PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies

Abstract

Background: There are no univocal opinions on the role of genetic thrombophilia on splanchnic vein thrombosis (SVT). We defined genetic thrombophilia the presence of one of these thrombophilic genetic factors (THRGFs): PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and prothrombin 20210A. Objectives: To evaluate the frequencies of these THRGFs in SVT patients, we analyzed individual data of 482 Caucasian patients, recruited from 2000 to 2014 in three prospective studies. SVT was defined as the presence of thrombosis of portal (PVT), mesenteric (MVT), splenic (SPVT), cava (CT), and hepatic vein (Budd Chiari syndrome, BCS). Pre-hepatic SVT (pre-HSVT) was defined as PVT with or without MVT/SPVT, without BCS. Post-hepatic SVT (post-HSVT) was BCS with or without PVT/MVT/SPVT. Methods: We compared 350 patients with liver cirrhosis (LC), 47 hepatocellular carcinoma (HCC), 37 myeloproliferative neoplasm (MPN), 38 associated disease (AD), 10 without any associated disease (WAD), vs 150 healthy controls (HC); 437 patients showed pre-HSVT and 45 post-HSVT. Results: Thrombophilia was present in 294/482 (60.9%) patients: 189/350 LC (54.0%), 31/47 (66.0%) HCC, 29/39 (74.4%) MPN, 35/38 AD (92.1%), and 10/10 (100%) WAD, and 54/150 (36.0%) in HC. In the total group, we found 175 PAI-1 4G-4G, 130 MTHFR 677TT, 42V Leiden 506Q, and 27 prothrombin 20210A; 75 patients showed presence of >1 TRHGF; the more frequent association was PAI-1 4G-4G/MTHFR 677TT, in 36 patients. PAI-1 4G-4G and MTHFR 677TT were significantly more frequent in patients with SVT (P values <0.005), whereas V Leiden Q506 and prothrombin G20210A were not. PAI-1 4G-4G and MTHFR 677TT distributions deviated significantly from that expected from a population in Hardy-Weinberg equilibrium. Thrombophilia was significantly less frequent in patients with pre-HSVT (250/437, 57.2%) than in patients with post-HSVT (44/45, 97.8%). Conclusions: Our study shows the significant prevalence of PAI-1 4G-4G and MTHFR 677TT in SVT, mainly in post-HSVT. ( J CLIN EXP HEPATOL 2016;6:10-14)

Congenital Thrombophilia in Patients With Superior Mesenteric Venous Thrombosis or Portal Vein Thrombosis

“…Deep vein thrombosis (DVT) was diagnosed using echography or venography, and disseminated intravascular coagulation (DIC) was diagnosed according to the International Society of Thrombosis and Haemostasis overt DIC diagnostic criteria. 10 Cerebral vascular disease was diagnosed with computed tomography or magnetic resonance imaging (MRI), and cerebral venous sinus thrombosis (CVST) was diagnosed based on MRI, magnetic resonance venography, or cerebral angiography (CAG) findings. 11,12…”

“…A delayed diagnosis or treatment of SMVT allows intestinal infarction to develop, which can be life-threatening. Thrombophilia, 10 such as plasminogen activator inhibitor I 4G-4G, methylene tetrahydrofolate reductase (MTHFR) 677TT, factor V Leiden 506Q, prothrombin 20210A, and antithrombin (AT), protein C (PC), and protein S (PS) abnormalities, can frequently cause PVT or MVT. Few reports have explored the prevalence of MTHFR 677TT, factor V Leiden 506Q, and prothrombin 20210A in Japan.…”

Pathogenetic mechanisms of thrombosis in patients with myeloproliferative neoplasm

“…21,22 The association between the presence of II, V or PAI1 factor mutations and chronic myeloproliferation frequently leads to intra abdominal thrombosis, the most important role being that of PAI-14G-4G and MTHFR677TT mutations. 23 In another study, there was a 2.7-fold increase in the incidence of thrombotic complications in patients with chronic myeloproliferative disorders that associated the JAK mutation and factor V Leiden -thrombophilia or resistance to C protein activated.…”

Portal Thrombosis in Cirrhosis: Role of Thrombophilic Disorders

“…The limited number of studies available are mostly case-control studies with small sample sizes. Their study design, target population (diverse ethnicities and geographical locations), diagnostic criteria for PVT, and assessment of thrombophilic conditions vary widely, and contribute to the inconsistent results [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Moreover, none of these studies have properly evaluated whether the presence of thrombophilia impact the progression rate or response to treatment.…”

“…Their levels, however, do not seem to be associated with PVT development [ 37 ]. The methylene tetrahydrofolate reductase C677T and plasminogen activator inhibitor– type 1 4G-4G mutations have also been described as independent predictors of PVT [ 18 ], although these polymorphisms have not been conclusively associated with increased thrombotic risk [ 38 ]. The role of acquired prothrombotic disorders has been less evaluated in patients with liver cirrhosis and PVT.…”