Thrombophilic Genetic Factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A in Noncirrhotic Portal Vein Thrombosis and Budd-Chiari Syndrome in a Caucasian Population
Thrombophilic genetic factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A were studied as risk factors in 235 Caucasian subjects: 85 patients with abdominal thrombosis (54 with portal vein thrombosis (PVT) and 31 with Budd-Chiari syndrome (BCS) without liver cirrhosis or hepatocellular carcinoma) and 150 blood bank donors. Seventy-five patients with PVT/BCS showed associated disease or particular clinical status (46 PVT/29 BCS): 37 myeloproliferative neoplasm (20 PVT/17 BCS), 12 abdominal surgery (10 PVT/2 BCS), 10 contraception or pregnancy (6 PVT/4 BCS), 7 abdominal acute disease (6 PVT/1 BCS), and 9 chronic disease (4 PVT/5 BCS); ten patients did not present any association (8 PVT/2 BCS). PAI-14G-4G, MTHFR677TT, and V Leiden 506Q were significantly frequent (OR 95% CI and test with value) in abdominal thrombosis; in these patients PAI-14G-4G and MTHFR677TT distributions deviated from that expected from a population in the Hardy-Weinberg equilibrium (PAI-1: , ; MTHFR677: , ), whereas the equilibrium was respected in healthy controls. V Leiden Q506 and Prothrombin 20210A were in the Hardy-Weinberg equilibrium both in patients with abdominal thrombosis and healthy controls. Our study shows an important role of PAI-14G-4G and MTHFR677TT in abdominal thrombosis without liver cirrhosis or hepatocellular carcinoma. 1. Introduction Thrombophilic genetic factors (THRGFs) such as PAI-1, MTHFR677, V Leiden 506Q, and Prothrombin 20210A mutations have been studied in patients with abdominal thrombosis, but never in the same study. We have recently published two studies on the prevalence of these THRGFs in liver cirrhosis and hepatocellular carcinoma: MTHFR677TT was highlighted as a significant risk factor for PVT in liver cirrhosis [1], but PAI-1 was not analyzed in the first study; in the second study [2] MTHFR677TT, PAI-1 4G-4G, and Prothrombin 20210A were found to be significant risk factors in hepatocellular carcinoma, mainly in the presence of portal vein thrombosis (PVT). It is well known that several chronic or acute diseases or some clinical status, other than cirrhosis or hepatocellular carcinoma, are considered risk factors for abdominal thrombosis, as recently reviewed by Parikh et al. [3] who found, underlying the etiology of PVT, two orders of causes classified in local (including all known diseases associated with PVT) and systemic (including congenital thrombophilia) orders. For these reasons we planned this prospective study, in which patients with abdominal thrombosis, without liver cirrhosis or hepatocellular carcinoma, were
References
[1]
L. Pasta, C. Marrone, M. D'Amico et al., “MTHFR C677T mutations in liver cirrhosis with and without portal vein thrombosis,” Liver International, vol. 26, no. 2, pp. 269–270, 2006.
[2]
M. D'Amico, L. Pasta, and P. Sammarco, “MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, and prothrombin G20210A in hepatocellular carcinoma with and without portal vein thrombosis,” Journal of Thrombosis and Thrombolysis, vol. 28, no. 1, pp. 70–73, 2009.
[3]
S. Parikh, R. Shah, and P. Kapoor, “Portal vein thrombosis,” The American Journal of Medicine, vol. 123, no. 2, pp. 111–119, 2010.
[4]
M. Primignani and P. M. Mannucci, “The role of thrombophilia in splanchnic vein thrombosis,” Seminars in Liver Disease, vol. 28, no. 3, pp. 293–301, 2008.
[5]
E. S. Jaffe, N. L. Harris, H. Stein, and J. W. Vardiman, Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumors, IARC Press, Lyon, France, 2001.
[6]
S. Rodriguez, T. R. Gaunt, and I. N. Day, “Hardy-Weinberg equilibrium testing of biological ascertainment for mendelian randomization studies,” The American Journal of Epidemiology, vol. 169, no. 4, pp. 505–514, 2008.
G. Balta, C. Altay, and A. Gurgey, “PAI-1 gene 4G/5G genotype: a risk factor for thrombosis in vessels of internal organs,” The American Journal of Hematology, vol. 71, no. 2, pp. 89–93, 2002.
[9]
A. E. Tsantes, G. K. Nikolopoulos, P. G. Bagos, S. Bonovas, P. Kopterides, and G. Vaiopoulos, “The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk,” Thrombosis Research, vol. 122, no. 6, pp. 736–742, 2008.
[10]
R. Palmirotta, P. Ferroni, A. Savonarola et al., “Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer,” Thrombosis Research, vol. 124, no. 4, pp. 403–408, 2009.
[11]
A. Mostowska, M. Myka, M. Lianeri, A. Roszak, and P. P. Jagodziński, “Folate and choline metabolism gene variants and development of uterine cervical carcinoma,” Clinical Biochemistry, vol. 44, no. 8-9, pp. 596–600, 2011.
[12]
M. Zoodsma, I. M. Nolte, M. Schipper et al., “Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease,” Human Genetics, vol. 116, no. 4, pp. 247–254, 2005.
[13]
A. F. Lambropoulos, T. Agorastos, Z. J. Foka et al., “Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the risk of cervical dysplasia,” Cancer Letters, vol. 191, no. 2, pp. 187–191, 2003.
[14]
H. L. A. Janssen, J. R. Meinardi, F. P. Vleggaar et al., “Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study,” Blood, vol. 96, no. 7, pp. 2364–2368, 2000.
[15]
M. Bhattacharyya, G. Makharia, M. Kannan, R. P. H. Ahmed, P. K. Gupta, and R. Saxena, “Inherited prothrombotic defects in Budd-Chiari syndrome and portal vein thrombosis: a study from North India,” The American Journal of Clinical Pathology, vol. 121, no. 6, pp. 844–847, 2004.
[16]
M. Primignani, I. Martinelli, P. Bucciarelli et al., “Risk factors for thrombophilia in extrahepatic portal vein obstruction,” Hepatology, vol. 41, no. 3, pp. 603–608, 2005.
[17]
A. K. Dutta, A. Chacko, B. George, J. A. Joseph, S. C. Nair, and V. Mathews, “Risk factors of thrombosis in abdominal veins,” World Journal of Gastroenterology, vol. 14, no. 28, pp. 4518–4522, 2008.
[18]
S. D. Murad, A. Plessier, M. Hernandez-Guerra et al., “Etiology, management, and outcome of the Budd-Chiari syndrome,” Annals of Internal Medicine, vol. 151, no. 3, pp. 167–175, 2009.
[19]
P. L. Bittencourt, C. A. Couto, and D. D. Ribeiro, “Portal vein thrombosis and Budd-Chiari syndrome,” Clinics in Liver Disease, vol. 13, no. 1, pp. 127–144, 2009.
[20]
J. Bosch, J. G. Abraldes, M. Fernández, and J. C. García-Pagán, “Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension,” Journal of Hepatology, vol. 53, no. 3, pp. 558–567, 2010.
