI  - (c) 2016 International Society on Thrombosis and Haemostasis.
FAU - Colucci, M
AU  - Colucci M
AD  - Department of Biomedical Sciences and Human Oncology, Section of General and 
      Experimental Pathology, Aldo Moro University, Bari, Italy.
FAU - Incampo, F
AU  - Incampo F
AD  - Department of Biomedical Sciences and Human Oncology, Section of General and 
      Experimental Pathology, Aldo Moro University, Bari, Italy.
FAU - Cannavo, A
AU  - Cannavo A
AD  - Department of Pathophysiology and Transplantation, Universita degli Studi di 
      Milano, Milan, Italy.
FAU - Menegatti, M
AU  - Menegatti M
AD  - Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' 
      Granda Ospedale Maggiore Policlinico, Milan, Italy.
FAU - Siboni, S M
AU  - Siboni SM
AD  - Department of Pathophysiology and Transplantation, Universita degli Studi di 
      Milano, Milan, Italy.
FAU - Zaccaria, F
AU  - Zaccaria F
AD  - Department of Biomedical Sciences and Human Oncology, Section of General and 
      Experimental Pathology, Aldo Moro University, Bari, Italy.
FAU - Semeraro, N
AU  - Semeraro N
AD  - Department of Biomedical Sciences and Human Oncology, Section of General and 
      Experimental Pathology, Aldo Moro University, Bari, Italy.
FAU - Peyvandi, F
AU  - Peyvandi F
AD  - Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' 
      Granda Ospedale Maggiore Policlinico, Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160718
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Thrombomodulin)
RN  - 9001-31-4 (Fibrin)
RN  - 9013-55-2 (Factor XI)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
SB  - IM
CIN - J Thromb Haemost. 2016 Aug;14 (8):1600-2. PMID: 27279430
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Blood Coagulation
MH  - Case-Control Studies
MH  - Child
MH  - Child, Preschool
MH  - Factor XI
MH  - Factor XI Deficiency/*blood
MH  - Female
MH  - Fibrin/chemistry
MH  - Fibrinolysis/*genetics
MH  - Follow-Up Studies
MH  - Hemorrhage
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Phenotype
MH  - Thrombin/*chemistry
MH  - Thrombolytic Therapy/methods
MH  - Thrombomodulin/metabolism
MH  - Thrombosis
MH  - Tissue Plasminogen Activator/chemistry
MH  - Young Adult
OTO - NOTNLM
OT  - factor XI deficiency
OT  - fibrinolysis
OT  - hemorrhage
OT  - plasma procarboxypeptidase B
OT  - thrombin
EDAT- 2016/04/21 06:00
MHDA- 2018/01/04 06:00
CRDT- 2016/04/21 06:00
PHST- 2015/11/03 00:00 [received]
PHST- 2016/04/21 06:00 [entrez]
PHST- 2016/04/21 06:00 [pubmed]
PHST- 2018/01/04 06:00 [medline]
AID - S1538-7836(22)03525-5 [pii]
AID - 10.1111/jth.13342 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2016 Aug;14(8):1603-14. doi: 10.1111/jth.13342. Epub 2016 Jul 
      18.