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Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken. Karolinska Univ Hosp, Coagulat Unit, Div Haematol, Dept Med, Stockholm, Sweden.
Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Division of Gastroenterology & Hepatology, University Hospital, Lund, Sweden.
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2014 (Engelska)Ingår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, nr 2, s. 455-461Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2014. Vol. 134, nr 2, s. 455-461
Nyckelord [en]
Thrombin generation, portal vein thrombosis, Budd-Chiari syndrome, cirrhosis, thrombomodulin
Nationell ämneskategori
Klinisk medicin
Identifikatorer
URN: urn:nbn:se:liu:diva-100216DOI: 10.1016/j.thromres.2014.05.012ISI: 000341309200040PubMedID: 24913997OAI: oai:DiVA.org:liu-100216DiVA, id: diva2:660780
Tillgänglig från: 2013-10-30 Skapad: 2013-10-30 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Thrombin generation in different cohorts: Evaluation of the haemostatic potential
Öppna denna publikation i ny flik eller fönster >>Thrombin generation in different cohorts: Evaluation of the haemostatic potential
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2013. s. 105
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1383
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-100218 (URN)10.3384/diss.diva-100218 (DOI)978-91-7519-490-5 (ISBN)
Disputation
2013-11-22, Lindensalen, Campus US, Linköpings universitet, Linköping, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2013-10-31 Skapad: 2013-10-31 Senast uppdaterad: 2014-10-14Bibliografiskt granskad

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