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Thrombin generation in different cohorts: Evaluation of the haemostatic potential
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1383
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-100218DOI: 10.3384/diss.diva-100218ISBN: 978-91-7519-490-5 (print)OAI: oai:DiVA.org:liu-100218DiVA: diva2:660831
Public defence
2013-11-22, Lindensalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-10-31 Created: 2013-10-31 Last updated: 2014-10-14Bibliographically approved
List of papers
1. 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.
Open this publication in new window or tab >>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.
2009 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18992 (URN)10.1016/j.thromres.2008.12.033 (DOI)19232683 (PubMedID)
Available from: 2009-06-07 Created: 2009-06-07 Last updated: 2017-12-13
2. Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInkoping Study on Thrombosis (LIST) - A 7-year follow-up
Open this publication in new window or tab >>Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInkoping Study on Thrombosis (LIST) - A 7-year follow-up
2013 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, 135-139 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Venous thromboembolism(VTE) is considered a chronic disease, since a high percentage of patients experience recurrences. Oral anticoagulants are effective in preventing recurrences at a price of potential bleeding complications, which underlines the importance of finding reliable markers for estimating the individual recurrence risk. In this report we evaluate thrombin generation markers at the time of an acute VTE as predictive markers for recurrence risk. Gender, presence of factor V Leiden and acquired provocative factors were taken into consideration. Additionally, we study the correlation between thrombin generation at the time of an acute VTE and thrombin generation measured four to eight weeks after discontinuation of anticoagulants. less thanbrgreater than less thanbrgreater thanMaterials and Methods: Themain cohort consisted of 115 patients with a confirmed thromboembolic event at inclusion. The follow-up period was seven years. less thanbrgreater than less thanbrgreater thanResults: Patients with an initial unprovoked VTE and at least one recurrence had significantly prolonged thrombin generation, whereas those without recurrences had higher maximum and total thrombin concentration. In contrast, when thrombin generation was measured one to two months after discontinuation of anticoagulant treatment, it was shown that the patients who experienced recurrences had higher maximum thrombin concentration. less thanbrgreater than less thanbrgreater thanConclusions: Our study shows that thrombin generation profiles at the time of a VTE correlate to the clinical course after the acute episode. The great over-lap in thrombin generation between patients with and without recurrences though, makes the use of thrombin generation profiles for advice on length of oral anticoagulation for an individual patient doubtful at the present stage of knowledge.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Venous thromboembolism, Recurrence, Thrombin generation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89518 (URN)10.1016/j.thromres.2012.11.015 (DOI)000313719400010 ()
Note

Funding Agencies|County Council of Ostergotland||Research Funds of the University Hospital, Linkoping, Sweden||

Available from: 2013-02-27 Created: 2013-02-26 Last updated: 2017-12-06
3. Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle
Open this publication in new window or tab >>Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle
Show others...
2013 (English)In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 28, no 7, 1846-1852 p.Article in journal (Refereed) Published
Abstract [en]

Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle? less thanbrgreater than less thanbrgreater thanTotal thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle. less thanbrgreater than less thanbrgreater thanThe coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results. less thanbrgreater than less thanbrgreater thanThrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication. less thanbrgreater than less thanbrgreater thanThe study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods. less thanbrgreater than less thanbrgreater thanIt was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P 0.027). Factor X was significantly higher during the follicular phase (P 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P 0.043 and P 0.033, respectively) and with factors II and VII during the luteal phase (P 0.034 and P 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level 0.8). less thanbrgreater than less thanbrgreater thanThe wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified. less thanbrgreater than less thanbrgreater thanThe associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use. less thanbrgreater than less thanbrgreater thanThis study was supported by the Karolinska Institutet, Linkping University and the County Council of stergtland. The authors report no conflicts of interest.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B1 - Oxford Open Option B, 2013
Keyword
coagulation factors, thrombin generation, menstrual cycle, progesterone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95817 (URN)10.1093/humrep/det092 (DOI)000320855600014 ()
Note

Funding Agencies|Karolinska Institutet||Linkoping University||County Council of Ostergotland||

Available from: 2013-07-26 Created: 2013-07-26 Last updated: 2017-12-06
4. Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event
Open this publication in new window or tab >>Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event
Show others...
2014 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, 455-461 p.Article in journal (Refereed) Published
Abstract [en]

Background: In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding.

Aims: To evaluate the haemostatic potential in patients with liver disease.

Methods: We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n=47), Budd-Chiari syndrome (BCS, n=15) and cirrhosis (n=24) and compared the results to those obtained from healthy controls (n=21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared with an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence]/[marker measured in the absence of thrombomodulin].

Results: There were no differences between patients with BCS, patients on warfarin treatment and controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared with controls [p=0.006 for endogenous thrombin potential (ETP) and p<0.001 for peak thrombin. P<0.001 for both ratios ETP and peak] and patients with non-cirrhotic PVT (p=0.001, p=0.006, p<0.001, p<0.001 for ETP, peak, ratio ETP, ratio peak). The patients with cirrhotic PVT exhibited higher ETP (p=0.044) and peak (p=0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP ratio: p=0.001, peak ratio: p=0.001).

Conclusions: Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer treatment with anticoagulants in this group.

Keyword
Thrombin generation, portal vein thrombosis, Budd-Chiari syndrome, cirrhosis, thrombomodulin
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-100216 (URN)10.1016/j.thromres.2014.05.012 (DOI)000341309200040 ()24913997 (PubMedID)
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2017-12-06Bibliographically approved
5. Thrombin generation and levels of factor VII activity measured in the presence of rabbit and human thromboplastins in patients with mild factor VII deficiency – effects of mutations in factor VII
Open this publication in new window or tab >>Thrombin generation and levels of factor VII activity measured in the presence of rabbit and human thromboplastins in patients with mild factor VII deficiency – effects of mutations in factor VII
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background/Aim: It is known that spontaneous prolonged prothrombin time-international normalized ratio may be caused by deficiency of factor VII (FVII). The activity of FVII in the presence of thromboplastins of different origin is affected by the presence of specific mutations in the F7 gene. The present study aims to evaluate patients with mild FVII deficiency and somewhat discrepant FVII activity depending on the use of human or rabbit thromboplastin in relation to mutations in the FVII gene and markers of thrombin generation.

Patients and methods: A cohort of 10 patients with mild deficiency of FVII and discrepant FVII activity was investigated. The median ratio of the FVII activity in the presence of human/rabbit thromboplastin was 1.4. All but 1 patient had mild to no bleeding symptoms. A genetic analysis of the F7 gene was performed. Thrombin generation was measured by the calibrated automated thrombogram in platelet poor plasma in the presence of human recombinant and different dilutions of rabbit thromboplastin and compared with thrombin generation in healthy controls (n=12). Thrombin generation was measured in 9 patients as 1 was treated with warfarin at the time of the blood sampling.

Results: Six previously described mutations were found. Two of those (FVII Padua and FVII Shinjo) are known to affect the results for FVII activity dependent on the species origin of the thromboplastin. Nine out of 10 patients had one mutation in common (Arg353Gln), which however does not affect the binding site of FVII to tissue factor. Lagtime and ttpeak increased with decreasing concentrations of thromboplastin and total and maximum thrombin concentrations increased with increasing thromboplastin concentrations in the patients with FVII deficiency. ETP in patients with FVII deficiency was 86% of ETP in controls.

Discussion: The Arg353Gln mutation was very common, however it does not appear to affect the reactivity towards thromboplastins of different origins. Although ETP was higher in the healthy controls, thrombin generation in FVII deficient patients was enough to sustain normal haemostasis. The expected thrombin generation patterns with increasing thromboplastin concentrations were confirmed for the patients in this study.

Keyword
Factor VII, thrombin generation, thromboplastin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100217 (URN)
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2013-10-31Bibliographically approved

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