Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension

Abstract

Idiopathic portal hypertension (IPH) is characterized by non-cirrhotic presinusoidal intrahepatic portal hypertension. The etiopathogenesis of the disease is poorly understood. Obliteration with microthrombosis of the small portal vein branches may lead to lesions underlying portal hypertension. We aimed to put forward a comprehensive thrombophilic mutation profile in IPH and its probable contribution to pathogenesis. Eleven patients and 12 controls were included. We used the CVD-StripAssay which is based on the reverse-hybridization principle to identify a total of 12 thrombophilic gene mutations: Factor V R506Q, Factor V H1299R, prothrombin G20210A, Factor XIII V34L, beta-Fibrinogen -455 G-A, PAI-1 4G/5G, platelet GPIIIa L33P, MTHFR C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q and Apo E2/E3/E4, respectively. We also evaluated some blood parameters and protein C, protein S, AT-III levels using commercially available assays. IPH patients and controls were similar in respect to gender distribution (P = 1.000). Mean age was 31.2 in patients and 29.1 in controls (P = 0.622). Pica history was present in 54.5% of the patients. Mean protein C and AT-III levels were lower in patients than that of controls (P = 0.002 and 0.001, respectively). Factor XIII V34L, PAI-1, GPIIIa L33P, MTHFR C677T and MTHFR A1298C frequencies of genetic polymorphisms were found to be significantly higher among patients than that of controls. Apolipoprotein E2/E3/E4 analysis showed an inverse relationship with IPH when E2 plus E4 compared with E3. A higher frequency of Beta-Fibrinogen -455G-A mutation was observed in patients, but this difference did not reach a statistical significance. Our data represent the most comprehensive study to date with respect to thrombophilic gene polymorphisms in IPH. The data support a possible pathogenetic role in IPH, at least by some of the prothrombotic mutations. In order to confirm or refuse this proposal, a larger cohort of patients is needed.

Clinical features of idiopathic portal hypertension in China: A retrospective study of 338 patients and literature review

“…[7][8][9][10] The etiology of IPH is still not clear. Some of the proposed etiological factors have included immunologic disorders, [11][12][13][14][15][16] chronic infection with some bacteria or human immunodeficiency virus, 13,[17][18][19] medication and toxins, [20][21][22][23][24] gene mutation, [25][26][27][28][29] and some other etiologies like dialysis. 30 The main clinical symptoms of IPH are those caused by portal hypertension, including splenomegaly, hypersplenism, hepatomegaly, gastrointestinal bleeding, ascites, and portal vein thrombosis (PVT).…”

Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension

“…As expected, portal hypertension induced by repetitive embolization in the portal vein was combined with increased mesenteric blood flow and mesenteric shunt volume, suggesting that the full picture of portal hypertension with hyperdynamic circulation was developed. Also, liver histology and intrahepatic fibrosis showed, that our model correctly reflects HSC activation and discrete periportal fibrosis accumulation, which has been observed in patients with NCIPH [3], and were discussed as an important pathogenic stress for the development of NCIPH [10]. Therefore, we offer a model for the development of NCIPH, which may help to test strategies for the improvement of portal hypertension and complications of NCIPH.…”

“…One reason for the absence of experimental models is that the underlying pathomechanisms of NCIPH have been poorly understood so far [3,9,10]. In liver samples of patients with NCIPH, vascular lesions in the portal venules have been observed [3].…”

“…In liver samples of patients with NCIPH, vascular lesions in the portal venules have been observed [3]. Micro-thrombotic lesions in small portal venules have been proposed as the initial cause of NCIPH [10]. …”

Bone morphogenetic protein receptor 2 in patients with idiopathic portal hypertension

“…The mechanisms causing these lesions remain largely unknown. Prothrombotic disorders are considered important causal features [4,5], but also infections [6], trace metals and chemicals [7] and immunological factors [8,9] have been proposed. Furthermore, genetic mutations may play a role in the pathogenesis of IPH [10,11].…”