The Defective Down Regulation of Fibrinolysis in Haemophilia A Can Be Restored by Increasing the TAFI Plasma Concentration

Mosnier, Laurent O.; Lisman, Ton; Berg, Marijke van den; Nieuwenhuis, Karel; Meijers, Joost C. M.; Bouma, Bonno N.

doi:10.1055/s-0037-1616530

Cited by 119 publications

(133 citation statements)

References 15 publications

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“…[16][17][18][19] This evidence is further supported by the observation that the enhancement of the initial rate of thrombin generation induced by a 10-fold higher thromboplastin concentration does not inhibit fibrinolysis as also shown by others. 20 Sustained thrombin formation associated with prothrombin G20210A mutation might dampen fibrinolysis by other mechanisms such as the increase of factor XIII activation, resulting in a hyperstabilized clot, 21 or the formation of a clot with an altered fibrin structure (reduced mass-to-length ratio). 22 It is unlikely, however, that these TAFI-independent mechanisms contributed significantly to the inhibition of fibrinolysis under our experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism

Colucci

Binetti

Tripodi

et al. 2004

Blood

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The prothrombin gene mutation G20210A is a common risk factor for thrombosis and is associated with increased prothrombin levels. However, the mechanism whereby hyperprothrombinemia predisposes to thrombosis remains unclear. Because thrombin is the physiologic activator of TAFI (thrombin activatable fibrinolysis inhibitor), the precursor of an antifibrinolytic carboxypeptidase (TAFIa), we evaluated the influence of hyperprothrombinemia on fibrinolysis. Thirty-two heterozygous carriers of the G20210A mutation and 30 noncarriers were studied.Plasma fibrinolytic factors and TAFI levels were similar in the 2 groups. Mean lysis time of tissue factor-induced plasma clots exposed to 25 ng/mL exogenous tissue-type plasminogen activator (t-PA) was significantly longer in 20210A carriers than in control donors. This difference disappeared on addition of a specific inhibitor of TAFIa. Determination of thrombin and TAFIa activity, generated during clot lysis, revealed that G20210A mutation was associated with a significant enhancement of late thrombin formation and an increase in TAFI activation.Plasma prothrombin level was highly significantly correlated with both clot lysis time and TAFI activation. The addition of purified prothrombin, but not of factors X or VIIa, to normal plasma caused a concentration-dependent, TAFI-mediated inhibition of fibrinolysis. These findings provide a new mechanism that might contribute to the thrombotic risk in prothrombin 20210A carriers. IntroductionThe prothrombin gene mutation G20210A is the second most common genetic disorder associated with venous thrombosis. It is found in 4.6% to 8% of unselected patients with a first episode of deep vein thrombosis, as contrasted to 0.7% to 2.6% in healthy controls, and heterozygote carriers have a 2-to 7-fold increased risk of thrombosis (reviewed in Vicente et al 1 ). The presence of the 20210A allele is associated with elevated prothrombin levels, and hyperprothrombinemia has been shown to be an independent risk factor for thrombosis. 2 However, the underlying mechanism by which elevated prothrombin promotes thrombosis is still unclear. On the basis of in vitro 3 and in vivo 4 data, it is surmised that hyperprothrombinemia enhances thrombin generation whenever blood clotting is activated in vivo, thereby promoting excessive fibrin formation. Thrombin plays also an important role in the down-regulation of fibrinolysis by catalyzing the activation of TAFI (thrombin activatable fibrinolysis inhibitor), a plasma precursor of a carboxypeptidase B that inhibits plasmin formation by removing the plasminogen binding sites from partially degraded fibrin. 5 This study was designed to evaluate the influence of the G20210A mutation and of hyperprothrombinemia on TAFI-mediated inhibition of fibrinolysis. Patients, materials, and methods PatientsThirty-two carriers of the prothrombin G20210A mutation (all heterozygous) and 30 noncarriers were studied. Blood was collected by vacuum collection tubes (Vacutainer; Becton Dickinson, Meylan, France) containing 1/1...

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Section: Discussionmentioning

confidence: 99%

Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism

Colucci

Binetti

Tripodi

et al. 2004

Blood

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“…14,90,91 In vitro studies suggest that reduced thrombin levels limit TAFI activation, leaving clots more vulnerable to fibrinolysis. 90,92,93 The physiologic importance of TAFI in clot stability is unclear, however, since TAFI-deficient animals exhibit minimal to no bleeding. [94][95][96] Recombinant factor VIIa (rFVIIa, NovoSeven) is approved for the treatment of severe bleeds in hemophilic patients with inhibitory antibodies, and has demonstrated efficacy under these conditions and in patients with acquired hemophilia.…”

Section: Hemophilia and Recombinant Factor Viiamentioning

confidence: 99%

Thrombin generation, fibrin clot formation and hemostasis

Wolberg

Campbell

2008

Transfusion and Apheresis Science

287

222

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Hemostatic clot formation entails thrombin-mediated cleavage of fibrinogen to fibrin. Previous in vitro studies have shown that the thrombin concentration present during clot formation dictates the ultimate fibrin structure. In most prior studies of fibrin structure, clotting was initiated by adding thrombin to a solution of fibrinogen; however, clot formation in vivo occurs in an environment in which the concentration of free thrombin changes over the reaction course. These changes depend on local cellular properties and available concentrations of pro-and anti-coagulants. Recent studies suggest that abnormal thrombin generation patterns produce abnormally structured clots associated with an increased risk of bleeding or thrombosis. Further studies of fibrin formation during in situ thrombin generation are needed to understand fibrin clot formation in vivo. Keywordsthrombin; fibrinogen; fibrin; plasmin; fibrinolysis; clot structure; hemophilia; thrombosis Fibrinogen and fibrin clot formationFibrinogen is a 450 Å, 340 kDa trinodular protein present at high (2 -4 mg/mL) concentrations in plasma. Fibrinogen consists of pairs of three different disulfide-linked polypeptide chains: Aα, Bβ, and γ. These six polypeptide chains are arranged with their N-termini converged in a central "E" domain of the molecule. The C-termini of the Bβ and γ chains extend outward into distal "D" domains. The C-termini of the Aα chains are globular and situated near the central E domain of fibrinogen where they interact intra-molecularly. 1 Comprehensive reviews on the biochemistry of fibrinogen and fibrin structure have been published. 2-4Mechanisms of fibrin production have been elucidated in studies conducted by adding exogenous thrombin to purified fibrinogen. These studies have shown that thrombin removes N-terminal peptides from the fibrinogen Aαl and Bβ chains, causing the spontaneous formation of half-staggered, double-stranded protofibrils followed by thickening of protofibril chains. 5 Initial formation of protofibrils occurs during a "lag" phase in which no turbidity increase is detected. Subsequent lateral aggregation of fibrin protofibrils causes a turbidity increase. The magnitude of the turbidity increase relates to the structure of the formed clot; formation of thicker fibers causes a greater increase in final turbidity. 6,7 Fibrin formation can be followed Address correspondence to: Alisa Wolberg, Ph. D., Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 815 Brinkhous-Bullitt Building, CB #7525, Chapel Hill, NC 27599-7525, phone: (919) 966-8430, fax: (919) 966-6718, email: alisa_wolberg@med.unc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production p...

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“…This test has been used to study fibrinolysis in a number of pathologies. We demonstrated a hyperfibrinolytic state in hemophilia, 11,12 factor XI deficiency, 13 and after use of heparin and heparin-like anticoagulants 14,15 as a consequence of reduced thrombin generation resulting in defective TAFI activation. In patients with liver disease, plasma fibrinolytic potential was similar to that in controls, despite severely reduced TAFI levels, which could be explained by a concomitant decrease in profibrinolytic proteins.…”

Section: Introductionmentioning

confidence: 99%

Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis

Lisman

Groot

Meijers

et al. 2005

Blood

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253

217

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The role of the fibrinolytic system in the development of deep vein thrombosis (DVT) is unclear. We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS), a population-based casecontrol study on risk factors for DVT. Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factorinduced and tissue-type plasminogen activator (tPA)-induced clot lysis assay. Using clot lysis times above the 70th, 80th, 90th, 95th, and 99th percentiles of the values found in control subjects as cutoff levels, we found a dose-dependent increase in risk for DVT in patients with hypofibrinolysis (odds ratios of 1.4, 1.6, 1.9, 2.1, and 2.2, respectively). This indicates a 2-fold increased risk of DVT in subjects with clot lysis times above the 90th percentile. The risk increase was not affected by age or sex (adjusted odds ratio for 90th percentile, 2.0), and after correction for all possible confounders (age, sex, and levels of procoagulant proteins shown to associate with clot lysis times in the control population), the risk estimate was marginally reduced (odds ratio, 1.6 for 90th percentile). Taken

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The Defective Down Regulation of Fibrinolysis in Haemophilia A Can Be Restored by Increasing the TAFI Plasma Concentration

Cited by 119 publications

References 15 publications

Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism

Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism

Thrombin generation, fibrin clot formation and hemostasis

Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis

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