Clinical Studies and Thrombin Generation in Patients Homozygous or Heterozygous for the G20210A Mutation in the Prothrombin Gene

Kyrle, Paul A.; Mannhalter, Christine; Béguin, S.; Stümpflen, Andreas; Hirschl, Mirko; Weltermann, Ansgar; Stain, Milena; Brenner, B; Speiser, Wolfgang; Pabinger, Ingrid; Lechner, Klaus; Eichinger, Sabine

doi:10.1161/01.atv.18.8.1287

Cited by 152 publications

(98 citation statements)

References 25 publications

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“…79-81 In in vitro assays, elevated prothrombin levels increase the maximal rate, peak and area under the curve of thrombin generation. 13,41,59,82 We have shown that elevated (pro)thrombin levels trigger the formation of densely-packed fibrin clots composed of thin fibrin fibers compared to normal clots. 13 Increased thrombin generation in these individuals also increases activation of the thrombin-activatable fibrinolysis inhibitor (TAFI) in vitro.…”

Section: Hyperprothrombinemiamentioning

confidence: 99%

Thrombin generation, fibrin clot formation and hemostasis

Wolberg

Campbell

2008

Transfusion and Apheresis Science

288

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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Section: Hyperprothrombinemiamentioning

confidence: 99%

Thrombin generation, fibrin clot formation and hemostasis

Wolberg

Campbell

2008

Transfusion and Apheresis Science

288

222

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“…Fluorescence based applications have now the widest distribution because these techniques have advantages over the absorption based approaches as the signal in the latter is disturbed by turbidity caused by coagulation events. It is now possible to perform measurements for the characterization of hereditary or acquired coagulation disturbances as well as for investigations into the influence of various medicines that affect the coagulation process beyond the time of clotting [9][10][11][12][13][14][15][16][17][18][19]. Hemker et al have reviewed further literature on such applications [20].…”

Section: Introductionmentioning

confidence: 99%

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Tapp¹,

Grundmann²,

Kusch³

et al. 2009

TOATHERTJ

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Abstract:The technique of thrombin generation has been established as a promising tool for the diagnosis, risk estimation, and perhaps prognosis of coagulation insufficiencies. Without further experimentation an indication can be obtained if a sample donor carries the risk for haemophilia or thrombophilia, either congenital or acquired. A comparison of two different thrombin generation assays is presented, demonstrating that a currently not commercially available test allows an easier and cheaper calibration than its commercial counterpart. This is achieved by employment of a less efficient but highly specific peptide substrate for thrombin and the involvement of low amounts of analyte (plasma samples).

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“…These are single point mutations in the genes coding for coagulation factor V and factor II (prothrombin), one in the major cleavage site of activated protein C (G to A at position 1691, also called factor V Leiden) (Kalafatis et al, 1995) that renders activated factor V less sensitive (resistant) to the inactivation by its naturally occurring inhibitor (Dahlba Èck et al, 1993) and the other in the 3 H -untranslated region of the prothrombin gene (G to A at position 20 210) that leads to high plasma levels of the zymogen (Poort et al, 1996) and increases its potential to form thrombin (Kyrle et al, 1998). Both these abnormalities are commonly found in patients with venous thromboembolism, with prevalences varying between 20% and 50% for factor V Leiden (Griffin et al, 1993;Koster et al, 1993;Svensson & Dahlba Èck, 1994) and between 5% and 19% for the prothrombin gene mutation (Poort et al, 1996;Arruda et al, 1997;Brown et al, 1997;Hillarp et al, 1997;Kapur et al, 1997;Cattaneo et al, 1998;Leroyer et al, 1998;Margaglione et al, 1998), depending on the criteria used for patients' selection.…”

mentioning

confidence: 99%

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both

et al. 2000

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Summary. Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non-carriers. The prevalence of venous thromboembolism was 5´7% in relatives with the prothrombin gene mutation, 7´8% in those with factor V Leiden, 17´1% in those with both mutations and 2´5% in non-carriers. Annual incidences of thrombosis were 0´13% [95% confidence interval (CI) 0´06±0´24], 0´19% (0´13±0´25), 0´42% (0´15±0´83) and 0´066% (0´03±0´11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non-carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.

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Clinical Studies and Thrombin Generation in Patients Homozygous or Heterozygous for the G20210A Mutation in the Prothrombin Gene

Cited by 152 publications

References 25 publications

Thrombin generation, fibrin clot formation and hemostasis

Thrombin generation, fibrin clot formation and hemostasis

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both

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