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Thrombin generation and D-dimer concentrations in a patient cohort investigated for venous thromboembolism. Relations to venous thrombosis, factor V Leiden and prothrombin G20210A. The LIST study.
(Landstinget i Östergötland)
Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
2009 (English)In: Thrombosis Research, ISSN 0049-3848, Vol. 124, no 2, 178-84 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: The present study evaluated possible relations between various markers of thrombin generation, D-dimer and venous thromboembolism in outpatients with and without the FV Leiden and the protrombin mutations. PATIENTS AND METHODS: Our cohort consisted of 98 patients with the FV Leiden and 15 with the prothrombin mutation and an equal number of age- and gender-matched controls. All subjects were investigated due to suspicion of venous thromboembolism and the diagnosis was objectively confirmed or refuted. RESULTS: We compared the D-dimer values and the thrombin generation markers among different patient groups (with/without thromboembolism, with/without genetic factors, gender-linked). The only statistically significant difference noted was prolonged time both for the initiation and termination of thrombin generation in patients with thrombosis. This applied to controls and to patients heterozygous for the FV Leiden. Additionally, the D-dimer values were elevated in patients with the FV Leiden. No difference was found among the patients with prothrombin mutation and their controls. DISCUSSION: Multi-variant analysis indicated that the difference in D-dimer between FV Leiden patients and controls was due to the greater number of patients with confirmed thrombosis in the former group, a finding supported by an independent prospective study on postoperative thrombosis. Neither D-dimer concentration nor thrombin generation depend on FV Leiden. The total amount of thrombin generated was not related to diagnosis. The prolonged thrombin generation noted in controls and FV Leiden heterozygotes with thrombosis may point out different thrombin generation profiles in different patient populations and requires further studies.

Place, publisher, year, edition, pages
2009. Vol. 124, no 2, 178-84 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-18992DOI: 10.1016/j.thromres.2008.12.033PubMedID: 19232683OAI: diva2:222204
Available from: 2009-06-07 Created: 2009-06-07 Last updated: 2013-10-31
In thesis
1. Thrombin generation in different cohorts: Evaluation of the haemostatic potential
Open this publication in new window or tab >>Thrombin generation in different cohorts: Evaluation of the haemostatic potential
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis is to evaluate thrombin generation in patients with thrombophilia (Paper I), in patients with venous thromboembolism (Paper II), in healthy women during the menstrual cycle (Paper III), in patients with liver disease (Paper IV) and in patients with mild deficiency of factor VII (Paper V).

For this purpose, thrombin generation was measured in platelet poor plasma by the calibrated automated thrombogram (CAT®) assay. Thrombin generation expresses the overall haemostatic potential, in contrast to the more traditional coagulation tests, which concentrate on individual factors or coagulation pathways. The thrombin generation markers that were measured and studied were: lagtime (clotting time), endogenous thrombin potential (ETP, total thrombin concentration), peak (maximum thrombin concentration) and time to peak (ttpeak).

The cohorts for Papers I and II are part of a larger cohort (The LInköping Study on Thrombosis, LIST), which included 516 consecutive patients who presented at the Emergency Department of Linköping University Hospital, Sweden with the clinical suspicion of venous thrombosis. In Paper I thrombin generation was measured in the absence of thrombomodulin in patients with thrombophilia (factor V Leiden, n=98 and prothrombin G20210A mutation, n=15) and in an equal number of age- and gendermatched controls. The results were associated with the presence of thrombosis, as well as gender and age. It was shown that thrombin generation did not differ significantly among patients and controls. Patients with and patients without thrombophilia who had suffered a thrombosis upon inclusion had longer lagtime compared with their counterparts without thrombosis. Neither age nor gender had any effect on the results.

In Paper II, thrombin generation at the time of an acute thromboembolic episode was studied as a potential early marker for recurrence during a 7-year follow-up in 115 patients with venous thrombosis upon inclusion. It was shown that patients with recurrences during follow-up had longer lagtime and ttpeak at the time of the acute thrombosis, whereas those without recurrences had higher ETP and peak. Those results were particularly evident in the group of patients with an unprovoked thrombosis upon inclusion.

In Paper III, thrombin generation was measured in the follicular and luteal phase of a normal menstrual cycle in 102 healthy women not taking oral contraceptives. The results were associated with haemostatic parameters (fibrinogen, antithrombin, D-dimer, plasminogen activator inhibitor-1, factors VII, VIII, X and von Willebrand) as well as the physiological concentrations of oestradiol, progesterone, antimüllerian hormone and sex hormone-binding globulin and the number of pregnancies and deliveries for these women. ETP was significantly higher during the luteal phase. However, this could not be explained by the elevation of other procoagulant factors during the same phase. Progesterone was found to exert a more significant effect on haemostasis than oestradiol during both phases (multiple regression analysis).

In Paper IV, thrombin generation was measured in the presence and absence of thrombomodulin in 47 patients with portal vein thrombosis, PVT (11 with cirrhotic PVT and 36 with non-cirrhotic PVT), 15 patients with Budd-Chiari syndrome and 24 patients with cirrhosis, as well as 21 healthy controls. Since 15 patients with PVT (2 with cirrhotic PVT and 13 with non-cirrhotic PVT) and 10 patients with Budd-Chiari syndrome were treated with warfarin at the time of the blood sampling, an equal number of patients matched for age, gender and prothrombin time-international normalized ratio with atrial fibrillation and no hepatic diseases were used as controls. It was shown that hypercoagulability, expressed as total and maximum concentration of generated thrombin as well as thrombomodulin resistance [thrombin generation markers measured in the presence]/[thrombin generation markers measured in the absence of thrombomodulin] was pronounced in the groups of patients with cirrhosis, regardless of the presence of splanchnic thrombosis.

In Paper V, thrombin generation in the presence of human and different concentrations of rabbit thromboplastin was measured in 10 patients with mild deficiency of factor VII and in 12 controls. In these patients, the levels of factor VII varied slightly depending on the origin of the thromboplastin used in the reagent. Nine out of 10 patients had a mutation in common (Arg353Gln), which was, however, not associated with the diversity in the factor VII measurements due to the origin of thromboplastin. ETP in patients with mild factor VII deficiency was about 86% of the ETP in the control group. The expected thrombin generation patterns with increasing concentrations of thromboplastin did not differ depending on the origin of thromboplastin in the patient group.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 105 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1383
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-100218 (URN)10.3384/diss.diva-100218 (DOI)978-91-7519-490-5 (print) (ISBN)
Public defence
2013-11-22, Lindensalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Available from: 2013-10-31 Created: 2013-10-31 Last updated: 2014-10-14Bibliographically approved

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Jennersjö, CeciliaLindahl, Tomas L
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Internal Medicine Faculty of Health SciencesDepartment of Acute Internal MedicineClinical ChemistryDepartment of Clinical Chemistry
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