Reduced fibrinolytic resistance in patients with factor XI deficiency. Evidence of a thrombin-independent impairment of the thrombin-activatable fibrinolysis inhibitor pathway.
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.



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.
Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
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Colucci
Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
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Incampo
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Cannavò
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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Menegatti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Siboni
Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
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Zaccaria
Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
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Semeraro
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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Peyvandi
D000293:Adolescent; D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005172:Factor XI; D005173:Factor XI Deficiency / Q000097:blood*; D005260:Female; D005337:Fibrin / Q000737:chemistry; D005342:Fibrinolysis / Q000235:genetics*; D005500:Follow-Up Studies; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013917:Thrombin / Q000737:chemistry*; D015912:Thrombolytic Therapy / Q000379:methods; D018180:Thrombomodulin / Q000378:metabolism; D013927:Thrombosis; D010959:Tissue Plasminogen Activator / Q000737:chemistry; D055815:Young Adult
D018180:Thrombomodulin; D005337:Fibrin; D005172:Factor XI; D013917:Thrombin; D010959:Tissue Plasminogen Activator
factor XI deficiency; fibrinolysis; hemorrhage; plasma procarboxypeptidase B; thrombin